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How does vasopressin work: Physiology, Vasopressin – StatPearls – NCBI Bookshelf

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Physiology, Vasopressin – StatPearls – NCBI Bookshelf

Introduction

Vasopressin or antidiuretic hormone (ADH) or arginine vasopressin (AVP) is a nonapeptide synthesized in the hypothalamus. Science has known it to play essential roles in the control of the body’s osmotic balance, blood pressure regulation, sodium homeostasis, and kidney functioning. Given its vital role in multiple functions, it is no surprise that ADH is of great clinical significance. ADH primarily affects the ability of the kidney to reabsorb water; when present, ADH induces expression of water transport proteins in the late distal tubule and collecting duct to increase water reabsorption. Several disease states arise when the body loses control of ADH secretion or responds to its presence.[1]

In states of hypovolemia or hypernatremia, ADH is released from the posterior pituitary gland and binds to the type-2 receptor in principal cells of the collecting duct. Binding to the receptor triggers an intracellular cyclic adenosine monophosphate (cAMP) pathway, which causes phosphorylation of the aquaporin-2 (AQP2). After achieving water homeostasis, the ADH levels decrease, and AQP2 is internalized from the plasma membrane, leaving the plasma membrane watertight again.[1]

Cellular

ADH synthesis occurs in the hypothalamus. Specifically, it is principally produced by neurons that have their cell bodies within the supraoptic nuclei of the hypothalamus. There is also production, albeit in smaller quantities, in neurons with cell bodies located in the paraventricular nuclei, the site primarily responsible for oxytocin, a homologous hormone mostly involved in uterine contraction and milk let down. These storage vesicles are transported down the neuron’s axon through the hypothalamic-hypophysial tract, where they are ultimately released in the posterior pituitary. The secreted hormones then enter nearby fenestrated capillaries where they enter the body’s systemic circulation.[1]

Development

ADH is a nonapeptide derived from the preprohormone called prepropressophysin, which contains a signal peptide, neurophysin II, and a glycoprotein. In the Golgi apparatus, the signal peptide portion is cleaved from prepropressophysin to produce a prohormone stored in secretory vesicles. In route to the posterior pituitary where ADH will be released, the prohormone is cleaved to produce ADH.

Organ Systems Involved

  • Kidneys

  • Posterior pituitary

Function

ADH is the primary hormone responsible for tonicity homeostasis. Hyperosmolar states most strongly trigger its release. ADH is stored in neurons within the hypothalamus. These neurons express osmoreceptors that are exquisitely responsive to blood osmolarity and respond to changes as little as two mOsm/L.[2] Therefore, slight elevations in osmolarity result in the secretion of ADH. ADH then acts primarily in the kidneys to increase water reabsorption, thus returning the osmolarity to baseline.

ADH secretion also occurs during states of hypovolemia or volume depletion. In these states, decreased baroreceptors sense arterial blood volume in the left atrium, carotid artery, and aortic arch. Information about low blood pressure sensed by these receptors is transmitted to the vagus nerve, which directly stimulates the release of ADH. ADH then promotes water reabsorption in the kidneys and, at high concentrations, will also cause vasoconstriction. These two mechanisms together serve to increase effective arterial blood volume and increase blood pressure to maintain tissue perfusion. It is also important to note that in states of hypovolemia, ADH will be secreted even in hypoosmotic states. Conversely, hypervolemia inhibits ADH secretion; therefore, in hyperosmotic hypervolemic states, ADH secretion will be reduced.[1]

Osmolarity and volume status are the two greatest factors that affect ADH secretion. However, a variety of other factors promote ADH secretion as well. These include angiotensin II, pain, nausea, hypoglycemia, nicotine, opiates, and certain medications. ADH secretion is also negatively affected by ethanol, alpha-adrenergic agonists, and atrial natriuretic peptide. Ethanol’s inhibitory effect helps to explain the increased diuresis experienced during intoxicated states as well as increased free water loss; without appropriate ADH secretion, the kidneys excrete more water.[3]

Mechanism

ADH principally exerts its effects by binding to the kidneys principal cells within the late distal tubule and collecting ducts. ADH binds to the V receptor on these cells and leads to the activation of adenylate cyclase, which causes a subsequent increase in the second messenger cyclic AMP (cAMP). cAMP activates protein kinase A (PKA), a phosphorylating enzyme that initiates an intracellular phosphorylation cascade. Ultimately, intracellular aquaporin-2 (AQP2) storage vesicles are phosphorylated, which promotes their movement and insertion into the apical membrane. AQP2 is a water channel that allows water to move passively into the cell guided by the osmotic gradient established by NaCl and urea, and thus promotes reabsorption of water in the kidney. This activity creates concentrated, or hyperosmotic, urine, and allows our body to conserve water in times of dehydration or loss of sufficient blood volume, as seen in hemorrhagic or edematous states.[1]

ADH also has a second action on vascular smooth muscle. ADH binds to V receptors on vascular smooth muscle and activates G protein. G activates phospholipase C (PLC), which results in the production of inositol triphosphate (IP-3) as well as diacylglycerol (DAG) from the cell membrane. IP-3 causes a release of intracellular calcium from the endoplasmic reticulum. DAG and calcium activate protein kinase C (PKC), which, like PKA, results in a signaling phosphorylation cascade. The net effect of this signaling cascade is a contraction of vascular smooth muscle leading to increases in total peripheral resistance and thus increases in blood pressure. This mechanism is synergistic with water reabsorption in that both mechanisms elevate blood pressure. This mechanism is crucial in periods where sufficient arterial blood volume is low to maintain tissue perfusion.[1]

Related Testing

The laboratory values commonly used to diagnose conditions associated with ADH abnormalities include serum osmolality, urine osmolality, urine electrolytes, thyroid function tests, cortisol levels, liver function tests, and serum uric acid.   

Pathophysiology

There are three pathologic states related to ADH. The first is the syndrome of inappropriate ADH (SIADH) and occurs when ADH is released in excessive unregulated quantities. SIADH results in excess water reabsorption and thus creates dilutional hyponatremia. Although water is retained in quantities greater than the body’s needs, these patients typically remain euvolemic and do not exhibit features of the third spacing of fluid such as edema. The mechanism behind this is that, regardless of the excess ADH present, the kidneys maintain their ability to excrete salt. As ADH signals for increased water reabsorption, the body senses the increase in extracellular volume, and natriuretic mechanisms come into play that cause increased salt excretion via the kidneys. The increased salt in the urine will osmotically attract water to be excreted as well, thus keeping the body in a euvolemic state. This increase in salt excretion also contributes to the hyponatremia seen in SIADH. Settings in which SIADH arises include malignancies (most often by autonomous production of ADH by small cell lung cancer), central nervous system (CNS) disturbances (e.g., stroke, hemorrhage, infection, trauma, etc.), drugs (e.g., selective serotonin reuptake inhibitors, carbamazepine, and others), surgery (most likely secondary to pain), and more. Patients with SIADH may be asymptomatic or present with a spectrum of severity of complaints based on their level of hyponatremia. Nausea and malaise are typically the earliest presenting symptoms and present when the sodium acutely falls below 125 to 130 mEq/L. Lower levels of sodium are associated with headache, obtundation, seizure, and even coma and respiratory arrest.[4] These symptoms arise due to the increased movement of water into neurons as the extracellular osmolarity falls. The intracellular swelling causes neuronal dysfunction.[5]

Unlike the excess ADH seen in SIADH, the remaining two pathologic states related to ADH result from either decreased ADH or resistance to its effects. A failure of ADH secretion causes central diabetes insipidus. In this scenario, ADH levels are low; thus, the collecting tubules are impermeable to water, resulting in excess water excretion. In nephrogenic diabetes insipidus, ADH secretion is normal, but there is a defect in the V receptor or other signaling mediators that makes the kidneys unresponsive to ADH. In either disease, the net effect is increased excretion of water. The depletion of water causes the production of large volumes of dilute water and the concentration of body fluids leading to hypernatremia and hyperosmolarity. This status results in polyuria, polydipsia, and the effects of electrolyte imbalances that ensue.[6]

Central diabetes insipidus is the more common form and often seen after brain trauma or surgery that damages either the hypothalamus or posterior pituitary. Other cerebral infiltrative processes such as infection, autoimmune disease, or neoplastic disease may also cause central diabetes insipidus. Nephrogenic diabetes insipidus can be either inherited or acquired. The most common inherited form is attributed to mutations in the V receptor and often manifests in childhood. Acquired causes of nephrogenic diabetes insipidus are more often at play in adulthood expression of the disease. Most often, acquired nephrogenic diabetes insipidus is due to drugs, notably lithium and some antibiotics such as tetracyclines.[6]

Clinical Significance

ADH is an important hormone that is responsible for water, osmolar, and blood pressure homeostasis. Its function is vital in times of thirst, hemorrhage, the third spacing of fluid, and other scenarios where there is the diminution of effective arterial blood flow. Its efforts serve to maintain volume status as well as blood pressure to continue adequate tissue perfusion. Additionally, the pathologic states discussed above are important considerations when working up patients with electrolyte imbalances. SIADH is a common cause of hyponatremia and may be a sign of an underlying occult malignancy when no other risk factor is present. Clinically, SIADH is the diagnosis in a hyponatremic patient who has evidence of decreased plasma osmolarity (less than 275 mOsm/kg), inappropriately concentrated urine (urine osmolarity greater than 100 mOsm/kg), elevated urine sodium (greater than 20 mEq/L), and euvolemia.[5]

Diabetes insipidus is an important cause of hypernatremia. They are distinguished from each other and primary polydipsia, a disease of dysregulated thirst mechanism resulting in excess fluid intake and, therefore, polydipsia and polyuria, by a water deprivation challenge. In this test, a patient’s urine and plasma osmolarity are measured at baseline and then repeatedly measured over a few hours while they are not allowed to drink water. If during this period of water deprivation, their urine osmolarity increases to above 750 mOsm/kg, then primary polydipsia is the diagnosis as this signals the body is adequately releasing ADH in response to a lack of fluid intake. If the urine osmolarity remains low, then this implies an issue with ADH is present, and diabetes insipidus is likely the culprit. To differentiate between nephrogenic and central forms of the disease, during the water deprivation challenge, one may administer desmopressin, an ADH analog. If after desmopressin administration urine osmolarity increases, then central diabetes insipidus is present as this scenario describes a working response ADH. If, however, desmopressin does not increase urine osmolarity, then we know the response to ADH is inappropriate, and it must be nephrogenic diabetes insipidus. This distinction is important to make as the treatment differs between nephrogenic and central diabetes insipidus. The treatment for the central form is to replace the inadequate ADH with desmopressin. In the nephrogenic form, the treatment of choice is thiazide diuretics. Thiazide diuretics act at the distal convoluted tubule to block sodium and chloride cotransport. The increased excretion of sodium chloride induces mild hypovolemia, which triggers increased sodium reabsorption in the proximal convoluted tubule. This increase in sodium reabsorption will promote the increase in passive water reabsorption in the same segment, resulting in a net decrease in water excretion, thus mitigating the polyuria seen in these patients.[6]

Aside from its role in homeostasis and its part in a variety of pathologies, ADH has also served as a medication to treat two important bleeding disorders: von Willebrand disease and hemophilia A. Von Willebrand disease is the most common inherited bleeding disorder in which mutations lead to disruption of the synthesis or function of von Willebrand factor (VWF), the factor that tethers platelets to endothelium by binding collagen on endothelial surface and GpIb on the platelet surface. VWF is a crucial factor in the development of primary hemostasis. Also, VWF plays a role in secondary hemostasis by binding to and stabilizing factor VIII. Desmopressin is used to treat von Willebrand disease as it leads to an increase in the secretion of VWF and factor VIII from endothelium.[7] Hemophilia A is a bleeding disorder owed to either an acquired or inherited lack of factor VIII. As stated, desmopressin also promotes the release of factor VIII from the endothelium, thus bridging the missing gap in hemophilia A’s coagulopathy.[8]

References

1.
Boone M, Deen PM. Physiology and pathophysiology of the vasopressin-regulated renal water reabsorption. Pflugers Arch. 2008 Sep;456(6):1005-24. [PMC free article: PMC2518081] [PubMed: 18431594]
2.
Davies AG. Antidiuretic and growth hormones. Br Med J. 1972 Apr 29;2(5808):282-4. [PMC free article: PMC1789001] [PubMed: 4553816]
3.
Schrier RW, Bichet DG. Osmotic and nonosmotic control of vasopressin release and the pathogenesis of impaired water excretion in adrenal, thyroid, and edematous disorders. J Lab Clin Med. 1981 Jul;98(1):1-15. [PubMed: 7019365]
4.
Sterns RH. Disorders of plasma sodium–causes, consequences, and correction. N Engl J Med. 2015 Jan 01;372(1):55-65. [PubMed: 25551526]
5.
Pillai BP, Unnikrishnan AG, Pavithran PV. Syndrome of inappropriate antidiuretic hormone secretion: Revisiting a classical endocrine disorder. Indian J Endocrinol Metab. 2011 Sep;15 Suppl 3:S208-15. [PMC free article: PMC3183532] [PubMed: 22029026]
6.
Kalra S, Zargar AH, Jain SM, Sethi B, Chowdhury S, Singh AK, Thomas N, Unnikrishnan AG, Thakkar PB, Malve H. Diabetes insipidus: The other diabetes. Indian J Endocrinol Metab. 2016 Jan-Feb;20(1):9-21. [PMC free article: PMC4743391] [PubMed: 26904464]
7.
Tuohy E, Litt E, Alikhan R. Treatment of patients with von Willebrand disease. J Blood Med. 2011;2:49-57. [PMC free article: PMC3262353] [PubMed: 22287863]
8.
Franchini M, Lippi G. The use of desmopressin in acquired haemophilia A: a systematic review. Blood Transfus. 2011 Oct;9(4):377-82. [PMC free article: PMC3200405] [PubMed: 21839010]

Physiology, Vasopressin – StatPearls – NCBI Bookshelf

Introduction

Vasopressin or antidiuretic hormone (ADH) or arginine vasopressin (AVP) is a nonapeptide synthesized in the hypothalamus. Science has known it to play essential roles in the control of the body’s osmotic balance, blood pressure regulation, sodium homeostasis, and kidney functioning. Given its vital role in multiple functions, it is no surprise that ADH is of great clinical significance. ADH primarily affects the ability of the kidney to reabsorb water; when present, ADH induces expression of water transport proteins in the late distal tubule and collecting duct to increase water reabsorption. Several disease states arise when the body loses control of ADH secretion or responds to its presence.[1]

In states of hypovolemia or hypernatremia, ADH is released from the posterior pituitary gland and binds to the type-2 receptor in principal cells of the collecting duct. Binding to the receptor triggers an intracellular cyclic adenosine monophosphate (cAMP) pathway, which causes phosphorylation of the aquaporin-2 (AQP2). After achieving water homeostasis, the ADH levels decrease, and AQP2 is internalized from the plasma membrane, leaving the plasma membrane watertight again.[1]

Cellular

ADH synthesis occurs in the hypothalamus. Specifically, it is principally produced by neurons that have their cell bodies within the supraoptic nuclei of the hypothalamus. There is also production, albeit in smaller quantities, in neurons with cell bodies located in the paraventricular nuclei, the site primarily responsible for oxytocin, a homologous hormone mostly involved in uterine contraction and milk let down. These storage vesicles are transported down the neuron’s axon through the hypothalamic-hypophysial tract, where they are ultimately released in the posterior pituitary. The secreted hormones then enter nearby fenestrated capillaries where they enter the body’s systemic circulation.[1]

Development

ADH is a nonapeptide derived from the preprohormone called prepropressophysin, which contains a signal peptide, neurophysin II, and a glycoprotein. In the Golgi apparatus, the signal peptide portion is cleaved from prepropressophysin to produce a prohormone stored in secretory vesicles. In route to the posterior pituitary where ADH will be released, the prohormone is cleaved to produce ADH.

Organ Systems Involved

  • Kidneys

  • Posterior pituitary

Function

ADH is the primary hormone responsible for tonicity homeostasis. Hyperosmolar states most strongly trigger its release. ADH is stored in neurons within the hypothalamus. These neurons express osmoreceptors that are exquisitely responsive to blood osmolarity and respond to changes as little as two mOsm/L.[2] Therefore, slight elevations in osmolarity result in the secretion of ADH. ADH then acts primarily in the kidneys to increase water reabsorption, thus returning the osmolarity to baseline.

