Arginine Vasopressin Antagonists for the Treatment of Heart Failure and Hyponatremia

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Arginine vasopressin has attracted attention as a potentially important neurohormonal mediator of the heart failure (HF) syndrome and hyponatremic states in humans1 because vasopressin influences renal handling of free water, vasoconstriction, and myocyte biology.2,3 Several vasopressin antagonists are under development,4 and one of these agents, conivaptan, recently received US Food and Drug Administration approval for short-term intravenous treatment in patients with euvolemic or hypervolemic hyponatremia. A neurohypophysial hormone, vasopressin (also called antidiuretic hormone [ADH]), affects free water reabsorption by the kidney, body fluid osmolality, blood volume, vasoconstriction, and myocardial contractile function.2,3 Vasopressin is synthesized by neurosecretory cells located predominantly in the supraoptic and paraventricular hypothalamic nuclei. These neurons have axons terminating in the neural lobe of the posterior pituitary (neurohypophysis) that release vasopressin and oxytocin.5 ### Physiology of Regulation of Vasopressin Release Normally, the dominant stimulant for vasopressin release is a change in plasma tonicity, plasma volume depletion, or blood pressure, the last 2 mediated by arterial baroreceptors. Osmoreceptors in the anterior hypothalamus sense the increase in serum osmolality and stimulate secretion of vasopressin from the posterior pituitary. In an attempt to normalize plasma osmolality, vasopressin acts on the V2 renal receptors, increasing free water reabsorption by insertion of protein water channels, aquaporins, in the luminal membranes of the principal cells of the renal collecting ducts.6 ### Receptor/Effector Mechanisms The 3 vasopressin receptor subtypes belong to a family of rhodopsin-like G-protein–coupled receptors.7 V1a (vascular) receptors are located on several cell types, including vascular smooth muscle cells and cardiomyocytes (Table 1), with effects on the maintenance and regulation of vascular tone and possibly myocardial function.3 View this table: Table 1. Vasopressin Receptors: Location and Function 5,8 V1b (pituitary) receptors are expressed on the surfaces of corticotrophic cells in the anterior pituitary and the pancreas and adrenal medulla (Table 1).5,8 V1a and V1b receptors are …