PHYSIOLOGY OF VASOPRESSIN

Arginine vasopressin (AVP, also known as antidiuretic hormone [ADH], 8-arginine-vasopressin, or β-hypophamine) is a natural, nine amino acid glycopeptide with a disulfide bond that is synthesized in the magnocellular neurons in the hypothalamus before transport down the pituitary stalk for storage in the pars nervosa of the posterior pituitary gland.¹ The entire process of vasopressin synthesis, transport, and storage in the pituitary takes 1 to 2 hours.

AVP is metabolized rapidly by hepatic and renal vasopressinases, and the half-life of AVP is 10 to 35 minutes. Vasopressin has shown teleologic persistence and is found in more than 120 species spanning four invertebrate phyla and the seven major vertebrate families.² In most mammals (dogs, cats, humans), the natural hormone is AVP, but the porcine species has a lysine in place of arginine, rendering the compound less potent than AVP.

The most potent stimuli for AVP release are increased plasma osmolality, decreased blood pressure, and a decrease in circulating blood volume.^3-5 Additional abnormalities that cause AVP release include pain, nausea, hypoxia, hypercarbia, pharyngeal stimuli, glycopenia, drugs or chemicals (i.e., acetylcholine, high-dose opioids, dopamine, angiotensin II, prostaglandins, glutamine, histamine), certain malignant tumors, and mechanical ventilation.^6-8

Release of AVP is inhibited by drugs such as glucocorticoids, low-dose opioids, atrial natriuretic factor, and γ-aminobutyric acid. Hyperosmolality is sensed by both peripheral and central osmoreceptors. Central osmoreceptors are located outside the blood-brain barrier and detect changes in systemic osmolality. Peripheral osmoreceptors in the hepatic portal veins enable early detection of the osmolality of ingested food and liquids. Afferent impulses ascend via the vagus nerve to the paraventricular and supraoptic nuclei within the blood-brain barrier to stimulate its release. In addition, plasma hypertonicity depolarizes the magnocellular neurons of the hypothalamus to cause more AVP release.

Decreases in blood volume or pressure also stimulate exponential increases in AVP. Hypovolemia and hypotension shift the osmolality-vasopressin response curve so that higher vasopressin levels are required to maintain a normal osmolality in hypotensive states.⁹ Afferent impulses from the left atrial, aortic arch, and carotid sinus stretch receptors tonically inhibit vasopressin secretion. Atrial stretch receptors respond to increases in blood volume, and the receptors in the aortic arch and carotid sinuses respond to increases in arterial blood pressure. A decrease in arterial baroreceptor activity increases vasopressin secretion during hypotensive states.

VASOPRESSIN RECEPTORS

Vasopressin receptors are G protein–coupled receptors. The cellular effects of vasopressin are mediated by interactions of the hormone with several types of receptors (Table 177-1). V₁ receptors (V₁R), previously known as V_1a receptors, are found primarily on vascular smooth muscle cells and cause vasoconstriction in most vascular beds that is mediated by G_q protein–coupled activation of the phospholipase C and phosphoinositide pathways. Increased levels of inositol phosphate and diacylglycerol activate voltage-gated calcium channels. This results in increased intracellular calcium levels and subsequent vasoconstriction.

Table 177-1 Vasopressin Receptors, Tissues Affected, and Principal Effects

Vasopressin also causes inactivation of the potassium–adenosine triphosphate channels in vascular smooth muscle cells. Opening of these channels (as occurs with acidosis or hypoxia) allows an efflux of potassium from the endothelial cells, subsequent hyperpolarization, and prevention of calcium from entering the cells. (An increase in cytosolic calcium is essential for vasoconstriction.) In contrast, inactivation of the potassium–adenosine triphosphate channel leads to depolarization, opening of the voltage-gated calcium channels, and an increase in cytosolic calcium with subsequent vasoconstriction.

Interestingly, vasodilation may occur in some vascular beds, most likely mediated by nitric oxide. V₁Rs are found in the vascular endothelium of the kidney, skin, skeletal muscle, pancreas, thyroid gland, myometrium, bladder, hepatocytes, adipocytes, and spleen. Platelets also express the V₁R, which causes an increase in intracellular calcium and facilitates thrombosis when stimulated. V₁Rs in the kidneys lead to reduced blood flow to the inner medulla, limit the antidiuretic effects of vasopressin, and selectively cause contraction of the efferent arterioles to increase glomerular filtration rate. There is considerable variation among species with respect to the location and function of the V₁R.

V₂ receptors (V₂Rs) are found primarily on the basolateral membrane of the distal tubule and in the principal cells of the cortical and medullary renal collecting duct. Coupling of the V₂R with the G_s signaling pathway increases intracellular cAMP. The cAMP triggers fusion of the aquaporin-2–bearing vesicles with the apical plasma membrane of the collecting duct principal cells to increase free water absorption. AVP regulates water homeostasis in two ways: (1) regulation of the fast shuttling of aquaporin-2 to the cell surface and (2) stimulation of the synthesis of messenger ribonucleic acid–encoding aquaporin-2. Most animals with nephrogenic diabetes insipidus have V₂R gene mutations.

V₂R activation also stimulates the release of platelets from the bone marrow and enhances the release of von Willebrand factor and factor VIII from endothelial cells. It causes a mild increase in the activity of factor VIII–related antigen and ristocetin cofactor. There may also be V₂Rs in the vascular endothelium, because the potent V₂R agonist 1-deamino-8-D-arginine vasopressin (DDAVP) causes vasodilation in addition to the release of von Willebrand factor and factor VIII.

The V₃ pituitary receptors (V₃R, previously known as V_1bR) activate G_q protein and release intracellular calcium after activation of phospholipase C and the phosphoinositol cascade. V₃R activation stimulates release of adrenocorticotropic hormone from the anterior pituitary gland.¹⁰ These receptors are also responsible for the actions of vasopressin on the central nervous system, where they act as a neurotransmitter or a modulator of memory, blood pressure, body temperature, sleep cycles, and release of pituitary hormones.

The oxytocin receptor is a nonselective vasopressin receptor with equal affinity for both AVP and oxytocin. Activation of the oxytocin receptor leads to smooth muscle contraction, primarily in the myometrium and mammary myoepithelial cells. AVP also acts on oxytocin receptors in the umbilical vein, aorta, and pulmonary artery, where it causes a nitric oxide–mediated vasodilation. Stimulation of cardiac oxytocin receptors leads to the release of atrial natriuretic peptide.

Vasopressin also stimulates the P₂ class of purinoreceptors (ATP receptors), which leads to vasodilation mediated by nitric oxide and prostacyclin. P₂ receptors are also positive inotropic agents without direct effects on heart rate.