ADH secretion also occurs during states of hypovolemia or volume depletion. In these states, decreased baroreceptors sense arterial blood volume in the left atrium, carotid artery, and aortic arch. Information about low blood pressure sensed by these receptors is transmitted to the vagus nerve, which directly stimulates the release of ADH. ADH then promotes water reabsorption in the kidneys and, at high concentrations, will also cause vasoconstriction. These two mechanisms together serve to increase effective arterial blood volume and increase blood pressure to maintain tissue perfusion. It is also important to note that in states of hypovolemia, ADH will be secreted even in hypoosmotic states. Conversely, hypervolemia inhibits ADH secretion; therefore, in hyperosmotic hypervolemic states, ADH secretion will be reduced.[1]

Osmolarity and volume status are the two greatest factors that affect ADH secretion. However, a variety of other factors promote ADH secretion as well. These include angiotensin II, pain, nausea, hypoglycemia, nicotine, opiates, and certain medications. ADH secretion is also negatively affected by ethanol, alpha-adrenergic agonists, and atrial natriuretic peptide. Ethanol’s inhibitory effect helps to explain the increased diuresis experienced during intoxicated states as well as increased free water loss; without appropriate ADH secretion, the kidneys excrete more water.[3]

Mechanism

ADH principally exerts its effects by binding to the kidneys principal cells within the late distal tubule and collecting ducts. ADH binds to the V receptor on these cells and leads to the activation of adenylate cyclase, which causes a subsequent increase in the second messenger cyclic AMP (cAMP). cAMP activates protein kinase A (PKA), a phosphorylating enzyme that initiates an intracellular phosphorylation cascade. Ultimately, intracellular aquaporin-2 (AQP2) storage vesicles are phosphorylated, which promotes their movement and insertion into the apical membrane. AQP2 is a water channel that allows water to move passively into the cell guided by the osmotic gradient established by NaCl and urea, and thus promotes reabsorption of water in the kidney. This activity creates concentrated, or hyperosmotic, urine, and allows our body to conserve water in times of dehydration or loss of sufficient blood volume, as seen in hemorrhagic or edematous states.[1]

ADH also has a second action on vascular smooth muscle. ADH binds to V receptors on vascular smooth muscle and activates G protein. G activates phospholipase C (PLC), which results in the production of inositol triphosphate (IP-3) as well as diacylglycerol (DAG) from the cell membrane. IP-3 causes a release of intracellular calcium from the endoplasmic reticulum. DAG and calcium activate protein kinase C (PKC), which, like PKA, results in a signaling phosphorylation cascade. The net effect of this signaling cascade is a contraction of vascular smooth muscle leading to increases in total peripheral resistance and thus increases in blood pressure. This mechanism is synergistic with water reabsorption in that both mechanisms elevate blood pressure. This mechanism is crucial in periods where sufficient arterial blood volume is low to maintain tissue perfusion.[1]

Related Testing

The laboratory values commonly used to diagnose conditions associated with ADH abnormalities include serum osmolality, urine osmolality, urine electrolytes, thyroid function tests, cortisol levels, liver function tests, and serum uric acid.   

Pathophysiology

There are three pathologic states related to ADH. The first is the syndrome of inappropriate ADH (SIADH) and occurs when ADH is released in excessive unregulated quantities. SIADH results in excess water reabsorption and thus creates dilutional hyponatremia. Although water is retained in quantities greater than the body’s needs, these patients typically remain euvolemic and do not exhibit features of the third spacing of fluid such as edema. The mechanism behind this is that, regardless of the excess ADH present, the kidneys maintain their ability to excrete salt. As ADH signals for increased water reabsorption, the body senses the increase in extracellular volume, and natriuretic mechanisms come into play that cause increased salt excretion via the kidneys. The increased salt in the urine will osmotically attract water to be excreted as well, thus keeping the body in a euvolemic state. This increase in salt excretion also contributes to the hyponatremia seen in SIADH. Settings in which SIADH arises include malignancies (most often by autonomous production of ADH by small cell lung cancer), central nervous system (CNS) disturbances (e.g., stroke, hemorrhage, infection, trauma, etc.), drugs (e.g., selective serotonin reuptake inhibitors, carbamazepine, and others), surgery (most likely secondary to pain), and more. Patients with SIADH may be asymptomatic or present with a spectrum of severity of complaints based on their level of hyponatremia. Nausea and malaise are typically the earliest presenting symptoms and present when the sodium acutely falls below 125 to 130 mEq/L. Lower levels of sodium are associated with headache, obtundation, seizure, and even coma and respiratory arrest.[4] These symptoms arise due to the increased movement of water into neurons as the extracellular osmolarity falls. The intracellular swelling causes neuronal dysfunction.[5]

Unlike the excess ADH seen in SIADH, the remaining two pathologic states related to ADH result from either decreased ADH or resistance to its effects. A failure of ADH secretion causes central diabetes insipidus. In this scenario, ADH levels are low; thus, the collecting tubules are impermeable to water, resulting in excess water excretion. In nephrogenic diabetes insipidus, ADH secretion is normal, but there is a defect in the V receptor or other signaling mediators that makes the kidneys unresponsive to ADH. In either disease, the net effect is increased excretion of water. The depletion of water causes the production of large volumes of dilute water and the concentration of body fluids leading to hypernatremia and hyperosmolarity. This status results in polyuria, polydipsia, and the effects of electrolyte imbalances that ensue.[6]

Central diabetes insipidus is the more common form and often seen after brain trauma or surgery that damages either the hypothalamus or posterior pituitary. Other cerebral infiltrative processes such as infection, autoimmune disease, or neoplastic disease may also cause central diabetes insipidus. Nephrogenic diabetes insipidus can be either inherited or acquired. The most common inherited form is attributed to mutations in the V receptor and often manifests in childhood. Acquired causes of nephrogenic diabetes insipidus are more often at play in adulthood expression of the disease. Most often, acquired nephrogenic diabetes insipidus is due to drugs, notably lithium and some antibiotics such as tetracyclines.[6]

Clinical Significance

ADH is an important hormone that is responsible for water, osmolar, and blood pressure homeostasis. Its function is vital in times of thirst, hemorrhage, the third spacing of fluid, and other scenarios where there is the diminution of effective arterial blood flow. Its efforts serve to maintain volume status as well as blood pressure to continue adequate tissue perfusion. Additionally, the pathologic states discussed above are important considerations when working up patients with electrolyte imbalances. SIADH is a common cause of hyponatremia and may be a sign of an underlying occult malignancy when no other risk factor is present. Clinically, SIADH is the diagnosis in a hyponatremic patient who has evidence of decreased plasma osmolarity (less than 275 mOsm/kg), inappropriately concentrated urine (urine osmolarity greater than 100 mOsm/kg), elevated urine sodium (greater than 20 mEq/L), and euvolemia.[5]

Diabetes insipidus is an important cause of hypernatremia. They are distinguished from each other and primary polydipsia, a disease of dysregulated thirst mechanism resulting in excess fluid intake and, therefore, polydipsia and polyuria, by a water deprivation challenge. In this test, a patient’s urine and plasma osmolarity are measured at baseline and then repeatedly measured over a few hours while they are not allowed to drink water. If during this period of water deprivation, their urine osmolarity increases to above 750 mOsm/kg, then primary polydipsia is the diagnosis as this signals the body is adequately releasing ADH in response to a lack of fluid intake. If the urine osmolarity remains low, then this implies an issue with ADH is present, and diabetes insipidus is likely the culprit. To differentiate between nephrogenic and central forms of the disease, during the water deprivation challenge, one may administer desmopressin, an ADH analog. If after desmopressin administration urine osmolarity increases, then central diabetes insipidus is present as this scenario describes a working response ADH. If, however, desmopressin does not increase urine osmolarity, then we know the response to ADH is inappropriate, and it must be nephrogenic diabetes insipidus. This distinction is important to make as the treatment differs between nephrogenic and central diabetes insipidus. The treatment for the central form is to replace the inadequate ADH with desmopressin. In the nephrogenic form, the treatment of choice is thiazide diuretics. Thiazide diuretics act at the distal convoluted tubule to block sodium and chloride cotransport. The increased excretion of sodium chloride induces mild hypovolemia, which triggers increased sodium reabsorption in the proximal convoluted tubule. This increase in sodium reabsorption will promote the increase in passive water reabsorption in the same segment, resulting in a net decrease in water excretion, thus mitigating the polyuria seen in these patients.[6]

Aside from its role in homeostasis and its part in a variety of pathologies, ADH has also served as a medication to treat two important bleeding disorders: von Willebrand disease and hemophilia A. Von Willebrand disease is the most common inherited bleeding disorder in which mutations lead to disruption of the synthesis or function of von Willebrand factor (VWF), the factor that tethers platelets to endothelium by binding collagen on endothelial surface and GpIb on the platelet surface. VWF is a crucial factor in the development of primary hemostasis. Also, VWF plays a role in secondary hemostasis by binding to and stabilizing factor VIII. Desmopressin is used to treat von Willebrand disease as it leads to an increase in the secretion of VWF and factor VIII from endothelium.[7] Hemophilia A is a bleeding disorder owed to either an acquired or inherited lack of factor VIII. As stated, desmopressin also promotes the release of factor VIII from the endothelium, thus bridging the missing gap in hemophilia A’s coagulopathy.[8]

References

1.
Boone M, Deen PM. Physiology and pathophysiology of the vasopressin-regulated renal water reabsorption. Pflugers Arch. 2008 Sep;456(6):1005-24. [PMC free article: PMC2518081] [PubMed: 18431594]
2.
Davies AG. Antidiuretic and growth hormones. Br Med J. 1972 Apr 29;2(5808):282-4. [PMC free article: PMC1789001] [PubMed: 4553816]
3.
Schrier RW, Bichet DG. Osmotic and nonosmotic control of vasopressin release and the pathogenesis of impaired water excretion in adrenal, thyroid, and edematous disorders. J Lab Clin Med. 1981 Jul;98(1):1-15. [PubMed: 7019365]
4.
Sterns RH. Disorders of plasma sodium–causes, consequences, and correction. N Engl J Med. 2015 Jan 01;372(1):55-65. [PubMed: 25551526]
5.
Pillai BP, Unnikrishnan AG, Pavithran PV. Syndrome of inappropriate antidiuretic hormone secretion: Revisiting a classical endocrine disorder. Indian J Endocrinol Metab. 2011 Sep;15 Suppl 3:S208-15. [PMC free article: PMC3183532] [PubMed: 22029026]
6.
Kalra S, Zargar AH, Jain SM, Sethi B, Chowdhury S, Singh AK, Thomas N, Unnikrishnan AG, Thakkar PB, Malve H. Diabetes insipidus: The other diabetes. Indian J Endocrinol Metab. 2016 Jan-Feb;20(1):9-21. [PMC free article: PMC4743391] [PubMed: 26904464]
7.
Tuohy E, Litt E, Alikhan R. Treatment of patients with von Willebrand disease. J Blood Med. 2011;2:49-57. [PMC free article: PMC3262353] [PubMed: 22287863]
8.
Franchini M, Lippi G. The use of desmopressin in acquired haemophilia A: a systematic review. Blood Transfus. 2011 Oct;9(4):377-82. [PMC free article: PMC3200405] [PubMed: 21839010]

Physiology, Vasopressin – StatPearls – NCBI Bookshelf

Introduction

Vasopressin or antidiuretic hormone (ADH) or arginine vasopressin (AVP) is a nonapeptide synthesized in the hypothalamus. Science has known it to play essential roles in the control of the body’s osmotic balance, blood pressure regulation, sodium homeostasis, and kidney functioning. Given its vital role in multiple functions, it is no surprise that ADH is of great clinical significance. ADH primarily affects the ability of the kidney to reabsorb water; when present, ADH induces expression of water transport proteins in the late distal tubule and collecting duct to increase water reabsorption. Several disease states arise when the body loses control of ADH secretion or responds to its presence.[1]

In states of hypovolemia or hypernatremia, ADH is released from the posterior pituitary gland and binds to the type-2 receptor in principal cells of the collecting duct. Binding to the receptor triggers an intracellular cyclic adenosine monophosphate (cAMP) pathway, which causes phosphorylation of the aquaporin-2 (AQP2). After achieving water homeostasis, the ADH levels decrease, and AQP2 is internalized from the plasma membrane, leaving the plasma membrane watertight again.[1]

Cellular

ADH synthesis occurs in the hypothalamus. Specifically, it is principally produced by neurons that have their cell bodies within the supraoptic nuclei of the hypothalamus. There is also production, albeit in smaller quantities, in neurons with cell bodies located in the paraventricular nuclei, the site primarily responsible for oxytocin, a homologous hormone mostly involved in uterine contraction and milk let down. These storage vesicles are transported down the neuron’s axon through the hypothalamic-hypophysial tract, where they are ultimately released in the posterior pituitary. The secreted hormones then enter nearby fenestrated capillaries where they enter the body’s systemic circulation.[1]

Development

ADH is a nonapeptide derived from the preprohormone called prepropressophysin, which contains a signal peptide, neurophysin II, and a glycoprotein. In the Golgi apparatus, the signal peptide portion is cleaved from prepropressophysin to produce a prohormone stored in secretory vesicles. In route to the posterior pituitary where ADH will be released, the prohormone is cleaved to produce ADH.

Organ Systems Involved

  • Kidneys

  • Posterior pituitary

Function

ADH is the primary hormone responsible for tonicity homeostasis. Hyperosmolar states most strongly trigger its release. ADH is stored in neurons within the hypothalamus. These neurons express osmoreceptors that are exquisitely responsive to blood osmolarity and respond to changes as little as two mOsm/L.[2] Therefore, slight elevations in osmolarity result in the secretion of ADH. ADH then acts primarily in the kidneys to increase water reabsorption, thus returning the osmolarity to baseline.

ADH secretion also occurs during states of hypovolemia or volume depletion. In these states, decreased baroreceptors sense arterial blood volume in the left atrium, carotid artery, and aortic arch. Information about low blood pressure sensed by these receptors is transmitted to the vagus nerve, which directly stimulates the release of ADH. ADH then promotes water reabsorption in the kidneys and, at high concentrations, will also cause vasoconstriction. These two mechanisms together serve to increase effective arterial blood volume and increase blood pressure to maintain tissue perfusion. It is also important to note that in states of hypovolemia, ADH will be secreted even in hypoosmotic states. Conversely, hypervolemia inhibits ADH secretion; therefore, in hyperosmotic hypervolemic states, ADH secretion will be reduced.[1]

Osmolarity and volume status are the two greatest factors that affect ADH secretion. However, a variety of other factors promote ADH secretion as well. These include angiotensin II, pain, nausea, hypoglycemia, nicotine, opiates, and certain medications. ADH secretion is also negatively affected by ethanol, alpha-adrenergic agonists, and atrial natriuretic peptide. Ethanol’s inhibitory effect helps to explain the increased diuresis experienced during intoxicated states as well as increased free water loss; without appropriate ADH secretion, the kidneys excrete more water.[3]

Mechanism

ADH principally exerts its effects by binding to the kidneys principal cells within the late distal tubule and collecting ducts. ADH binds to the V receptor on these cells and leads to the activation of adenylate cyclase, which causes a subsequent increase in the second messenger cyclic AMP (cAMP). cAMP activates protein kinase A (PKA), a phosphorylating enzyme that initiates an intracellular phosphorylation cascade. Ultimately, intracellular aquaporin-2 (AQP2) storage vesicles are phosphorylated, which promotes their movement and insertion into the apical membrane. AQP2 is a water channel that allows water to move passively into the cell guided by the osmotic gradient established by NaCl and urea, and thus promotes reabsorption of water in the kidney. This activity creates concentrated, or hyperosmotic, urine, and allows our body to conserve water in times of dehydration or loss of sufficient blood volume, as seen in hemorrhagic or edematous states.[1]

ADH also has a second action on vascular smooth muscle. ADH binds to V receptors on vascular smooth muscle and activates G protein. G activates phospholipase C (PLC), which results in the production of inositol triphosphate (IP-3) as well as diacylglycerol (DAG) from the cell membrane. IP-3 causes a release of intracellular calcium from the endoplasmic reticulum. DAG and calcium activate protein kinase C (PKC), which, like PKA, results in a signaling phosphorylation cascade. The net effect of this signaling cascade is a contraction of vascular smooth muscle leading to increases in total peripheral resistance and thus increases in blood pressure. This mechanism is synergistic with water reabsorption in that both mechanisms elevate blood pressure. This mechanism is crucial in periods where sufficient arterial blood volume is low to maintain tissue perfusion.[1]

Related Testing

The laboratory values commonly used to diagnose conditions associated with ADH abnormalities include serum osmolality, urine osmolality, urine electrolytes, thyroid function tests, cortisol levels, liver function tests, and serum uric acid.   

