A rginine vasopressin (AVP) is a human peptide hormone released during states of hypovolemia that stimulates the kidneys to conserve water by concentrating urine and reducing urine volume. It is synthesized in the hypothalamus as a pre-prohormone precursor and stored in the posterior pituitary gland.It is now believed that the role of AVP is central to the pathogenesis of various diseases such as congestive heart failure (CHF), cirrhosis, and the syndrome of inappropriate antidiuretic hormone secretion (SIADH). These clinical syndromes are characterized by elevated plasma levels of vasopressin and clinically manifest as a fluid retentive state. Therefore, patients become hyponatremic. There is a growing interest and effort to develop selective and long-lasting pharmaceutical agents that antagonize this effect.Over the past two decades, various vasopressin receptor antagonists (VRAs) have been developed and studied. The first nonpeptide vasopressin receptor antagonist was recently approved by the United States Food and Drug Administration (FDA), and other similar agents are presently in different stages of development. Clinically, these agents have the ability to reduce urine osmolality and increase free water excretion while preserving sodium and raising serum sodium concentration. This aquaretic effect is in contradistinction to that seen with traditional diuretics, which increase sodium excretion together with water excretion. Vasopressin PhysiologyArginine vasopressin, also known as antidiuretic hormone, is a 9-amino-acid peptide synthesized in the supraoptic and paraventricular nuclei of the hypothalamus. AVP is transported to the posterior lobe of the pituitary and stored in secretory granules. The two most important stimuli of AVP release are low blood volume and hypernatremia. Low blood volume is sensed by baroreceptors in the carotid artery, aortic arch, and left atrium and in response stimulate the release of vasopressin from the supraoptic and paraventricular nuclei. The body's protective mechanism to prevent the development of cardiovascular collapse when hypovolemia and hypotension are occurring is mediated by the vasoconstrictive properties of AVP.Vasopressin release is also regulated by osmoreceptors in the hypothalamus. The osmolality threshold for secretion is approximately 280 mOsm/kg, after which a small increase in plasma osmolality leads to enhanced vasopressin secretion. It is also known that vasopressin secretion also may be stimulated by non-osmotic and nonhemodynamic factors including nausea, pain, hypoglycemia, exercise, and drugs. Once secreted into serum, vasopressin has a half-life of approximately 10 minutes and is degraded by a cysteine amino-terminal peptidase called vasopressinase. Vasopressin ReceptorsADH receptors are G-protein-coupled receptors. There are 3 subtypes that differ in their localization and signal transduction mechanisms ( Table I). The vasopressin V1a receptor (V1aR) is a Gq-coupled receptor that activates phospholipase C and increases the concentration of intrace...