Vasopressin

Vasopressin, Cyclo (1-6) L-Cysteinyl-L-Tyrosyl-L-PhenylalanylL-Glutaminyl-L-Asparaginyl-L-Cysteinyl-L-Prolyl-L-Arginyl-L-Glycinamide, is a cyclic nonapeptide hormone primarily produced by the supraoptic and periventricular nuclei of the hypothalamus. Vasopressin release is mediated by sensory pathways, in which either a 2% increase in plasma osmolarity or a 10% decrease in blood pressure causes the release of endogenous vasopressin. Upon release, vasopressin mediates a variety of physiological effects, both centrally and systemically, primarily by binding to G-protein-coupled receptors termed V1 (V1A), V2, and V3 (V1B).

V1 receptors are abundantly expressed in the brain whereby vasopressin binding can increase blood pressure through autonomic pathways. Peripherally, V1 is localized in the blood vessels (vascular smooth muscle), platelets, adrenal glands, kidneys, and liver. Vasopressin binding to V1 causes hydrolysis of phosphatidylinositol-4,5-bisphosphate into inositol triphosphate (IP3) and diacylglycerol (DAG) by phospholipase C, which in turn release intracellular calcium and activate protein kinase C (PKC) to open voltage-gated calcium channels (VGCCs) while closing potassium channels. Overall, intracellular calcium levels rise, which bind calmodulin and cause muscular contraction, resulting in vasoconstriction. This is balanced by the apparent ability of vasopressin to induce vasodilation through binding oxytocin receptors and activating endothelial nitric oxide (NO) synthase; NO acts antagonistically to reduce muscle contraction. It is also thought that vasopressin, acting through both V1 and oxytocin receptors, causes the cardiac release of atrial natriuretic peptide (ANP), which has a negative inotropic effect; indeed, vasopressin tends to decrease heart rate and cardiac output, although the opposite effect has been noted with low doses.

V2 receptors are abundantly expressed in the distal convoluted tubules and the collecting ducts of the kidneys. Vasopressin binding to V2 causes activation of a Gs protein that subsequently activates protein kinase A (PKA) through adenylyl cyclase-mediated increase in cyclic adenosine monophosphate (cAMP), which leads to phosphorylation of the water channel aquaporin-2 (AQP2) and its trafficking to the cell surface. Increased AQP2 levels lead to increased water reabsorption and explains vasopressin's antidiuretic effects.

V3 (formerly V1B) receptors are primarily located in the anterior pituitary and brain. Vasopressin released during acute stress causes adrenocorticotropic hormone (ACTH) release from the pituitary through V3 and by potentiating the effects of corticotrophin-releasing factor. Within the brain itself, V3 activation modulates various effects, including recognition, memory, aggression, anxiety, and depression.

Thus, vasopressin can affect a wide variety of physiological processes, often in apparently contradictory ways depending on the patient's dose and physiological state. Vasodilatory shock causes an immediate release of vasopressin from 20 to 200 times its normal serum concentration, which falls again to normal levels in prolonged shock; in this context, normal serum levels are insufficient to control the pathologic vasodilation. In these cases, vasopressin acts to depolarize hyperpolarized vascular smooth muscle cells, restore sensitivity to catecholamines, and inhibit excessive nitric oxide production, primarily through acting through V1 receptors. Therefore, vasopressin helps decrease the dose requirement for norepinephrine and is routinely administered together with norepinephrine to restore normal blood pressure in shock states.