Pathophysiology

There are three pathologic states related to ADH. The first is the syndrome of inappropriate ADH (SIADH) and occurs when ADH is released in excessive unregulated quantities. SIADH results in excess water reabsorption and thus creates dilutional hyponatremia. Although water is retained in quantities greater than the body’s needs, these patients typically remain euvolemic and do not exhibit features of the third spacing of fluid such as edema. The mechanism behind this is that, regardless of the excess ADH present, the kidneys maintain their ability to excrete salt. As ADH signals for increased water reabsorption, the body senses the increase in extracellular volume, and natriuretic mechanisms come into play that cause increased salt excretion via the kidneys. The increased salt in the urine will osmotically attract water to be excreted as well, thus keeping the body in a euvolemic state. This increase in salt excretion also contributes to the hyponatremia seen in SIADH. Settings in which SIADH arises include malignancies (most often by autonomous production of ADH by small cell lung cancer), central nervous system (CNS) disturbances (e.g., stroke, hemorrhage, infection, trauma, etc.), drugs (e.g., selective serotonin reuptake inhibitors, carbamazepine, and others), surgery (most likely secondary to pain), and more. Patients with SIADH may be asymptomatic or present with a spectrum of severity of complaints based on their level of hyponatremia. Nausea and malaise are typically the earliest presenting symptoms and present when the sodium acutely falls below 125 to 130 mEq/L. Lower levels of sodium are associated with headache, obtundation, seizure, and even coma and respiratory arrest.[4] These symptoms arise due to the increased movement of water into neurons as the extracellular osmolarity falls. The intracellular swelling causes neuronal dysfunction.[5]

Unlike the excess ADH seen in SIADH, the remaining two pathologic states related to ADH result from either decreased ADH or resistance to its effects. A failure of ADH secretion causes central diabetes insipidus. In this scenario, ADH levels are low; thus, the collecting tubules are impermeable to water, resulting in excess water excretion. In nephrogenic diabetes insipidus, ADH secretion is normal, but there is a defect in the V receptor or other signaling mediators that makes the kidneys unresponsive to ADH. In either disease, the net effect is increased excretion of water. The depletion of water causes the production of large volumes of dilute water and the concentration of body fluids leading to hypernatremia and hyperosmolarity. This status results in polyuria, polydipsia, and the effects of electrolyte imbalances that ensue.[6]

Central diabetes insipidus is the more common form and often seen after brain trauma or surgery that damages either the hypothalamus or posterior pituitary. Other cerebral infiltrative processes such as infection, autoimmune disease, or neoplastic disease may also cause central diabetes insipidus. Nephrogenic diabetes insipidus can be either inherited or acquired. The most common inherited form is attributed to mutations in the V receptor and often manifests in childhood. Acquired causes of nephrogenic diabetes insipidus are more often at play in adulthood expression of the disease. Most often, acquired nephrogenic diabetes insipidus is due to drugs, notably lithium and some antibiotics such as tetracyclines.[6]

Clinical Significance

ADH is an important hormone that is responsible for water, osmolar, and blood pressure homeostasis. Its function is vital in times of thirst, hemorrhage, the third spacing of fluid, and other scenarios where there is the diminution of effective arterial blood flow. Its efforts serve to maintain volume status as well as blood pressure to continue adequate tissue perfusion. Additionally, the pathologic states discussed above are important considerations when working up patients with electrolyte imbalances. SIADH is a common cause of hyponatremia and may be a sign of an underlying occult malignancy when no other risk factor is present. Clinically, SIADH is the diagnosis in a hyponatremic patient who has evidence of decreased plasma osmolarity (less than 275 mOsm/kg), inappropriately concentrated urine (urine osmolarity greater than 100 mOsm/kg), elevated urine sodium (greater than 20 mEq/L), and euvolemia.[5]

Diabetes insipidus is an important cause of hypernatremia. They are distinguished from each other and primary polydipsia, a disease of dysregulated thirst mechanism resulting in excess fluid intake and, therefore, polydipsia and polyuria, by a water deprivation challenge. In this test, a patient’s urine and plasma osmolarity are measured at baseline and then repeatedly measured over a few hours while they are not allowed to drink water. If during this period of water deprivation, their urine osmolarity increases to above 750 mOsm/kg, then primary polydipsia is the diagnosis as this signals the body is adequately releasing ADH in response to a lack of fluid intake. If the urine osmolarity remains low, then this implies an issue with ADH is present, and diabetes insipidus is likely the culprit. To differentiate between nephrogenic and central forms of the disease, during the water deprivation challenge, one may administer desmopressin, an ADH analog. If after desmopressin administration urine osmolarity increases, then central diabetes insipidus is present as this scenario describes a working response ADH. If, however, desmopressin does not increase urine osmolarity, then we know the response to ADH is inappropriate, and it must be nephrogenic diabetes insipidus. This distinction is important to make as the treatment differs between nephrogenic and central diabetes insipidus. The treatment for the central form is to replace the inadequate ADH with desmopressin. In the nephrogenic form, the treatment of choice is thiazide diuretics. Thiazide diuretics act at the distal convoluted tubule to block sodium and chloride cotransport. The increased excretion of sodium chloride induces mild hypovolemia, which triggers increased sodium reabsorption in the proximal convoluted tubule. This increase in sodium reabsorption will promote the increase in passive water reabsorption in the same segment, resulting in a net decrease in water excretion, thus mitigating the polyuria seen in these patients.[6]

Aside from its role in homeostasis and its part in a variety of pathologies, ADH has also served as a medication to treat two important bleeding disorders: von Willebrand disease and hemophilia A. Von Willebrand disease is the most common inherited bleeding disorder in which mutations lead to disruption of the synthesis or function of von Willebrand factor (VWF), the factor that tethers platelets to endothelium by binding collagen on endothelial surface and GpIb on the platelet surface. VWF is a crucial factor in the development of primary hemostasis. Also, VWF plays a role in secondary hemostasis by binding to and stabilizing factor VIII. Desmopressin is used to treat von Willebrand disease as it leads to an increase in the secretion of VWF and factor VIII from endothelium.[7] Hemophilia A is a bleeding disorder owed to either an acquired or inherited lack of factor VIII. As stated, desmopressin also promotes the release of factor VIII from the endothelium, thus bridging the missing gap in hemophilia A’s coagulopathy.[8]

References

1.
Boone M, Deen PM. Physiology and pathophysiology of the vasopressin-regulated renal water reabsorption. Pflugers Arch. 2008 Sep;456(6):1005-24. [PMC free article: PMC2518081] [PubMed: 18431594]
2.
Davies AG. Antidiuretic and growth hormones. Br Med J. 1972 Apr 29;2(5808):282-4. [PMC free article: PMC1789001] [PubMed: 4553816]
3.
Schrier RW, Bichet DG. Osmotic and nonosmotic control of vasopressin release and the pathogenesis of impaired water excretion in adrenal, thyroid, and edematous disorders. J Lab Clin Med. 1981 Jul;98(1):1-15. [PubMed: 7019365]
4.
Sterns RH. Disorders of plasma sodium–causes, consequences, and correction. N Engl J Med. 2015 Jan 01;372(1):55-65. [PubMed: 25551526]
5.
Pillai BP, Unnikrishnan AG, Pavithran PV. Syndrome of inappropriate antidiuretic hormone secretion: Revisiting a classical endocrine disorder. Indian J Endocrinol Metab. 2011 Sep;15 Suppl 3:S208-15. [PMC free article: PMC3183532] [PubMed: 22029026]
6.
Kalra S, Zargar AH, Jain SM, Sethi B, Chowdhury S, Singh AK, Thomas N, Unnikrishnan AG, Thakkar PB, Malve H. Diabetes insipidus: The other diabetes. Indian J Endocrinol Metab. 2016 Jan-Feb;20(1):9-21. [PMC free article: PMC4743391] [PubMed: 26904464]
7.
Tuohy E, Litt E, Alikhan R. Treatment of patients with von Willebrand disease. J Blood Med. 2011;2:49-57. [PMC free article: PMC3262353] [PubMed: 22287863]
8.
Franchini M, Lippi G. The use of desmopressin in acquired haemophilia A: a systematic review. Blood Transfus. 2011 Oct;9(4):377-82. [PMC free article: PMC3200405] [PubMed: 21839010]

Physiology, Vasopressin – StatPearls – NCBI Bookshelf

Introduction

Vasopressin or antidiuretic hormone (ADH) or arginine vasopressin (AVP) is a nonapeptide synthesized in the hypothalamus. Science has known it to play essential roles in the control of the body’s osmotic balance, blood pressure regulation, sodium homeostasis, and kidney functioning. Given its vital role in multiple functions, it is no surprise that ADH is of great clinical significance. ADH primarily affects the ability of the kidney to reabsorb water; when present, ADH induces expression of water transport proteins in the late distal tubule and collecting duct to increase water reabsorption. Several disease states arise when the body loses control of ADH secretion or responds to its presence.[1]

In states of hypovolemia or hypernatremia, ADH is released from the posterior pituitary gland and binds to the type-2 receptor in principal cells of the collecting duct. Binding to the receptor triggers an intracellular cyclic adenosine monophosphate (cAMP) pathway, which causes phosphorylation of the aquaporin-2 (AQP2). After achieving water homeostasis, the ADH levels decrease, and AQP2 is internalized from the plasma membrane, leaving the plasma membrane watertight again.[1]

Cellular

ADH synthesis occurs in the hypothalamus. Specifically, it is principally produced by neurons that have their cell bodies within the supraoptic nuclei of the hypothalamus. There is also production, albeit in smaller quantities, in neurons with cell bodies located in the paraventricular nuclei, the site primarily responsible for oxytocin, a homologous hormone mostly involved in uterine contraction and milk let down. These storage vesicles are transported down the neuron’s axon through the hypothalamic-hypophysial tract, where they are ultimately released in the posterior pituitary. The secreted hormones then enter nearby fenestrated capillaries where they enter the body’s systemic circulation.[1]

Development

ADH is a nonapeptide derived from the preprohormone called prepropressophysin, which contains a signal peptide, neurophysin II, and a glycoprotein. In the Golgi apparatus, the signal peptide portion is cleaved from prepropressophysin to produce a prohormone stored in secretory vesicles. In route to the posterior pituitary where ADH will be released, the prohormone is cleaved to produce ADH.

Organ Systems Involved

  • Kidneys

  • Posterior pituitary

Function

ADH is the primary hormone responsible for tonicity homeostasis. Hyperosmolar states most strongly trigger its release. ADH is stored in neurons within the hypothalamus. These neurons express osmoreceptors that are exquisitely responsive to blood osmolarity and respond to changes as little as two mOsm/L.[2] Therefore, slight elevations in osmolarity result in the secretion of ADH. ADH then acts primarily in the kidneys to increase water reabsorption, thus returning the osmolarity to baseline.

ADH secretion also occurs during states of hypovolemia or volume depletion. In these states, decreased baroreceptors sense arterial blood volume in the left atrium, carotid artery, and aortic arch. Information about low blood pressure sensed by these receptors is transmitted to the vagus nerve, which directly stimulates the release of ADH. ADH then promotes water reabsorption in the kidneys and, at high concentrations, will also cause vasoconstriction. These two mechanisms together serve to increase effective arterial blood volume and increase blood pressure to maintain tissue perfusion. It is also important to note that in states of hypovolemia, ADH will be secreted even in hypoosmotic states. Conversely, hypervolemia inhibits ADH secretion; therefore, in hyperosmotic hypervolemic states, ADH secretion will be reduced.[1]

Osmolarity and volume status are the two greatest factors that affect ADH secretion. However, a variety of other factors promote ADH secretion as well. These include angiotensin II, pain, nausea, hypoglycemia, nicotine, opiates, and certain medications. ADH secretion is also negatively affected by ethanol, alpha-adrenergic agonists, and atrial natriuretic peptide. Ethanol’s inhibitory effect helps to explain the increased diuresis experienced during intoxicated states as well as increased free water loss; without appropriate ADH secretion, the kidneys excrete more water.[3]

Mechanism

ADH principally exerts its effects by binding to the kidneys principal cells within the late distal tubule and collecting ducts. ADH binds to the V receptor on these cells and leads to the activation of adenylate cyclase, which causes a subsequent increase in the second messenger cyclic AMP (cAMP). cAMP activates protein kinase A (PKA), a phosphorylating enzyme that initiates an intracellular phosphorylation cascade. Ultimately, intracellular aquaporin-2 (AQP2) storage vesicles are phosphorylated, which promotes their movement and insertion into the apical membrane. AQP2 is a water channel that allows water to move passively into the cell guided by the osmotic gradient established by NaCl and urea, and thus promotes reabsorption of water in the kidney. This activity creates concentrated, or hyperosmotic, urine, and allows our body to conserve water in times of dehydration or loss of sufficient blood volume, as seen in hemorrhagic or edematous states.[1]

ADH also has a second action on vascular smooth muscle. ADH binds to V receptors on vascular smooth muscle and activates G protein. G activates phospholipase C (PLC), which results in the production of inositol triphosphate (IP-3) as well as diacylglycerol (DAG) from the cell membrane. IP-3 causes a release of intracellular calcium from the endoplasmic reticulum. DAG and calcium activate protein kinase C (PKC), which, like PKA, results in a signaling phosphorylation cascade. The net effect of this signaling cascade is a contraction of vascular smooth muscle leading to increases in total peripheral resistance and thus increases in blood pressure. This mechanism is synergistic with water reabsorption in that both mechanisms elevate blood pressure. This mechanism is crucial in periods where sufficient arterial blood volume is low to maintain tissue perfusion.[1]

Related Testing

The laboratory values commonly used to diagnose conditions associated with ADH abnormalities include serum osmolality, urine osmolality, urine electrolytes, thyroid function tests, cortisol levels, liver function tests, and serum uric acid.   

Pathophysiology

There are three pathologic states related to ADH. The first is the syndrome of inappropriate ADH (SIADH) and occurs when ADH is released in excessive unregulated quantities. SIADH results in excess water reabsorption and thus creates dilutional hyponatremia. Although water is retained in quantities greater than the body’s needs, these patients typically remain euvolemic and do not exhibit features of the third spacing of fluid such as edema. The mechanism behind this is that, regardless of the excess ADH present, the kidneys maintain their ability to excrete salt. As ADH signals for increased water reabsorption, the body senses the increase in extracellular volume, and natriuretic mechanisms come into play that cause increased salt excretion via the kidneys. The increased salt in the urine will osmotically attract water to be excreted as well, thus keeping the body in a euvolemic state. This increase in salt excretion also contributes to the hyponatremia seen in SIADH. Settings in which SIADH arises include malignancies (most often by autonomous production of ADH by small cell lung cancer), central nervous system (CNS) disturbances (e.g., stroke, hemorrhage, infection, trauma, etc.), drugs (e.g., selective serotonin reuptake inhibitors, carbamazepine, and others), surgery (most likely secondary to pain), and more. Patients with SIADH may be asymptomatic or present with a spectrum of severity of complaints based on their level of hyponatremia. Nausea and malaise are typically the earliest presenting symptoms and present when the sodium acutely falls below 125 to 130 mEq/L. Lower levels of sodium are associated with headache, obtundation, seizure, and even coma and respiratory arrest.[4] These symptoms arise due to the increased movement of water into neurons as the extracellular osmolarity falls. The intracellular swelling causes neuronal dysfunction.[5]

Unlike the excess ADH seen in SIADH, the remaining two pathologic states related to ADH result from either decreased ADH or resistance to its effects. A failure of ADH secretion causes central diabetes insipidus. In this scenario, ADH levels are low; thus, the collecting tubules are impermeable to water, resulting in excess water excretion. In nephrogenic diabetes insipidus, ADH secretion is normal, but there is a defect in the V receptor or other signaling mediators that makes the kidneys unresponsive to ADH. In either disease, the net effect is increased excretion of water. The depletion of water causes the production of large volumes of dilute water and the concentration of body fluids leading to hypernatremia and hyperosmolarity. This status results in polyuria, polydipsia, and the effects of electrolyte imbalances that ensue.[6]

Central diabetes insipidus is the more common form and often seen after brain trauma or surgery that damages either the hypothalamus or posterior pituitary. Other cerebral infiltrative processes such as infection, autoimmune disease, or neoplastic disease may also cause central diabetes insipidus. Nephrogenic diabetes insipidus can be either inherited or acquired. The most common inherited form is attributed to mutations in the V receptor and often manifests in childhood. Acquired causes of nephrogenic diabetes insipidus are more often at play in adulthood expression of the disease. Most often, acquired nephrogenic diabetes insipidus is due to drugs, notably lithium and some antibiotics such as tetracyclines.[6]

Clinical Significance

ADH is an important hormone that is responsible for water, osmolar, and blood pressure homeostasis. Its function is vital in times of thirst, hemorrhage, the third spacing of fluid, and other scenarios where there is the diminution of effective arterial blood flow. Its efforts serve to maintain volume status as well as blood pressure to continue adequate tissue perfusion. Additionally, the pathologic states discussed above are important considerations when working up patients with electrolyte imbalances. SIADH is a common cause of hyponatremia and may be a sign of an underlying occult malignancy when no other risk factor is present. Clinically, SIADH is the diagnosis in a hyponatremic patient who has evidence of decreased plasma osmolarity (less than 275 mOsm/kg), inappropriately concentrated urine (urine osmolarity greater than 100 mOsm/kg), elevated urine sodium (greater than 20 mEq/L), and euvolemia.[5]

Diabetes insipidus is an important cause of hypernatremia. They are distinguished from each other and primary polydipsia, a disease of dysregulated thirst mechanism resulting in excess fluid intake and, therefore, polydipsia and polyuria, by a water deprivation challenge. In this test, a patient’s urine and plasma osmolarity are measured at baseline and then repeatedly measured over a few hours while they are not allowed to drink water. If during this period of water deprivation, their urine osmolarity increases to above 750 mOsm/kg, then primary polydipsia is the diagnosis as this signals the body is adequately releasing ADH in response to a lack of fluid intake. If the urine osmolarity remains low, then this implies an issue with ADH is present, and diabetes insipidus is likely the culprit. To differentiate between nephrogenic and central forms of the disease, during the water deprivation challenge, one may administer desmopressin, an ADH analog. If after desmopressin administration urine osmolarity increases, then central diabetes insipidus is present as this scenario describes a working response ADH. If, however, desmopressin does not increase urine osmolarity, then we know the response to ADH is inappropriate, and it must be nephrogenic diabetes insipidus. This distinction is important to make as the treatment differs between nephrogenic and central diabetes insipidus. The treatment for the central form is to replace the inadequate ADH with desmopressin. In the nephrogenic form, the treatment of choice is thiazide diuretics. Thiazide diuretics act at the distal convoluted tubule to block sodium and chloride cotransport. The increased excretion of sodium chloride induces mild hypovolemia, which triggers increased sodium reabsorption in the proximal convoluted tubule. This increase in sodium reabsorption will promote the increase in passive water reabsorption in the same segment, resulting in a net decrease in water excretion, thus mitigating the polyuria seen in these patients.[6]

Aside from its role in homeostasis and its part in a variety of pathologies, ADH has also served as a medication to treat two important bleeding disorders: von Willebrand disease and hemophilia A. Von Willebrand disease is the most common inherited bleeding disorder in which mutations lead to disruption of the synthesis or function of von Willebrand factor (VWF), the factor that tethers platelets to endothelium by binding collagen on endothelial surface and GpIb on the platelet surface. VWF is a crucial factor in the development of primary hemostasis. Also, VWF plays a role in secondary hemostasis by binding to and stabilizing factor VIII. Desmopressin is used to treat von Willebrand disease as it leads to an increase in the secretion of VWF and factor VIII from endothelium.[7] Hemophilia A is a bleeding disorder owed to either an acquired or inherited lack of factor VIII. As stated, desmopressin also promotes the release of factor VIII from the endothelium, thus bridging the missing gap in hemophilia A’s coagulopathy.[8]

References

1.
Boone M, Deen PM. Physiology and pathophysiology of the vasopressin-regulated renal water reabsorption. Pflugers Arch. 2008 Sep;456(6):1005-24. [PMC free article: PMC2518081] [PubMed: 18431594]
2.
Davies AG. Antidiuretic and growth hormones. Br Med J. 1972 Apr 29;2(5808):282-4. [PMC free article: PMC1789001] [PubMed: 4553816]
3.
Schrier RW, Bichet DG. Osmotic and nonosmotic control of vasopressin release and the pathogenesis of impaired water excretion in adrenal, thyroid, and edematous disorders. J Lab Clin Med. 1981 Jul;98(1):1-15. [PubMed: 7019365]
4.
Sterns RH. Disorders of plasma sodium–causes, consequences, and correction. N Engl J Med. 2015 Jan 01;372(1):55-65. [PubMed: 25551526]
5.
Pillai BP, Unnikrishnan AG, Pavithran PV. Syndrome of inappropriate antidiuretic hormone secretion: Revisiting a classical endocrine disorder. Indian J Endocrinol Metab. 2011 Sep;15 Suppl 3:S208-15. [PMC free article: PMC3183532] [PubMed: 22029026]
6.
Kalra S, Zargar AH, Jain SM, Sethi B, Chowdhury S, Singh AK, Thomas N, Unnikrishnan AG, Thakkar PB, Malve H. Diabetes insipidus: The other diabetes. Indian J Endocrinol Metab. 2016 Jan-Feb;20(1):9-21. [PMC free article: PMC4743391] [PubMed: 26904464]
7.
Tuohy E, Litt E, Alikhan R. Treatment of patients with von Willebrand disease. J Blood Med. 2011;2:49-57. [PMC free article: PMC3262353] [PubMed: 22287863]
8.
Franchini M, Lippi G. The use of desmopressin in acquired haemophilia A: a systematic review. Blood Transfus. 2011 Oct;9(4):377-82. [PMC free article: PMC3200405] [PubMed: 21839010]

Physiology, Vasopressin – StatPearls – NCBI Bookshelf

Introduction

Vasopressin or antidiuretic hormone (ADH) or arginine vasopressin (AVP) is a nonapeptide synthesized in the hypothalamus. Science has known it to play essential roles in the control of the body’s osmotic balance, blood pressure regulation, sodium homeostasis, and kidney functioning. Given its vital role in multiple functions, it is no surprise that ADH is of great clinical significance. ADH primarily affects the ability of the kidney to reabsorb water; when present, ADH induces expression of water transport proteins in the late distal tubule and collecting duct to increase water reabsorption. Several disease states arise when the body loses control of ADH secretion or responds to its presence.[1]

In states of hypovolemia or hypernatremia, ADH is released from the posterior pituitary gland and binds to the type-2 receptor in principal cells of the collecting duct. Binding to the receptor triggers an intracellular cyclic adenosine monophosphate (cAMP) pathway, which causes phosphorylation of the aquaporin-2 (AQP2). After achieving water homeostasis, the ADH levels decrease, and AQP2 is internalized from the plasma membrane, leaving the plasma membrane watertight again.[1]

Cellular

ADH synthesis occurs in the hypothalamus. Specifically, it is principally produced by neurons that have their cell bodies within the supraoptic nuclei of the hypothalamus. There is also production, albeit in smaller quantities, in neurons with cell bodies located in the paraventricular nuclei, the site primarily responsible for oxytocin, a homologous hormone mostly involved in uterine contraction and milk let down. These storage vesicles are transported down the neuron’s axon through the hypothalamic-hypophysial tract, where they are ultimately released in the posterior pituitary. The secreted hormones then enter nearby fenestrated capillaries where they enter the body’s systemic circulation.[1]

Development

ADH is a nonapeptide derived from the preprohormone called prepropressophysin, which contains a signal peptide, neurophysin II, and a glycoprotein. In the Golgi apparatus, the signal peptide portion is cleaved from prepropressophysin to produce a prohormone stored in secretory vesicles. In route to the posterior pituitary where ADH will be released, the prohormone is cleaved to produce ADH.

Organ Systems Involved

  • Kidneys

  • Posterior pituitary

Function

ADH is the primary hormone responsible for tonicity homeostasis. Hyperosmolar states most strongly trigger its release. ADH is stored in neurons within the hypothalamus. These neurons express osmoreceptors that are exquisitely responsive to blood osmolarity and respond to changes as little as two mOsm/L.[2] Therefore, slight elevations in osmolarity result in the secretion of ADH. ADH then acts primarily in the kidneys to increase water reabsorption, thus returning the osmolarity to baseline.

ADH secretion also occurs during states of hypovolemia or volume depletion. In these states, decreased baroreceptors sense arterial blood volume in the left atrium, carotid artery, and aortic arch. Information about low blood pressure sensed by these receptors is transmitted to the vagus nerve, which directly stimulates the release of ADH. ADH then promotes water reabsorption in the kidneys and, at high concentrations, will also cause vasoconstriction. These two mechanisms together serve to increase effective arterial blood volume and increase blood pressure to maintain tissue perfusion. It is also important to note that in states of hypovolemia, ADH will be secreted even in hypoosmotic states. Conversely, hypervolemia inhibits ADH secretion; therefore, in hyperosmotic hypervolemic states, ADH secretion will be reduced.[1]

Osmolarity and volume status are the two greatest factors that affect ADH secretion. However, a variety of other factors promote ADH secretion as well. These include angiotensin II, pain, nausea, hypoglycemia, nicotine, opiates, and certain medications. ADH secretion is also negatively affected by ethanol, alpha-adrenergic agonists, and atrial natriuretic peptide. Ethanol’s inhibitory effect helps to explain the increased diuresis experienced during intoxicated states as well as increased free water loss; without appropriate ADH secretion, the kidneys excrete more water.[3]

Mechanism

ADH principally exerts its effects by binding to the kidneys principal cells within the late distal tubule and collecting ducts. ADH binds to the V receptor on these cells and leads to the activation of adenylate cyclase, which causes a subsequent increase in the second messenger cyclic AMP (cAMP). cAMP activates protein kinase A (PKA), a phosphorylating enzyme that initiates an intracellular phosphorylation cascade. Ultimately, intracellular aquaporin-2 (AQP2) storage vesicles are phosphorylated, which promotes their movement and insertion into the apical membrane. AQP2 is a water channel that allows water to move passively into the cell guided by the osmotic gradient established by NaCl and urea, and thus promotes reabsorption of water in the kidney. This activity creates concentrated, or hyperosmotic, urine, and allows our body to conserve water in times of dehydration or loss of sufficient blood volume, as seen in hemorrhagic or edematous states.[1]

ADH also has a second action on vascular smooth muscle. ADH binds to V receptors on vascular smooth muscle and activates G protein. G activates phospholipase C (PLC), which results in the production of inositol triphosphate (IP-3) as well as diacylglycerol (DAG) from the cell membrane. IP-3 causes a release of intracellular calcium from the endoplasmic reticulum. DAG and calcium activate protein kinase C (PKC), which, like PKA, results in a signaling phosphorylation cascade. The net effect of this signaling cascade is a contraction of vascular smooth muscle leading to increases in total peripheral resistance and thus increases in blood pressure. This mechanism is synergistic with water reabsorption in that both mechanisms elevate blood pressure. This mechanism is crucial in periods where sufficient arterial blood volume is low to maintain tissue perfusion.[1]

Related Testing

The laboratory values commonly used to diagnose conditions associated with ADH abnormalities include serum osmolality, urine osmolality, urine electrolytes, thyroid function tests, cortisol levels, liver function tests, and serum uric acid.   

Pathophysiology

There are three pathologic states related to ADH. The first is the syndrome of inappropriate ADH (SIADH) and occurs when ADH is released in excessive unregulated quantities. SIADH results in excess water reabsorption and thus creates dilutional hyponatremia. Although water is retained in quantities greater than the body’s needs, these patients typically remain euvolemic and do not exhibit features of the third spacing of fluid such as edema. The mechanism behind this is that, regardless of the excess ADH present, the kidneys maintain their ability to excrete salt. As ADH signals for increased water reabsorption, the body senses the increase in extracellular volume, and natriuretic mechanisms come into play that cause increased salt excretion via the kidneys. The increased salt in the urine will osmotically attract water to be excreted as well, thus keeping the body in a euvolemic state. This increase in salt excretion also contributes to the hyponatremia seen in SIADH. Settings in which SIADH arises include malignancies (most often by autonomous production of ADH by small cell lung cancer), central nervous system (CNS) disturbances (e.g., stroke, hemorrhage, infection, trauma, etc.), drugs (e.g., selective serotonin reuptake inhibitors, carbamazepine, and others), surgery (most likely secondary to pain), and more. Patients with SIADH may be asymptomatic or present with a spectrum of severity of complaints based on their level of hyponatremia. Nausea and malaise are typically the earliest presenting symptoms and present when the sodium acutely falls below 125 to 130 mEq/L. Lower levels of sodium are associated with headache, obtundation, seizure, and even coma and respiratory arrest.[4] These symptoms arise due to the increased movement of water into neurons as the extracellular osmolarity falls. The intracellular swelling causes neuronal dysfunction.[5]

Unlike the excess ADH seen in SIADH, the remaining two pathologic states related to ADH result from either decreased ADH or resistance to its effects. A failure of ADH secretion causes central diabetes insipidus. In this scenario, ADH levels are low; thus, the collecting tubules are impermeable to water, resulting in excess water excretion. In nephrogenic diabetes insipidus, ADH secretion is normal, but there is a defect in the V receptor or other signaling mediators that makes the kidneys unresponsive to ADH. In either disease, the net effect is increased excretion of water. The depletion of water causes the production of large volumes of dilute water and the concentration of body fluids leading to hypernatremia and hyperosmolarity. This status results in polyuria, polydipsia, and the effects of electrolyte imbalances that ensue.[6]

Central diabetes insipidus is the more common form and often seen after brain trauma or surgery that damages either the hypothalamus or posterior pituitary. Other cerebral infiltrative processes such as infection, autoimmune disease, or neoplastic disease may also cause central diabetes insipidus. Nephrogenic diabetes insipidus can be either inherited or acquired. The most common inherited form is attributed to mutations in the V receptor and often manifests in childhood. Acquired causes of nephrogenic diabetes insipidus are more often at play in adulthood expression of the disease. Most often, acquired nephrogenic diabetes insipidus is due to drugs, notably lithium and some antibiotics such as tetracyclines.[6]

Clinical Significance

ADH is an important hormone that is responsible for water, osmolar, and blood pressure homeostasis. Its function is vital in times of thirst, hemorrhage, the third spacing of fluid, and other scenarios where there is the diminution of effective arterial blood flow. Its efforts serve to maintain volume status as well as blood pressure to continue adequate tissue perfusion. Additionally, the pathologic states discussed above are important considerations when working up patients with electrolyte imbalances. SIADH is a common cause of hyponatremia and may be a sign of an underlying occult malignancy when no other risk factor is present. Clinically, SIADH is the diagnosis in a hyponatremic patient who has evidence of decreased plasma osmolarity (less than 275 mOsm/kg), inappropriately concentrated urine (urine osmolarity greater than 100 mOsm/kg), elevated urine sodium (greater than 20 mEq/L), and euvolemia.[5]

Diabetes insipidus is an important cause of hypernatremia. They are distinguished from each other and primary polydipsia, a disease of dysregulated thirst mechanism resulting in excess fluid intake and, therefore, polydipsia and polyuria, by a water deprivation challenge. In this test, a patient’s urine and plasma osmolarity are measured at baseline and then repeatedly measured over a few hours while they are not allowed to drink water. If during this period of water deprivation, their urine osmolarity increases to above 750 mOsm/kg, then primary polydipsia is the diagnosis as this signals the body is adequately releasing ADH in response to a lack of fluid intake. If the urine osmolarity remains low, then this implies an issue with ADH is present, and diabetes insipidus is likely the culprit. To differentiate between nephrogenic and central forms of the disease, during the water deprivation challenge, one may administer desmopressin, an ADH analog. If after desmopressin administration urine osmolarity increases, then central diabetes insipidus is present as this scenario describes a working response ADH. If, however, desmopressin does not increase urine osmolarity, then we know the response to ADH is inappropriate, and it must be nephrogenic diabetes insipidus. This distinction is important to make as the treatment differs between nephrogenic and central diabetes insipidus. The treatment for the central form is to replace the inadequate ADH with desmopressin. In the nephrogenic form, the treatment of choice is thiazide diuretics. Thiazide diuretics act at the distal convoluted tubule to block sodium and chloride cotransport. The increased excretion of sodium chloride induces mild hypovolemia, which triggers increased sodium reabsorption in the proximal convoluted tubule. This increase in sodium reabsorption will promote the increase in passive water reabsorption in the same segment, resulting in a net decrease in water excretion, thus mitigating the polyuria seen in these patients.[6]

Aside from its role in homeostasis and its part in a variety of pathologies, ADH has also served as a medication to treat two important bleeding disorders: von Willebrand disease and hemophilia A. Von Willebrand disease is the most common inherited bleeding disorder in which mutations lead to disruption of the synthesis or function of von Willebrand factor (VWF), the factor that tethers platelets to endothelium by binding collagen on endothelial surface and GpIb on the platelet surface. VWF is a crucial factor in the development of primary hemostasis. Also, VWF plays a role in secondary hemostasis by binding to and stabilizing factor VIII. Desmopressin is used to treat von Willebrand disease as it leads to an increase in the secretion of VWF and factor VIII from endothelium.[7] Hemophilia A is a bleeding disorder owed to either an acquired or inherited lack of factor VIII. As stated, desmopressin also promotes the release of factor VIII from the endothelium, thus bridging the missing gap in hemophilia A’s coagulopathy.[8]

References

1.
Boone M, Deen PM. Physiology and pathophysiology of the vasopressin-regulated renal water reabsorption. Pflugers Arch. 2008 Sep;456(6):1005-24. [PMC free article: PMC2518081] [PubMed: 18431594]
2.
Davies AG. Antidiuretic and growth hormones. Br Med J. 1972 Apr 29;2(5808):282-4. [PMC free article: PMC1789001] [PubMed: 4553816]
3.
Schrier RW, Bichet DG. Osmotic and nonosmotic control of vasopressin release and the pathogenesis of impaired water excretion in adrenal, thyroid, and edematous disorders. J Lab Clin Med. 1981 Jul;98(1):1-15. [PubMed: 7019365]
4.
Sterns RH. Disorders of plasma sodium–causes, consequences, and correction. N Engl J Med. 2015 Jan 01;372(1):55-65. [PubMed: 25551526]
5.
Pillai BP, Unnikrishnan AG, Pavithran PV. Syndrome of inappropriate antidiuretic hormone secretion: Revisiting a classical endocrine disorder. Indian J Endocrinol Metab. 2011 Sep;15 Suppl 3:S208-15. [PMC free article: PMC3183532] [PubMed: 22029026]
6.
Kalra S, Zargar AH, Jain SM, Sethi B, Chowdhury S, Singh AK, Thomas N, Unnikrishnan AG, Thakkar PB, Malve H. Diabetes insipidus: The other diabetes. Indian J Endocrinol Metab. 2016 Jan-Feb;20(1):9-21. [PMC free article: PMC4743391] [PubMed: 26904464]
7.
Tuohy E, Litt E, Alikhan R. Treatment of patients with von Willebrand disease. J Blood Med. 2011;2:49-57. [PMC free article: PMC3262353] [PubMed: 22287863]
8.
Franchini M, Lippi G. The use of desmopressin in acquired haemophilia A: a systematic review. Blood Transfus. 2011 Oct;9(4):377-82. [PMC free article: PMC3200405] [PubMed: 21839010]

Vasopressin – an overview | ScienceDirect Topics

Vasopressin

Vasopressin is a hormone of the posterior pituitary that is secreted in response to high serum osmolarity. Excitation of atrial stretch receptors inhibits vasopressin secretion. Vasopressin is also released in response to stress, inflammatory signals, and some medications. Hypotension, morphine, nicotine, angiotensin II, glucocorticoids, and IL-6 all stimulate release of vasopressin.2 Circulating vasopressin levels are usually high in the early phase of septic shock, but vasopressin deficiency as been described in vasodilatory shock states in both adults and children.34,35 The level of vasopressin that is normal in the late phase of sepsis is unclear.36

In general, vasopressin decreases water excretion by the kidneys by increasing water reabsorption in the collecting ducts, hence its other name of antidiuretic hormone. Vasopressin also has a potent constricting effect on arterioles throughout the body.6 Vasopressin potentiates ACTH release leading to cortisol release, which may contribute to its salutary effects in cardiac arrest and vasodilatory shock.2 Vasopressin has been proposed as a replacement or adjunct to epinephrine in the resuscitation of cardiac arrest and of catecholamine-unresponsive shock. The interest in vasopressin for resuscitation is based on the fact that vasopressin may increase coronary perfusion without increasing myocardial oxygen demand and without the arrhythmogenic effects of epinephrine. Also, repeated doses of vasopressin tend to support blood pressure after the epinephrine response wanes.37 When given as the first drug in cardiac arrest, vasopressin has been shown to confer a survival advantage in out-of-hospital arrest but not in arrests occurring in stressed, hospitalized patients.38,39 Vasopressin’s effects on NEI mediators may explain this discrepancy. In a person with normal adrenal reserves of cortisol, exogenous vasopressin may cause a surge of endogenous cortisol, which should improve catecholamine responsiveness. Hospitalized patients with decreased adrenal reserves may not experience this benefit of vasopressin.

Vasopressin is a powerful vasoconstrictor, even in patients with catecholamine unresponsiveness. Because vasopressin dilates the pulmonary, cerebral, and myocardial circulations, it may help to preserve vital organ blood flow. Vasopressin and its synthetic analogue, terlipressin, have also been used as a rescue therapy for severe shock. Case series of the use of vasopressin in patients with catecholamine refractory shock have described the use of doses in the range of 0.00001 to 0.08 units/kg/min.40-43 Vasopressin has also been used as a catecholamine-sparing hormone replacement, with a goal of restoring high-normal levels rather than titrating to clinical effect. A recent, large, randomized controlled trial of low-dose vasopressin infusion in adult patients found a good safety profile but no impact on mortality when compared with norepinephrine alone.44 The only pediatric randomized controlled trial so far showed used a dose of 0.0005 units/kg/min, similar to adult trials, and found an increase in mean arterial pressure but no differences in time to hemodynamic stability or other clinical outcomes.45

High doses of vasopressin are associated with unacceptable side effects, such as gut and digital ischemia and decreased urine output. However, several small clinical studies have suggested that these problems do not occur at physiologic doses.

Vasopressin has effects on the immune system independent of its effect in stimulating the HPA axis. When given intraventricularly to rats, vasopressin decreases the T-cell response to mitogen independently of the HPA axis, probably via the sympathetic nervous system.46 Like CRH, vasopressin stimulates immune responses in peripheral tissues. Circulating or local vasopressin enhances lymphocyte reactions and potentiates primary antibody responses.47 Elevated vasopressin levels are found in a mouse model of autoimmune disease, and antibody neutralization ameliorates the inflammatory response in these mice.2 Vasopressin can potentiate the release of prolactin, a proinflammatory peptide hormone.48

Because vasopressin has immunosuppressive effects when present in the central nervous system and immunosupportive effects when present in peripheral tissues, predicting which effect would predominate during vasopressin infusion in the ICU is difficult.

Vasopressin and its role in critical care | BJA Education

Vasopressin or antidiuretic hormone is a potent endogenous hormone which is responsible for regulating plasma osmolality and volume. It acts as a neurotransmitter in the brain to control circadian rhythm, thermoregulation, and adrenocorticotrophic hormone release (ACTH). The therapeutic use of vasopressin has become increasingly important in the critical care environment in the management of cranial diabetes insipidus, bleeding abnormalities, oesophageal variceal haemorrhage, asystolic cardiac arrest, and septic shock.

Physiology

Vasopressin is a nonapeptide, synthesized as a pro-hormone in magnocellular neurone cell bodies of the paraventricular and supraoptic nuclei of the posterior hypothalamus. It is bound to a carrier protein, neurohypophysin, and transported along the supraoptic hypophyseal tract to the axonal terminals of magnocellular neurones located in the posterior pituitary. Synthesis, transport, and storage takes 1–2 h. Normal plasma concentrations are <4 pg ml−1. It has a half-life of 10–35 min, being metabolized by vasopressinases which are found in the liver and kidney. Vasopressin acts on V1, V2, V3, and oxytocin-type receptors (OTR).

V1 receptors are found on vascular smooth muscle of the systemic, splanchnic, renal, and coronary circulations. They are also located on myometrium and platelets. These G-protein- coupled receptors activate phospholipase C via Gq G-protein, which ultimately leads to an increase in intracellular calcium. The major effect is to induce vasoconstriction, the magnitude of which is dependent on the vascular bed. In the pulmonary circulation, vasodilation is produced via nitric oxide release.

V2 receptors are predominantly located in the distal tubule and collecting ducts of the kidney. These G-protein-coupled receptors stimulate Gs G-protein to activate adenylate cyclase, increasing CAMP, causing the mobilization of aquaporin channels. These channels insert into the apical membrane of the distal tubules and collecting duct cells. V2 receptors are essential for plasma volume and osmolality control. Their presence on endothelial cells induces the release of Von Willebrand Factor (VWF) and Factor VIII:coagulant (FVIII:c). VWF protects FVIII from breakdown in plasma and is important in binding platelets to the site of bleeding.

V3 receptors are found mainly in the pituitary. They are Gq-coupled G-protein receptors which increase intracellular calcium when activated. They are thought to be involved in ACTH release and may act as a neurotransmitter or mediator involved with memory consolidation or retrieval and body temperature regulation.1, 2

Vasopressin has equal affinity for OTR as oxytocin. Activation of these receptors raises intracellular calcium via the phospholipase C and phosphoinositide pathway. They are found predominantly on myometrium and vascular smooth muscle. In addition, they are located on vascular endothelial cells where they increase constitutive endothelial nitric oxide synthase activity, increasing nitric oxide, which is a potent vasodilator. It is postulated that OTR placement on vascular endothelium and their subsequent activation may account for vasopressin’s selective response on different vascular beds. V1 and V2 receptors located on the vascular endothelium may also have a role by increasing NO production.3

Control of release

Table 1 illustrates the factors which affect the release of vasopressin. Most factors (physical or chemical) cause direct stimulation of vasopressin release. Hypoxaemia and acidosis stimulate the carotid body chemoreceptors causing vasopressin release. Catecholamine stimulation of central adrenergic receptors has a variety of effects on vasopressin release. At low concentration, catecholamines activate α1 receptors inducing vasopressin release. At higher concentration, their actions on α2 and β receptors inhibit vasopressin release.3

Table 1

The major factors involved in the release of vasopressin from the posterior pituitary. *Norepinephrine can stimulate release by α1 receptors and inhibit release by stimulation of α2 and β receptors

Stimulate release
Inhibit release
Increasing plasma osmolality  Decreasing plasma osmolality 
Reduced plasma volume  Increased plasma volume 
Chemical mediators  Chemical mediators 
 Norepinephrine*, dopamine, acetylcholine, histamine, prostaglandins, angiotensin II, endotoxin, cytokines   Opioids, GABA, ANP, norepinephrine* 
Nausea, vomiting   
Pain, Stress   
Hypoxia, ↑Paco2, acidosis   
Exercise, IPPV   
Stimulate release
Inhibit release
Increasing plasma osmolality  Decreasing plasma osmolality 
Reduced plasma volume  Increased plasma volume 
Chemical mediators  Chemical mediators 
 Norepinephrine*, dopamine, acetylcholine, histamine, prostaglandins, angiotensin II, endotoxin, cytokines   Opioids, GABA, ANP, norepinephrine* 
Nausea, vomiting   
Pain, Stress   
Hypoxia, ↑Paco2, acidosis   
Exercise, IPPV   

Table 1

The major factors involved in the release of vasopressin from the posterior pituitary. *Norepinephrine can stimulate release by α1 receptors and inhibit release by stimulation of α2 and β receptors

Stimulate release
Inhibit release
Increasing plasma osmolality  Decreasing plasma osmolality 
Reduced plasma volume  Increased plasma volume 
Chemical mediators  Chemical mediators 
 Norepinephrine*, dopamine, acetylcholine, histamine, prostaglandins, angiotensin II, endotoxin, cytokines   Opioids, GABA, ANP, norepinephrine* 
Nausea, vomiting   
Pain, Stress   
Hypoxia, ↑Paco2, acidosis   
Exercise, IPPV   
Stimulate release
Inhibit release
Increasing plasma osmolality  Decreasing plasma osmolality 
Reduced plasma volume  Increased plasma volume 
Chemical mediators  Chemical mediators 
 Norepinephrine*, dopamine, acetylcholine, histamine, prostaglandins, angiotensin II, endotoxin, cytokines   Opioids, GABA, ANP, norepinephrine* 
Nausea, vomiting   
Pain, Stress   
Hypoxia, ↑Paco2, acidosis   
Exercise, IPPV   

The most potent stimulus for vasopressin release is an increased plasma osmolality. Central osmoreceptors in the subfornical organ nuclei, located outside the blood–brain barrier, monitor systemic plasma osmolality. Peripheral osmoreceptors are found in the portal veins and give early warning of ingested food and fluid osmolality. Signals are transmitted via the vagus to the nucleus tractus solitarius, area postrema, and ventrolateral medulla, and finally to the paraventricular nuclei and supraoptic nuclei, where vasopressin is manufactured in the magnocellular neurone cell bodies. Osmolality is finely controlled in the range of 275–290 mOsm kg−1. A 2% decrease in total body water results in a doubling of the vasopressin plasma concentration. This acts on V2 receptors increasing the collecting duct permeability to water. Conversely, a 2% increase in total body water will result in maximal suppression of vasopressin release and maximally dilute urine of 100 mOsm kg−1.

Plasma volume and the resultant change in arterial pressure are less sensitive controllers of vasopressin release, but the potential response far exceeds that induced by changes in plasma osmolality. A 20–30% reduction in mean arterial pressure (MAP) is needed to induce a response. This results in a reduced arterial baroreceptor output causing an exponential increase in vasopressin release. The response to a reduction in plasma volume and its effect on vasopressin release is not well defined but is probably qualitatively and quantitatively similar. An 8–10% reduction in plasma volume, detected by atrial stretch receptors, is required to induce an exponential increase in vasopressin release. A reduction in plasma volume increases the sensitivity of the osmoreceptors and vice versa. However, as the plasma volume decreases, it becomes increasingly difficult to maintain a normal plasma osmolality. The defence of plasma volume always takes precedence over plasma osmolality. Less is known about acute elevations in arterial pressure and volume, but both appear to suppress vasopressin release.4

Pharmacology

In most mammals, 8-arginine vasopressin is the native antidiuretic hormone. Original preparations were extracted from posterior pituitary cells (Fig. 1). It is now made as a synthetic peptide, argipressin. It is metabolized in a way similar to endogenous vasopressin and has a half-life of 24 min.

Fig. 1

The structure of vasopressin (8-arginine-vasopressin) which is the exact synthetic protein of human endogenous vasopressin is shown. Terlipressin (triglycyl-lysine-vasopressin) is a prodrug requiring the enzymic cleavage of the three glycyl residues to form the active lysine vasopressin found naturally in pigs. Desmopressin, DDAVP, is an arginine vasopressin analogue.

Fig. 1

The structure of vasopressin (8-arginine-vasopressin) which is the exact synthetic protein of human endogenous vasopressin is shown. Terlipressin (triglycyl-lysine-vasopressin) is a prodrug requiring the enzymic cleavage of the three glycyl residues to form the active lysine vasopressin found naturally in pigs. Desmopressin, DDAVP, is an arginine vasopressin analogue.

Tri-glycyl-lysine-vasopressin is terlipressin or glypressin. Arginine is replaced with lysine at position 8 and has three glycine residues at the beginning of the peptide. The lysine substitution makes it identical to pig vasopressin. The three glycine residues make terlipressin a prodrug. In the body, these are enzymatically cleaved by endothelial peptidases to produce lysine vasopressin. It has an elimination half-life of 50 min, but an effect half-life of 6 h.

Desmopressin (1-deamino-8-O-arginine-vasopressin, DDAVP) is a synthetic analogue of arginine vasopressin. It has 10 times the antidiuretic action of vasopressin, but 1500 times less vasoconstrictor action. These modifications make metabolism slower (half-life of 158 min).

Therapeutic uses

Cranial diabetes insipidus

The causes of diabetes insipidus are listed in Table 2. In cranial diabetes insipidus, there is a lack of vasopressin due to destruction of part or all of the hypothalamus or pituitary gland. This is in contrast to nephrogenic diabetes insipidus where there is a resistance of the kidney to vasopressin’s action. Clinically, the patient produces vast quantities of dilute urine. The key feature is that urine osmolality is inappropriately low compared with the plasma osmolality. Desmopressin (DDAVP) can reduce the polyuria, nocturia, and polydypsia. It is given nasally, sublingually, i.m., or if in critical care setting, i.v..

Table 2

The causes of diabetes insipidus

Cranial
Nephrogenic
Familial  Familial 
Idiopathic  Idiopathic 
 Neurosurgery   
Tumours   
 Craniopharyngioma; hypothalamic gliomas; metastases, e.g. breast; lymphoma/leukaemia  Renal tubular acidosis; hypokalaemia; hypercalcaemia 
Infections  Drugs 
 Tuberculosis; meningitis; cerebral abscess   Lithuim; glibenclamide; demeclocycline 
Infiltrations   
 Sarcoidosis   
Vascular   
 Haemorrhage; aneurysms; thrombosis   
Trauma   
 Head injury   
Cranial
Nephrogenic
Familial  Familial 
Idiopathic  Idiopathic 
 Neurosurgery   
Tumours   
 Craniopharyngioma; hypothalamic gliomas; metastases, e.g. breast; lymphoma/leukaemia  Renal tubular acidosis; hypokalaemia; hypercalcaemia 
Infections  Drugs 
 Tuberculosis; meningitis; cerebral abscess   Lithuim; glibenclamide; demeclocycline 
Infiltrations   
 Sarcoidosis   
Vascular   
 Haemorrhage; aneurysms; thrombosis   
Trauma   
 Head injury   

Table 2

The causes of diabetes insipidus

Cranial
Nephrogenic
Familial  Familial 
Idiopathic  Idiopathic 
 Neurosurgery   
Tumours   
 Craniopharyngioma; hypothalamic gliomas; metastases, e.g. breast; lymphoma/leukaemia  Renal tubular acidosis; hypokalaemia; hypercalcaemia 
Infections  Drugs 
 Tuberculosis; meningitis; cerebral abscess   Lithuim; glibenclamide; demeclocycline 
Infiltrations   
 Sarcoidosis   
Vascular   
 Haemorrhage; aneurysms; thrombosis   
Trauma   
 Head injury   
Cranial
Nephrogenic
Familial  Familial 
Idiopathic  Idiopathic 
 Neurosurgery   
Tumours   
 Craniopharyngioma; hypothalamic gliomas; metastases, e.g. breast; lymphoma/leukaemia  Renal tubular acidosis; hypokalaemia; hypercalcaemia 
Infections  Drugs 
 Tuberculosis; meningitis; cerebral abscess   Lithuim; glibenclamide; demeclocycline 
Infiltrations   
 Sarcoidosis   
Vascular   
 Haemorrhage; aneurysms; thrombosis   
Trauma   
 Head injury   

Syndrome of inappropriate antidiuretic hormone

The syndrome of inappropriate antidiuretic hormone is a form of hyponatraemia where the level of antidiuretic hormone is inappropriate to the osmotic or volume stimuli, almost a reverse of cranial diabetes insipidus. The causes can be grouped into ectopic secretion by tumours, particularly small cell carcinoma of the lung, central nervous system disorders, including tumours, infection, and trauma, and pulmonary lesions, mainly infections and drugs, for example, carbamazepine. There are strict diagnostic criteria which include the need for normovolaemia, normal endocrine, cardiac, and liver function, in the presence of urinary osmolality greater than plasma osmolality. Treatment is the correction of hyponatraemia appropriate to the speed of onset and eradication of the underlying cause.

Bleeding abnormalities

Vasopressin acts via extra-renal V2 receptors to increase predominantly FVIII:c and VWF. These actions are very useful in certain types of Von Willebrand disease and in mild forms of haemophilia A, where there is a relative deficiency of FVIII:c. Likewise, in patients with impaired platelet function due to drugs such as aspirin or renal failure, DDAVP (0.3 µg kg−1 i.v. over 15–30 min) may be useful before minor surgical procedures. The exact mechanism of its effect in these situations is not fully understood, but the increase in FVIII levels which allows activation of FX and the more efficient activation of platelets are all important.5

Oesophageal variceal haemorrhage

In chronic liver disease, fibrosis of the liver results in an increase in portal venous pressure as the mesenteric blood requires increasing pressure to flow through the scarred liver. Eventually, collateral circulation opens up to allow the return of blood to the systemic circulation through shunts. One of these is the intrinsic and extrinsic gastro-oesophageal veins. These veins become increasing dilated, forming varices. Vasopressin, acting via V1 receptors, reduces portal blood flow, portal systemic collateral blood flow, and variceal pressure. Its side-effects include increased peripheral vascular resistance, reduced cardiac output, and decreased coronary blood flow. The combined use of glyceryl trinitrate with vasopressin has been shown to reduce these side-effects. Terlipressin, a prodrug of vasopressin, is more commonly used. A Cochrane review6 found that terlipressin produced a relative risk reduction in mortality from variceal haemorrhage of 34% compared with placebo. The i.v. dose is typically 2 mg 4 hourly.

Asystolic cardiac arrest

Epinephrine has been considered the main drug for resuscitation for over 100 years. Recently, some doubt has been cast over its use. Patients who were sucessfully resuscitated with epinephrine showed increased myocardial oxygen consumption and ventricular arrhythmias, ventilation–perfusion mismatch, and myocardial dysfunction post-resuscitation. In survivors of cardiac arrest, vasopressin levels have been shown to be higher than in those who died. Wenzel and colleagues7 performed a multicentre randomized double-blinded trial in 1186 patients who had an out-of-hospital cardiac arrest. They were randomly assigned to receive either 40 IU of vasopressin or 1 mg of epinephrine during resuscitation. In the asystolic group, significantly more patients reached hospital who received vasopressin, compared with those who received epinephrine (29% vs 20%, P=0.02). In the vasopressin group, 4.7% were discharged from hospital compared with 1.5% in the epinephrine group. Of the 732 patients where spontaneous circulation was not achieved initially, in those who received vasopressin then epinephrine, 25.6% reached hospital and 6.7% were discharged compared with 16.4% and 1.7% of those who received epinephrine alone. There was no difference between the groups in those patients who suffered pulseless electrical activity or ventricular fibrillation cardiac arrests. There is a suggestion that vasopressin may work better than epinephrine in hypoxaemic, acidotic conditions. Other trials have shown a varying response to vasopressin in all forms of cardiac arrest. These differences may be related to poor initial cardiopulmonary resuscitation and prolonged time to advanced life support. The trend suggests a better outcome in the vasopressin groups, if there was delayed or prolonged resuscitation. The use of epinephrine in resuscitation is universal, yet there is a paucity of evidence to show it improves survival in humans. The European resuscitation guidelines state there is insufficient evidence for the use of vasopressin with or instead of epinephrine in any type of cardiac arrest and that further evidence is required.

Septic shock

The cause of hypotension in septic shock is multifactorial. Inappropriate vasodilation compromises organ perfusion. Fluid, vasoconstrictors, and inotropes are usually used to maintain arterial pressure. Norepinephrine is the most commonly used vasoconstrictor. Unfortunately, cardiac and vascular smooth muscle can become resistant, requiring increasing doses of norepinephrine. This produces adverse effects which include increasing tissue oxygen demand, reducing renal and mesenteric blood flow, pulmonary hypertension, and arrhythmias. Vasopressin’s role in maintaining arterial pressure has been investigated in septic shock. Landry and colleagues8 were the first to show vasopressin was inappropriately low in vasodilatory septic shock. In 19 patients with vasodilatory septic shock, vasopressin levels were 3.1 pg ml−1 with systolic arterial pressure (SAP) of 92 mm Hg and cardiac output of 8 litre min−1 (all data are given as mean values). In patients who had cardiogenic shock, vasopressin levels were 22.7 pg ml−1. If an infusion of 0.04 IU min−1 of vasopressin was started, SAP increased from 92 to 146 mm Hg and then decreased when vasopressin was withdrawn. An infusion of 0.01 IU min−1 was shown to increase vasopressin levels into the normal range in these patients suggesting that reduced secretion, not increased metabolism, was the cause of vasopressin deficiency.

Why vasopressin is low in septic shock is open to conjecture. There appears to be a biphasic response. Initially, vasopressin levels are elevated but 6 h after the onset of hypotension levels may be inappropriately low for the degree of hypotension. Possible explanations include exhaustion of stores and autonomic nervous system dysfunction. Large doses of norepinephrine are inhibitory to vasopressin release. Nitric oxide, an inflammatory mediator, may also act on the pituitary to prevent release.4

Numerous case studies and small trials show vasopressin increases arterial pressure in septic shock. The largest randomized prospective controlled study was published in 2003 by Dunser and colleagues.9 In this study, 48 patients with catecholamine-resistant vasodilatory shock were prospectively randomized to receive a combined infusion of vasopressin, 4 IU h−1 (0.066 IU min−1) and norepinephrine or norepinephrine alone to maintain a MAP above 70 mm Hg. The vasopressin group showed a significant increase in MAP, cardiac index, systemic vascular resistance index, and left-ventricular stroke work index as well as reduced norepinephrine requirements and heart rates. Compared with the norepinephrine group, there was better preservation of gut mucosal blood flow and a significantly lower incidence of tachyarrhythmias.

In sepsis, there is an increased sensitivity to vasopressin. The theories suggested include increased receptor density as endogenous vasopressin levels are reduced and alteration in receptor expression on different vascular beds with possible changes in signal transduction. Vasopressin and norepinephrine are believed to have a synergistic action when used together. Vasopressin increases intracellular calcium, maintaining vascular tone when norepinephrine receptor sensitivity is reduced. In endotoxic shock, excessive activation of potassium-sensitive ATP channels causes increased potassium conductance leading to the closure of voltage-gated calcium channels and the reduction in vascular tone. Vasopressin blocks these potassium-sensitive ATP channels, restoring vascular tone. The additional action on other hormone systems like cortisol and endothelin1 may also play a role in the maintenance of arterial pressure.

The use of vasopressin is not without side-effects. Myocardial ischaemia may occur, but this effect is limited by avoiding high doses. A varied effect on splanchnic blood flow has been found. At lower doses, a minimal response occurs provided the patients are adequately intravascularly filled. Both the dosage and timing of the use of vasopressin in sepsis are currently under investigation. However, in the literature, a dose range of 0.01–0.04 IU min−1 is commonly used to replace falling vasopressin levels. It is usually started when increasing norepinephrine doses are being used to maintain arterial pressure. It is best administered through central access as extravasations can cause skin necrosis.

The vasopressin and septic shock trial (VASST)10 was the first multicentre, blinded randomized trial comparing low dose vasopressin with norepinephrine in 778 patients with septic shock. The use of vasopressin did not reduce mortality but was shown to be as safe as norepinephrine. Vasopressin is acknowledged as an adjunct vasopressor in the Surviving Sepsis Guidelines and certainly its use is increasing, but further investigations are needed to define its exact role in sepsis related hypotension.

References

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The physiology of vasopresin relevant to the management of septic shock

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993

1001

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33

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© The Board of Management and Trustees of the British Journal of Anaesthesia [2008]. All rights reserved. For Permissions, please email: [email protected]

90,000 Found “genes of infidelity” for men – Gazeta.Ru

Unfaithful men can blame mice. In the latter, mating behavior determines the smell of urine, and in humans, the “infidelity gene” encodes one of the receptors for the “urinary” hormone. Games with him are dangerous: instead of a love potion, you can get a diuretic drug.

For animals and for humans, monogamy is a great way to save material resources. Nevertheless, in the animal kingdom, the attitude towards polygamy is, as a rule, the same for all representatives of the same species.All swans choose for themselves a couple of times and forever, and all males fertilize as many bitches as they can get to.

People got a greater variety – some believe in love to the grave, while others continue to “walk to the left” until the grave. This behavior is rare among animals, and vole mice are one example. Studying the diversity of their sexual behavior, scientists have long established that genes distinguish “swan” mice from “male” mice. More precisely, the gene that encodes one of the brain’s signaling substances is a neuropeptide called arginine-vasopressin.

Vasopressin, or antidiuretic hormone

the hormone of the posterior lobe of the pituitary gland, is secreted with an increase in the osmolarity of blood plasma and with a decrease in the volume of extracellular fluid. Increases the reabsorption of water by the kidney, thus increasing the concentration of urine and decreasing f …

This hormone, secreted in the hypothalamus of all mammals, has a very wide spectrum of action: firstly, it affects the amount of urine excreted, which in rodents is directly related to the choice of a mate.And secondly, it is a neurotransmitter involved in the reactions of memory, stress, and in humans – even in the development of depression.

It would seem that Homo sapiens is a much more complexly organized creature with a psyche. But, as it turned out, general biological laws are not alien to us:

men with two copies of a particular variant of the mentioned gene turned out to be much more prone to riotous behavior.

To find out, Hasse Valum and his colleagues from the Stockholm Karolinska Institute interviewed a thousand Swedes about their personal lives and compared the results of the survey with the genetic characteristics of the experimental subjects.It would be interesting to know how different in their behavior adherents of different religions and residents of different countries are, but the scientists limited themselves to the inhabitants of Sweden. Perhaps the relatively free morals of this northern European country predetermined the success of the study, the results of which were 90,019 published in the latest issue of the Proceedings of the National Academy of Sciences.

It should be noted that it is not so easy to study the marriage behavior of people. It’s simple with mice – and males are able to mate much more often, and it is easier to assess their personal life: to change mates, mice just need to enter another territory.To obtain data on people’s personal lives, Valum needed a variety of psychological tests and statistics. Since the concept of monogamy itself is relatively difficult to assess, scientists have studied several parameters of the personal life and mental status of volunteers at once, relying on their honesty and sincerity. Naturally, anonymity was guaranteed.

Effects of vasopressin

Vasopressin is the only physiological regulator of water excretion by the kidney.Its binding to V2 receptors of the collecting duct leads to the incorporation of aquaporin 2 into the apical membrane of the water channel protein, which …

The question of the choice of a genetic marker, with which the result of the test for mating behavior was to be associated, was not raised: it was the genes encoding vasopressin and its receptor. It was the type and quantity of the latter that turned out to be the most important.

Swedish specialists have found that one of the variants of the DNA sequence encoding the receptor for vasopressin type 1a can be called a “gene of infidelity”.

By the way, this receptor is found not only in the brain, but also in the liver and blood vessels.

Vasopressin receptors and their location

V1A receptors (V1R) are localized in vascular smooth muscle and in the liver, agonists of these receptors are cognitive stimulants and eliminate the impairments in spatial memory caused by scopolamine; antagonists impair reproduction…

In men with two copies of the “infidelity gene”, some parameters of “marital happiness” differed almost twofold. For example, 34% of those with two ill-fated alleles had problems in marriage, compared with 16% with one copy and 15% among those who had no “infidelity genes” at all. At the same time, only 68% of men in the “freedom-loving” group were in this very marriage, and all 83% were in a cohort that did not possess the corresponding genes.

Since among the surveyed there were twins – both identical and twins, scientists, using the 90,019 twin method , were even able to determine that such differences in mating behavior are determined by genes by at least a third.

No such connection could be established for women.

Perhaps for historical, evolutionary, or simply cultural reasons. After all, although in nature females most often choose a male, and not vice versa, it is the latter that is given more biological opportunities to “walk to the left”.And the more inclined the owner of the corresponding genes to such walks, the more children he has.

So now ladies who do not want to let a man go should line up not to the magicians, but to the geneticists and pharmacologists of the Karolinska Institute: the receptors encoded by the mentioned genes are well studied, and there are even experimental drugs that affect them; however, it is not yet possible to find them in pharmacies.

But it is not recommended to influence men in an alternative way – by changing the content of vasopressin itself in the body instead of the number of type 1a receptors for it – although such drugs do exist.The hormone regulates the reabsorption of water by the kidneys, and playing with it can lead to the fact that instead of fulfilling marital duties, a man will stand over a urinal for days.

90,000 Scientists spoke about the medicinal properties of ordinary water

https://ria.ru/20201216/voda-1589509891.html

Scientists spoke about the medicinal properties of ordinary water

Scientists spoke about the medicinal properties of ordinary water – RIA Novosti, 03.03.2021

Scientists talked about the healing properties of ordinary water

Scientists have found that ordinary drinking water suppresses the hormone that causes obesity and diabetes.According to the authors, water consumption can become effective … RIA Novosti, 03.03.2021

2020-12-16T15: 07

2020-12-16T15: 07

2021-03-03T18: 13

Science

usa

health

diabetes

biology

hormones

obesity

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MOSCOW, December 16 – RIA Novosti. Scientists have found that regular drinking water suppresses the hormone that causes obesity and diabetes. According to the authors, water consumption can be an effective means of preventing and treating metabolic syndrome. The results of the study are published in the journal JCI Insight. Researchers at the Anschutz Medical Campus of the University of Colorado, USA, along with colleagues from Japan, Mexico and Turkey in experiments on mice found that fructose stimulates the release of vasopressin, a hormone associated with obesity and diabetes, and that ordinary water helps to suppress the formation of this hormone.The authors gave the rodents sweet water with fructose, which stimulated the production of vasopressin. The hormone, in turn, triggered reactions in which water was stored as fat. This led to animal dehydration and obesity. “We found that vasopressin does this by working through a specific receptor V1b,” said study leader Dr. Miguel Lanaspa, associate professor of medical school at the University of Colorado, in a press release. could understand its functions.We found that mice lacking V1b were completely protected from the effects of sugar. “In the case when the mice drank unsweetened water, obesity was not only stopped, but also reduced. Plain water suppressed the vasopressin receptor and prevented the deposition of fat.” block vasopressin – drink water, explains Lanaspa. “This is reassuring because it means there is a cheap and easy way to improve the lives of many people and cure metabolic syndrome.” “Sugar causes metabolic syndrome in part by activating vasopressin.Vasopressin stimulates fat production, probably as a storage mechanism for metabolic water, “continues study author Dr. Richard Johnson, professor at the University of Colorado School of Medicine.” Consideration should be given to the potential role of hydration and salt reduction in treating obesity and metabolic syndrome. These results explain why vasopressin levels are elevated in obese and diabetic people, and why people with metabolic syndrome often show signs of dehydration.It also explains why a diet high in salt, leading to chronic dehydration and can lead to obesity and diabetes. According to scientists, high levels of vasopressin are also observed in desert mammals, since they do not have easy access to water, and when they drink, the hormone retains water as fat. “Our study shows that simply increasing water intake can effectively reduce obesity and metabolic syndrome. This is the first time that vasopressin has been shown to respond to dietary sugar,” Lanaspa notes.The authors recommend increasing water intake for anyone with signs of metabolic syndrome – high blood pressure, high blood sugar, and high triglyceride levels – given that the combination of these factors dramatically increases the risk of heart disease, stroke, and type 2 diabetes.

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USA, health, diabetes, biology, hormones, obesity

MOSCOW, Dec 16 – RIA Novosti. Scientists have found that regular drinking water suppresses the hormone that causes obesity and diabetes. According to the authors, water consumption can be an effective means of preventing and treating metabolic syndrome.The results of the study are published in the journal JCI Insight. Researchers at the Anschutz Medical Campus of the University of Colorado, USA, along with colleagues from Japan, Mexico and Turkey in experiments on mice found that fructose stimulates the release of vasopressin, a hormone associated with obesity and diabetes, and that ordinary water helps to suppress the formation of this hormone.

The authors gave rodents sweet water with fructose, which stimulated the production of vasopressin. The hormone, in turn, triggered reactions in which water was stored as fat.This led to animal dehydration and obesity.

“We found that vasopressin does this by working through a specific receptor V1b,” study director Dr. Miguel Lanaspa, associate professor at the University of Colorado School of Medicine, said in a press release. “This receptor has been known for a while, but no one could not really understand its function. We found that mice lacking V1b were completely protected from the effects of sugar. ”

In the case when the mice drank unsweetened water, obesity was not only stopped, but also reduced.Plain water suppressed the vasopressin receptor and prevented fat deposition.

December 15, 2020, 18:41 Science A new method to combat hypertension proposed

“The best way to block vasopressin is to drink water,” Lanaspa explains. …

“Sugar causes metabolic syndrome in part by activating vasopressin. Vasopressin stimulates fat production, probably as a storage mechanism for metabolic water,” continues study author Dr. Richard Johnson, professor at the University of Colorado School of Medicine.“Consideration should be given to the potential role of hydration and salt reduction in treating obesity and metabolic syndrome.”

These results explain why vasopressin levels are elevated in people with obesity and diabetes, and why people with metabolic syndrome often show signs of dehydration. also explains why a diet high in salt, leading to chronic dehydration and can cause obesity and diabetes.

According to scientists, desert mammals also have high vasopressin levels because they do not have easy access to water, and when they drink, the hormone retains water as fat.

“Our study shows that simply increasing water intake can effectively reduce obesity and metabolic syndrome. This is the first time that vasopressin has been shown to respond to dietary sugar,” Lanaspa notes.

The authors recommend increasing water intake for anyone with signs of metabolic syndrome – high blood pressure, high blood sugar and high triglyceride levels, given that the combination of these factors dramatically increases the risk of cardiovascular disease, stroke and type 2 diabetes …

December 3, 2020, 14:50 Science Scientists have proven that stress hormone activates cancer cells 90,000 Vasopressin antidiuretic effect

The main biological effect of oxytocin in mammals is associated with the stimulation of contraction of smooth muscles of the uterus during labor and muscle fibers around the alveoli of the mammary glands, which causes the secretion of milk. Vasopressin stimulates the contraction of vascular smooth muscle fibers, exerting a strong vasopressor effect, but its main role in the body is reduced to the regulation of water metabolism, whence its second name is antidiuretic hormone.In small concentrations (0.2 ng per 1 kg of body weight), vasopressin has a powerful antidiuretic effect — it stimulates the reverse flow of water through the membranes of the renal tubules. Normally, it controls the osmotic pressure of blood plasma and the water balance of the human body. With pathology, in particular atrophy of the posterior lobe of the pituitary gland, diabetes insipidus develops, a disease characterized by the excretion of extremely large amounts of fluid in the urine. In this case, the reverse process of water absorption in the kidney tubules is disturbed. [c.257]

The antidiuretic effect of vasopressin appears even at very low concentrations. [c.149]

Vasopressin (antidiuretic hormone) increases the permeability of the wall of the renal tubules in relation to water, which contributes to its better reabsorption. The action of this hormone leads to a decrease in the volume of urine (the name of this hormone antidiuretic stands for volume decreasing, since the term diuresis means the volume of urine). [c.118]

Vasopressin is often called antidiuretic hormone, as it controls the reabsorption of water in the renal tubules. The action of vasopressin is carried out by a membrane-mediated mechanism. As a result of the binding of vasopressin to receptors in the renal tubules, a cascade of reactions is triggered. The formation of cAMP and the activation of protein kinase lead to the phosphorylation of membrane proteins in the kidney, which affects the transport of water. [c.150]

The antidiuretic activity of vasopressin disappears when the disulfide cycle is opened by the action of thioglycolic acid, cysteine ​​or glutathione [600] and is again reduced by oxidation of the linear nonapeptide.Enzymes present in kidney homogenates also inactivate vasopressin, restoring the S – S bond [600]. The incubation of Arg -vasopressin and Lys -vasopressin with trypsin, accompanied by the cleavage of the C-terminal residue of glycine amide, leads to a loss of hormonal activity [637] similar to [c.462]

The posterior lobe of the pituitary gland contains two active hormones, vasopressin and oxytocystin. Vasopressin, which got its name from its ability to increase blood pressure when administered in pharmacological doses, is more correctly called antidiuretic hormone (ADH), since its most important physiological effect is to stimulate the reabsorption of water in the distal renal tubules.The name of another hormone, oxytocin, is also related to its effect, which is to speed up labor by increasing the contraction of the smooth muscles of the uterus. The likely physiological role of this hormone is to stimulate the release of milk from the mammary gland. [c.183]

Vasopressin (antndiuretin, adiuretic) has an antidiuretic effect, that is, it causes the reabsorption of water by the kidneys under the influence of vasopressin. urine only 1-1.5 l).At relatively high doses, vasopressin also increases blood pressure. Tax, as already 2 ng of this hormone can cause a noticeable antidiuretic effect in humans, then in terms of its physiological action and pharmacological properties it belongs to [c.248]

Recently, a work came out from Du Vigneau’s laboratory in which the synthesis of porcine vasopressin was described [580]. Noteworthy is the fact that the terminal residue in the molecules of the above hormones is glycinamide.In this regard, an important question arises whether such bonds also exist in proteins. In the porcine vasopressin molecule, the arginine residue is replaced by lysine. Despite this species difference, both vasopressins have almost the same physiological activity. Oxytocin is one of the main hormones of the posterior lobe. In the pituitary gland, it causes contraction of the muscles of the uterus and the release of milk. Vasopressin increases blood pressure, which is associated with its vasoconstrictor effect; in addition, it exhibits an antidiuretic effect.The similarity of the structure of the molecules of vasopressin and oxytocin makes it possible to explain the presence of weak oxytocytic activity in vasopressin preparations and, possibly, also the presence of weak pressor activity in oxytocin preparations. [c.74]

Vasopressin controls the water balance, thereby maintaining the necessary isotonic pressure of the body fluid B. The physiological feasibility of the antihypertensive properties of vasopressin has not yet been fully elucidated and requires further research.Vasopressin has an antidiuretic effect on the distal glomeruli of the kidneys, increasing their permeability to resorbable water, as a result of which water is retained in the body and the concentration of salts in the urine increases. With a reduced content of vasopressin, the permeability of the glomeruli decreases, and this leads to a decrease in water sorption. However, salts continue to be resorbed normally, which leads to the release of more low-density urine (c (1-day diuresis, diabetes insipidus). [c.425]

GIy-ys) -Lys-Ba3onpe HH was isolated in the form of diacetate trihydrate [a] 5 —64 2 ° (c = 0.07 1 N acetic acid). Its antidiuretic activity is equal to 40 IU / mg at doses of 5 10 μg and 10 I … 10 mcg). The pressor and antidiuretic effect of the synthetic analogue persists for a significantly longer period of time (three times) than after the administration of Lys-vasopressin. [c.458]

The aromatic hydroxyl group in position 2 plays an insignificant role in the manifestation of hormonal activity, the phenyl group is of much greater importance. The hydroxyl group is more important for oxytotic than vasopressor activity. Its protection in the series of oxytocin analogs is accompanied by the appearance of strong inhibitory properties in the series of vasopressin; such analogs have a lower absolute activity and a higher selectivity of antidiuretic action. [c.467]

Hormones of the neurohypophysis. Vasopressin is a polypeptide of eight amino acids, molecular weight 1025. Increases blood pressure by constricting peripheral arterioles and capillaries. However, it dilates the vessels of the brain and kidneys. In small doses, it has an antidiuretic effect, that is, it enhances the reabsorption of water in the urinary tubules. [c.65]

The effect of vasopressin is due to the fact that it narrows the vessels of the arterioles and capillaries. Vasopressin, when injected in very small doses, has an antidiuretic effect.The maximum effect was observed when 0.0001 mg of vasopressin was administered to humans. The urine excreted from the body turns out to be concentrated. It has an increased concentration of chlorides, phosphates and nitrogenous substances (urea, creatinine, etc.). [c.161]

Vasotocin is a vasopressor hormone of the posterior lobe of the pituitary gland in all vertebrates except for mammals. This hormone was synthesized by Katsoyannis and Du Vigno in 1958 before studying the structure of the natural hormone. The authors synthesized an ortan nona-peptide consisting of a ring with a —S — S — bridge of oxytocin and a side chain of vasopressin.The resulting drug has the activity of vasopressin and oxytocin, which is four to five times weaker. Vasotocin is a natural hormone in birds, reptiles, amphibians and fish. The study of its physiological action showed that it has different effects in representatives of different classes of vertebrates. In terrestrial animals, it exhibits an antidiuretic effect, that is, it causes water retention in the body, in fish it stimulates diuresis and increases the release of water into the external environment. These differences may be associated with the nature of the habitat, since in both cases its action is aimed at maintaining homeostasis. [c.270]

Serotonin narrows arterioles and increases blood pressure, enhances intestinal motility, stimulating posganglionic nerve fibers in its muscle layer. It acts as an antidiuretic, promoting the elimination of vasopressin from the posterior lobe of the pituitary gland into the bloodstream. In the brain, serotonin serves as a mediator (or modulator) for the transmission of nerve impulses from one neuron to another. It is widely distributed in various tissues (brain, intestinal wall, spleen, platelets). [c.287]

Giy-ys) -Tyr (Me) 2-Lys-Ba3onpe HH isolated as diacetate dihydrate [a] -70 2 ° (c = 0.07 1 N acetic acid) he has a weak antidiuretic effect (corresponding to an activity of about 1.5 IU / mg), although somewhat longer (1.5-2 times) than that of Lys -vasopressin. Doses of 20 µg have a short-term depressant effect on blood pressure in rats, and administration of 25-50 µg of the analogue leads to suppression of the effect of simultaneously administered Lys-vasopressin. [c.458]

The pressor effect in the case of Pbe-buz-vasotocin (XIX) [290], as in the case of Phe-buz-vasopressin (VIII), is more pronounced than the antidiuretic one; at the same time, compound XIX has a higher oxntotic activity associated with the presence of the Pei residue. [c.466]

Blocking the e-amino group of Lys -vasopressin [Lys (Form) -vasopressin (IIIa)] [291a] is accompanied by a decrease in the pressor (up to 32 2 M.E. / mg) and antidiuretic (up to 10 1 IU / mg) activity while maintaining the level of oxytotic action. [c.467]

These hormones are characterized by high biological activity. Oxytocin affects the muscles of the uterus in the postpartum period and vasopressin acts on the smooth muscles of blood vessels (causes the so-called stressor effect), and also affects the activity of the kidneys in higher animals and humans (antidiuretic factor) [c.173]

Hormones pituitary gland.In the pituitary gland, tropic hormones are synthesized – tropines (from the Greek tropos – turn, direction), which have a stimulating effect on the endocrine glands. These include growth hormone – somatotropin, which is a polypeptide containing 191 amino acid residues. Growth hormone affects almost all cells and is responsible for the normal growth of the body. Among other hormones synthesized by the pituitary gland, we note li-potropins, which have a specific fat-mobilizing effect, lutropin, which is responsible for puberty, the antidiuretic hormone vasopressin, which is a nonapeptide of the following structure [p.295]

At the same time, many other RPs are capable, depending on the type of receptors, to change the content of both cyclic nucleotides and products of hydrolysis of phosphoinositides. The most studied example of this kind is the V2 receptors of vasopressin. The activation of urreceptors associated with vasopressor and glycogenolytic action is accompanied by the induction of diacylglycerol and inositol phosphates, the activation of the Uz receptors that determine the antidiuretic effect is the induction of cAMP synthesis. [c.329]


Publications in the media

Science has published a series of review and theoretical articles on the relationship between genes and behavior. Recent evidence from genetics and neurobiology indicates the complexity and ambiguity of this relationship. Genes even influence such complex aspects of human behavior as family and social relationships and political activities. However, there is also an inverse influence of behavior on the work of genes and their evolution.

Genes influence our behavior, but their power is not unlimited
It is well known that behavior largely depends on genes, although in most cases there is no need to speak of strict determinism. The genotype does not determine behavior as such, but rather the general principles of constructing neural circuits responsible for processing incoming information and making decisions, and these “computing devices” are capable of learning and are constantly being rebuilt throughout life. The lack of a clear and unambiguous correspondence between genes and behavior does not at all contradict the fact that certain mutations can change behavior in a very specific way.However, it must be remembered that each behavioral trait is determined not by one or two, but by a huge set of genes that work in concert. For example, if it is found that a mutation in a gene leads to the loss of the gift of speech, this does not mean that “scientists have discovered the gene for speech.” This means that they discovered a gene that, along with many other genes, is necessary for the normal development of neural structures, thanks to which a person can learn to speak.

This range of topics is the subject of behavioral genetics.Review articles published in the latest issue of Science provide some striking examples of how changes in individual genes can radically change behavior. For example, back in 1991, it was shown that if a small fragment of the period gene is transplanted from a Drosophila simulans fly to another fly species (D. melanogaster), transgenic males of the second species begin to sing the mating song of D. simulans during courtship.

Another example is the for gene, which determines the activity of searching for food in insects.The gene was first found in Drosophila: flies with one variant of this gene seek food more actively than carriers of the other variant. The same gene was found to regulate the feeding behavior of bees. True, it is not differences in the structure of the gene that play a role here, but the activity of its work (see below): in bees collecting nectar, the for gene works more actively than in those who take care of juveniles in the hive. How did it happen that one and the same gene affects the behavior in a similar way in such different insects with completely different levels of intellectual development? There is no clear answer to this question yet.Below we will come across other examples of amazing evolutionary conservatism (stability, immutability) of molecular mechanisms of behavior regulation.

The Baldwin Effect: Learning Drives Evolution
The relationship between genes and behavior is by no means limited to the unidirectional influence of the former on the latter. Behavior can also influence genes, and this influence can be traced both on an evolutionary time scale and throughout the life of an individual organism.

Changed behavior can lead to a change in selection factors and, accordingly, to a new direction of evolutionary development.This phenomenon is known as the “Baldwin effect” – after the American psychologist James Baldwin, who first put forward this hypothesis in 1896. For example, if a new predator has appeared, from which you can escape by climbing a tree, prey can learn to climb trees without having an innate (instinctive) predisposition to this. At first, each individual will learn new behavior throughout its life. If this continues long enough, those individuals that learn to climb trees faster or do it more dexterously due to some innate variations in body structure (slightly more tenacious paws, claws, etc.)will receive a selective advantage, that is, they will leave more offspring. Consequently, the selection will begin for the ability to climb trees and the ability to quickly learn it. Thus, a behavioral trait that initially reappears every time as a result of life-long learning may eventually become instinctive (innate) – the changed behavior will be “inscribed” into the genotype. The paws are also likely to become more tenacious.

Another example: the spread of a mutation that allows adults to digest milk sugar lactose has occurred in those human populations where dairy farming has come into use.Behavior changed (people began to milk cows, mares, sheep or goats) – and as a result, the genotype changed (the hereditary ability to assimilate milk in adulthood developed).

The Baldwin effect is superficially similar to the Lamarckian mechanism of inheritance of acquired traits (the results of exercise or non-exercise of organs), but it acts in a completely Darwinian way: through a change in the vector of natural selection. This mechanism is very important for understanding evolution. For example, it implies that as learning ability grows, evolution will look more “focused” and “meaningful.”It also predicts that there may be a positive feedback loop in the development of intelligence: the higher the learning ability, the higher the likelihood that selection for an even greater learning ability will begin.

Social behavior affects the work of genes

Behavior also affects the work of genes during the life of an organism. This topic is further elaborated in an article by Gene E. Robinson of the University of Illinois at Urbana-Champaign and coauthors.The paper examines the relationship between genes and social behavior in animals, with particular attention to how social behavior (or socially significant information) affects the genome. This phenomenon began to be investigated in detail relatively recently, but a number of interesting finds have already been made.

When a male zebra finch ( Taeniopygia guttata ) – a bird from the weaver family – hears the song of another male, the gene egr1 begins to be expressed (work) in a certain part of the auditory region of the forebrain.This does not happen when the bird hears individual tones, white noise, or any other sounds – this is a specific molecular response to socially significant information.

The songs of unfamiliar males evoke a stronger molecular genetic response than the twittering of old acquaintances. In addition, if the male sees other birds of his own species (not singing), the activation of the gene egr1 in response to the sound of someone else’s song is more pronounced than when he sits alone. It turns out that one type of socially significant information (the presence of relatives) modulates the reaction to another type of it (the sound of someone else’s song).Other socially significant external signals lead to the activation of the gene egr1 in other parts of the brain.

Ironically, this same gene plays an important role in social life in fish. “Elements” have already written about the complex social life and remarkable mental abilities of the aquarium fish Astatotilapia burtoni (see: Fish have the ability to deduce, “Elements”, 01/30/2007). In the presence of a dominant male winner, the subordinate male fades and does not show interest in females.But as soon as a high-ranking male is removed from the aquarium, the subordinate is rapidly transformed, and not only his behavior changes, but also his color: he begins to look and behave like a dominant. The transformation begins with the fact that the already familiar gene egr1 is turned on in the neurons of the hypothalamus. Soon, these neurons begin to vigorously produce the sex hormone (gonadotropin-releasing hormone, GnRH), which plays a key role in reproduction.

The protein encoded by the gene egr1 is a transcription factor, that is, a regulator of the activity of other genes.A characteristic feature of this gene is that a very short-term external influence (for example, one sound signal) is sufficient to turn it on, and the activation occurs very quickly – the time counts for minutes. Another of its peculiarities is that it can have an immediate and very strong influence on the work of many other genes.

egr1 – is far from the only gene whose work in the brain is determined by social stimuli. It is already clear that the nuances of social life affect the work of hundreds of genes and can lead to the activation of complex and multilevel “gene networks”.

This phenomenon is being studied, in particular, on bees. The age at which a worker bee stops caring for juveniles and begins to fly for nectar and pollen is partly predetermined genetically, partly depends on the situation in the collective (see: A gene regulating the division of labor in bees has been identified, “Elements”, 13.03.2007). If the family does not have enough “hunters”, young bees determine this by a decrease in the concentration of pheromones secreted by older bees, and can proceed to collecting food at a younger age.It turned out that these odor signals change the expression of many hundreds of genes in the bee’s brain, and especially strongly affect the genes encoding transcription factors.

Very rapid changes in the expression of many genes in response to social stimuli have been found in the brains of birds and fish. For example, in female fish, contact with attractive males activates some genes in the brain, while contact with females activates others.

Relationships with relatives can lead to long-term stable changes in gene expression in the brain, and these changes can even be transmitted from generation to generation, that is, inherited almost completely “according to Lamarck”.This phenomenon is based on epigenetic modifications of DNA, for example, methylation of promoters, which leads to long-term changes in gene expression. It was noticed that if a mother rat is very caring towards her children, often licks them and protects them in every possible way, then her daughters are likely to be just as caring mothers. It was thought that this trait is predetermined genetically and is inherited in the usual way, that is, “recorded” in the nucleotide sequences of DNA. One could also assume cultural inheritance – the transmission of a behavioral trait from parents to descendants through training.However, both of these versions turned out to be wrong. In this case, the epigenetic mechanism works: frequent contacts with the mother lead to methylation of the promoters of certain genes in the brain of rat pups, in particular, genes encoding receptors on which the response of neurons to certain hormones depends (the sex hormone estrogen and stress hormones – glucocorticoids). Such examples are still rare, but there is every reason to believe that this is only the tip of the iceberg.

The relationship between genes and social behavior can be extremely complex and bizarre.The red fire ants Solenopsis invicta have a gene that determines the number of queens in a colony. Homozygous workers with genotype BB do not tolerate having more than one queen in a colony, and therefore their colonies are small. Heterozygous Bb ants willingly take care of several females at once, and their colonies turn out to be large. Workers with different genotypes have very different levels of expression of many genes in the brain. It turned out that if BB workers live in an anthill dominated by Bb workers, they follow the lead of the majority and subdue their instincts, agreeing to take care of several queens.At the same time, the pattern of gene expression in their brain becomes almost the same as that of Bb workers. But if you carry out the opposite experiment, that is, move the Bb workers to an anthill where the BB genotype predominates, then the guests do not change their beliefs and do not adopt the intolerance of “superfluous” queens from the hosts.

Thus, in a wide variety of animals – from insects to mammals – there are very complex and sometimes very similar systems of interactions between genes, their expression, epigenetic modifications, the functioning of the nervous system, behavior and social relations.The same picture is observed in humans.

Neurochemistry of personal relationships

The relationship between people until recently seemed to biologists too complex to seriously investigate them at the cellular and molecular level. Moreover, philosophers, theologians and humanitarians have always been happy to support such fears. And the millennial cultural traditions that have inhabited this region from time immemorial with all sorts of absolutes, “higher meanings” and other ghosts cannot be easily discarded.

However, the advances made in recent decades by geneticists, biochemists and neurophysiologists have shown that the study of the molecular foundations of our social life is not at all hopeless. The first steps in this direction are described in an article by neuroscientists from Emory University Zoe Donaldson and Larry J. Young.

One of the most interesting discoveries is that some of the molecular mechanisms regulating social behavior turned out to be extremely conservative – they exist, almost unchanged, for hundreds of millions of years and work with equal efficiency in both humans and other animals.A typical example is the system of regulation of social behavior and social relations with the participation of the neuropeptides oxytocin and vasopressin.

These neuropeptides can work both as neurotransmitters (that is, transmit a signal from one neuron to another on an individual basis), and as neurohormones (that is, they excite many neurons at once, including those located far from the neuropeptide ejection point).

Oxytocin and vasopressin are short peptides consisting of nine amino acids, and they differ from each other by only two amino acids.These or very similar (homologous, related) neuropeptides are found in almost all multicellular animals (from hydra to humans, inclusive), and they appeared at least 700 million years ago. These tiny proteins have their own genes, and invertebrates have only one such gene, and, accordingly, a peptide, and vertebrates have two (the result of gene duplication).

In mammals, oxytocin and vasopressin are produced by neurons in the hypothalamus. In invertebrates without a hypothalamus, the corresponding peptides are produced in analogous (or homologous) neurosecretory parts of the nervous system.When rats were transplanted the fish gene isotocin (this is the name of the oxytocin homolog in fish), the transplanted gene began to work in rats not just anywhere, but in the hypothalamus. This means that not only the neuropeptides themselves, but also the systems for regulating their expression (including the regulatory regions of neuropeptide genes) are very conservative, that is, they are similar in their functions and properties in animals that are very distant from each other.

In all studied animals, these peptides regulate social and sexual behavior; however, the specific mechanisms of their action can vary greatly in different species.

For example, in snails, the homologue of vasopressin and oxytocin (conopressin) regulates oviposition and ejaculation. In vertebrates, the original gene doubled, and the paths of the two resulting neuropeptides diverged: oxytocin affects more females, and vasopressin affects males, although this is not a strict rule (see: Males become calmer and bolder after mating, “Elements”, 10.16.2007 ). Oxytocin regulates the sexual behavior of females, childbirth, lactation, attachment to children and mate. Vasopressin affects erection and ejaculation in a variety of species, including rats, humans, and rabbits, as well as aggression, territorial behavior, and relationships with wives.

If a virgin rat is injected into the brain with oxytocin, it begins to take care of other people’s rats, although in a normal state they are deeply indifferent to them. Conversely, if a mother rat suppresses oxytocin production or blocks oxytocin receptors, she loses interest in her children.

If in rats oxytocin causes caring for children in general, including strangers, then in sheep and people the situation is more complicated: the same neuropeptide provides the mother’s selective attachment to her own children.For example, in sheep, under the influence of oxytocin, after childbirth, changes occur in the olfactory part of the brain (olfactory bulb), thanks to which the sheep remembers the individual smell of its lambs, and only to them it develops attachment.

In prairie voles, which are characterized by strict monogamy, females become attached to their chosen one for life under the influence of oxytocin. Most likely, in this case, the previously existing oxytocin system for the formation of attachment to children was “co-opted” for the formation of inseparable marital ties.In males of the same species, marital fidelity is regulated by vasopressin, as well as by the neurotransmitter dopamine (see: Love and fidelity are controlled by dopamine, “Elements”, 07.12.2005).

The formation of personal attachments (to children or to a husband), apparently, is only one of the aspects (manifestations, realizations) of a more general function of oxytocin – the regulation of relations with relatives. For example, mice with a disabled gene for oxytocin cease to recognize relatives with whom they previously met. At the same time, their memory and all senses function normally.

The same neuropeptides can act completely differently even on representatives of closely related species, if their social behavior is very different. For example, administering vasopressin to male prairie voles quickly turns them into loving husbands and caring fathers. However, on males of a closely related species, which is not characterized by the formation of strong married couples, vasopressin does not have such an effect. The introduction of vasotocin (the avian homologue of vasopressin) to male territorial birds makes them more aggressive and makes them sing more, but if the same neuropeptide is introduced to males of zebra finches, which live in colonies and do not protect their sites, then nothing like this happens.Obviously, neuropeptides do not create this or that type of behavior out of nothing, but only regulate existing (genetically determined) behavioral stereotypes and predispositions.

This, however, cannot be said about the receptors for oxytocin and vasopressin, which are located on the membranes of neurons in some parts of the brain. In the above-mentioned note “Love and fidelity are controlled by dopamine” it was told that scientists tried, by acting on dopamine receptors, to teach a male non-monogamous vole to be a faithful husband, and they did not succeed (I then noticed on this occasion that “the neurochemistry of family relationship continues to keep its secrets “).Three years later (that is, already this year), neuroscientists nevertheless picked up a key to this secret, and finally turned the inveterate revelers into faithful husbands. For this, as it turned out, it is sufficient to increase the expression of vasopressin receptors V1a in the brain. Thus, by regulating the work of genes of vozopressin receptors, it is possible to create a new demeanor, which is not normally characteristic of this animal species.

In voles, the expression of vasopressin receptors depends on a non-coding DNA region – a microsatellite, located in front of the V1a receptor gene.In the monogamous vole, this microsatellite is longer than in the non-monogamous species. Individual variability in the length of the microsatellite correlates with individual differences in behavior (with the degree of marital fidelity and care for the offspring).

In humans, of course, it is much more difficult to research all this – who will allow genetic engineering experiments with people. However, much can be understood without gross interference with the genome or the brain. Surprising results were obtained by comparing the individual variability of people in microsatellites located near the V1a receptor gene with psychological and behavioral differences.For example, it turned out that the length of microsatellites correlates with the time of puberty, as well as with character traits associated with social life, including altruism. Do you want to be kinder? In brain cells, increase the length of the RS3 microsatellite near the vasopressin receptor gene.

This microsatellite also affects family life. A 2006 study in Sweden found that men who are homozygous for one of the allelic variants of the microsatellite (this variant is called RS3 334) are half as likely to be married as other men to romance.In addition, they are twice as likely to be unhappy in family life. In women, nothing of the kind was found: women who are homozygous for this allele are happy in their personal lives no less than the others. However, those women who got a husband with a “wrong” version of the microsatellite are usually unhappy with family relationships.

Carriers of the RS3 334 allele have several other characteristic features. Their proportion is increased among people with autism (the main symptom of autism, as you know, is the inability to communicate normally with other people).In addition, it turned out that when looking at other people’s faces (for example, in tests where it is necessary to determine the mood of another person by facial expression) in carriers of the RS3 334 allele, the amygdala (amygdala) is more excited – a part of the brain that processes socially significant information and is associated with such feelings like fear and mistrust (see below).

Similar studies have begun only recently, so many results need additional verification, but the overall picture is beginning to emerge.It seems that in the nature of the influence of the oxytocin and vasopressin systems on the relationship between individuals, humans are not very different from voles.

It is difficult to inject neuropeptides into the brain of living people, and intravenous administration has a completely different effect, because these substances do not pass through the blood-brain barrier. Surprisingly, however, it turned out that you can enter them pernasally, that is, drip into the nose, and the effect is approximately the same as in rats when injected directly into the brain. It is not yet clear why this happens, and so far very few such studies have been carried out, but the results, nevertheless, are impressive.

When vasopressin is dripped into the nose of men, the faces of other people begin to seem less friendly to them. In women, the effect is the opposite: strangers’ faces become more pleasant, and the subjects themselves mimicry becomes more friendly (in men – vice versa).

Experiments with pernasal administration of oxytocin have so far been carried out only on men (it is more dangerous to do this with women, since oxytocin strongly affects female reproductive function). It turned out that oxytocin in men improves the ability to understand the mood of other people by their facial expressions.In addition, men begin to look the other person in the eye more often.

In other experiments, another surprising effect of pernasal administration of oxytocin was found – an increase in gullibility. Men who have been injected with oxytocin are more generous in the “game of trust” (this standard psychological test is described in the article Credibility and Gratitude – Hereditary Traits, “Elements”, 03/07/2008). They give more money to their gambling partner if the partner is a living person, however, the generosity does not increase from oxytocin if the partner is a computer.

Two independent studies have shown that the administration of oxytocin can lead to harmful consequences for a person, because gullibility can become excessive. A normal person in the “trust game” becomes less generous (trusting) after his trust has once been deceived by a partner. But in men who have oxytocin instilled into their noses, this does not happen: they continue to blindly trust their partner even after their partner has “betrayed” them.

If a person is told unpleasant news when he looks at someone’s face, then this face will subsequently seem to him less attractive.This does not happen in men who have oxytocin instilled into their nose.

The neurological mechanism of action of oxytocin is also beginning to become clear: it turned out that it suppresses the activity of the amygdala. Apparently, this leads to a decrease in distrust (people cease to fear that they will be deceived).

According to researchers, society may soon face a whole series of new “bioethical” problems. Should traders be allowed to spray oxytocin in the air around their products? Is it possible to prescribe oxytocin drops to quarreled spouses who want to save the family? Does a person have the right to find out the allelic state of the vasopressin receptor gene from his partner before marriage?

While the trial is on, oxytocin is sold in any pharmacy.True, only with a doctor’s prescription. It is administered intravenously to women in labor to enhance uterine contractions. As we recall, it regulates both labor and oviposition in molluscs, and many other aspects of reproductive behavior.

It’s time for political scientists to learn biology

Aristotle, who is considered the founder of scientific political science, called man a “political animal.” However, until very recently, political scientists did not seriously consider the possibility of the influence of biological factors (such as genetic variability) on political processes.Political scientists developed their own models, taking into account dozens of different sociological indicators, but even the most complex of these models could explain no more than a third of the observed variability in people’s behavior during elections. What explains the other two-thirds? It seems that the answer to this question can be provided by geneticists and neuroscientists.

The first scientific evidence indicating that political views are in part dependent on genes was obtained in the 1980s, but at first these results seemed dubious.Convincing evidence of the heritability of political beliefs, as well as other important personal characteristics that affect political and economic behavior, has been obtained in the last 3-4 years in the course of studying twins (one of such studies is described in the article Trustfulness and Gratitude – Heritable Traits, “Elements “, 07.03.2008).

These studies showed that political addictions are largely hereditary, but they did not say anything about which genes influence those addictions.So far, only the very first steps have been taken in this direction. A number of correlations were found between political views and allelic variants of genes. For example, the variability of the gene encoding the dopamine receptor DRD2 correlates with the adherence to a particular political party. True, these results are preliminary and need to be verified.

“Political thinking” appears to be one of the most important aspects of social intelligence (see: Found the key difference between human and ape intelligence, “Elements”, 13.09.2007). In everyday life, we (like other primates) constantly have to solve problems of a “political” nature: who can be trusted and who can not; how to behave with different people depending on their position in the social hierarchy; how to raise your own status in this hierarchy; with whom to conclude an alliance and against whom. Neurobiological studies have shown that when solving such problems, the same parts of the brain are excited as when thinking about global political problems, making judgments about a particular politician, party, etc.p.

However, this is only seen in people who are versed in politics – for example, among the staunch supporters of the Democratic or Republican Party in the United States. Democrats and Republicans use the same “socially oriented” regions of the brain to generate political judgments. If you ask people who are not interested in politics to speak about national politics, then completely different parts of the brain are excited – those that are responsible for solving abstract problems that are not related to human relationships (for example, problems in mathematics).This does not mean at all that politically naive people have poor social intelligence. It only means that they do not understand national politics, and therefore the corresponding tasks in their minds fall into the category of “abstract”, and socially oriented contours are not involved. Dysfunction of these circuits is common in autistic people, who can do very well at abstract tasks, but cannot communicate with people.

Large-scale political problems first confronted people quite recently on an evolutionary time scale.Apparently, we use old, proven genetic and neural circuits that have evolved over the course of evolution to regulate our relationships with fellow tribesmen in small groups to solve world problems. And if so, then to understand the political behavior of people it is completely insufficient to take into account only sociological data. It’s time for political scientists to join forces with behavioral geneticists, neuroscientists, and evolutionary psychologists.

Sources:
1) Gene E.Robinson, Russell D. Fernald, David F. Clayton. Genes and Social Behavior // Science . 2008. V. 322. P. 896-900.
2) Zoe R. Donaldson, Larry J. Young. Oxytocin, Vasopressin, and the Neurogenetics of Sociality // Science . 2008. V. 322. P. 900-904.
3) James H. Fowler, Darren Schreiber. Biology, Politics, and the Emerging Science of Human Nature // Science . 2008. V. 322. P. 912-914.

90,000 The hormone vasopressin, or the hormone of attachment.Interesting to know

Numerous studies have long proven that love is primarily a hormonal process in the body. It is hormones that affect how lovers feel: ardent passion or tender love. The hormone vasopressin, or attachment hormone , begins to be produced in people in love and reduces the production of passion hormones, influencing the formation of long-term relationships.

Vasopressin is also referred to as hormones of emotional happiness , as it increases the emotional relationship of lovers.This hormone is produced in the hypothalamus and accumulates in the posterior lobe of the pituitary gland, and from there enters the bloodstream. Like other love hormones, vasopressin is not solely responsible for a person’s emotional attachment. For example, it regulates the excretion of water by the kidneys, increases vascular tone, and much more.

Vasopressin acts on the central nervous system in the following way: it regulates aggressive behavior, participates in memory mechanisms, plays a role in finding a partner and is responsible for paternal love in men .In women, vasopressin is similar in action to oxytocin. Vasopressin binds to oxytocin and through receptors stimulates the tone and contractions of the uterus.

Interestingly, the hormone vasopressin, responsible for the formation of long-term relationships , is not necessarily produced when falling in love. For example, its production increases with injuries, blood loss, shock conditions, and even with some psychoses.

The effect of the hormone vasopressin as a hormone of attachment was discovered in 1999 as a result of experiments on steppe vole mice , which implement monogamous relationships.Scientists have found that if you block this hormone, the behavior of the voles becomes more “lecherous”. Other monogamous animals have been found to have higher levels of vasopressin in the reward centers of the brain than non-monogamous ones. Thanks to numerous studies, it was possible to draw a parallel with human behavior, which gives a scientific reason to consider vasopressin as an attachment hormone.

ACTH, Get tested for adrenocorticotropic hormone

Method of determination
Solid phase chemiluminescence immunoassay.

Study material
Blood plasma

Adrenocorticotropic hormone – pituitary hormone, regulator of glucocorticoid production in the adrenal cortex.

Synonyms: Blood test for ACTH; Adrenocorticotropin; Corticotropic hormone.

Adrenocorticotropin; Corticotropin.

Brief characteristics of the analyte Adrenocorticotropic hormone

ACTH is a peptide hormone (composed of 39 amino acids) produced by the anterior pituitary gland.ACTH secretion is under the stimulatory control of the hypothalamic corticotropin-releasing hormone. ACTH, in turn, stimulates the production of cortisol by the adrenal cortex.

The activity of the hypothalamic-pituitary-adrenal system is under the influence of the internal circadian rhythm (at 6-8 hours the concentration of ACTH is maximum, at 21-22 hours – minimum). With a sharp change in time zones, the daily rhythm of ACTH secretion is normalized within 7-10 days.

The hypothalamic-pituitary-adrenal system under the influence of the central nervous system and humoral factors is activated in states of stress (both physical and emotional).A strong stressful situation leads to a violation of the daily rhythm, a sharp increase in cortisol in the blood 25-30 minutes after the onset of stress. Infections, inflammatory processes accompanied by the release of cytokines also cause activation of the hypothalamus-pituitary-adrenal gland system. Cortisol, the end product of the system, acts on various organs and tissues to activate numerous adaptive responses. An increase in cortisol concentration by feedback mechanisms inhibits the secretion of both hypothalamic corticotropin-releasing hormone and ACTH.The half-life of ACTH from the blood is short, measured in minutes. In primary adrenal insufficiency, the ACTH level is increased and the cortisol level is decreased; with secondary adrenal insufficiency (pituitary), the level of ACTH is reduced or at the lower limit of the norm, the concentration of cortisol is reduced.

What is the purpose of determining the level of adrenocorticotropic hormone in blood serum

Since ACTH is the most important regulator of the synthesis and secretion of hormones in the adrenal cortex, the determination of its level in the blood is used to identify dysfunction of the adrenal cortex and associated pathologies.

What can affect the level of adrenocorticotropic hormone in the blood

It should be borne in mind that the content of ACTH is influenced by the phase of the menstrual cycle, pregnancy, emotional state, pain, fever, physical activity, surgical interventions.

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