1 OPC-31260, a benzazepine derivative, has been studied for its ability to antagonize the binding of arginine vasopressin (AVP) to receptors in rat liver (V1) and kidney (V2) plasma membranes, for antagonism of the antidiuretic action of AVP in alcohol-anaesthetized rats and for diuretic action in conscious normal rats. 2 OPC-31260 caused a competitive displacement of [3H]-AVP binding to both V1 and V2 receptors with IC50 values of 1.2 + 0.2 x 106M and 1.4 + 0.2 x 10-8M, respectively. 3 OPC-31260 at doses of 10 to 100pg kg-', i.v., inhibited the antidiuretic action of exogenously administered AVP in water-loaded, alcohol-anaesthetized rats in a dose-dependent manner. OPC-31260 did not exert an antidiuretic activity suggesting that it is not a partial V2 receptor agonist. 4 After oral administration at doses of 1 to 30mgkg-1 in normal conscious rats, OPC-31260 dosedependently increased urine flow and decreased urine osmolality. The diuretic action of OPC-31260 was characterized as aquaresis, the mode of diuretic action being different from previously known diuretic agents such as furosemide, hydrochlorothiazide and spironolactone. 5 The results indicate that OPC-31260 is a selective V2 receptor antagonist and behaves as an aquaretic agent. OPC-31260 will be a useful tool in studying the physiological role of AVP and in the treatment of various conditions characterized by water retention.

An orally effective, nonpeptide, vasopressin V1 receptor antagonist, OPC-21268, has been identified. This compound selectively antagonized binding to the V1 subtype of the vasopressin receptor in a competitive manner. In vivo, the compound acted as a specific antagonist of arginine vasopressin (AVP)-induced vasoconstriction. After oral administration in conscious rats, the compound also antagonized pressor responses to AVP. OPC-21268 can be used to study the physiological role of AVP and may be therapeutically useful in the treatment of hypertension and congestive heart failure.

Arginine-vasopressin (AVP) is a hormone that is essential for both osmotic and cardiovascular homeostasis, and exerts important physiological regulation through three distinct receptors, V1a, V1b, and V2. Although AVP is used clinically as a potent vasoconstrictor (V1a receptor-mediated) in patients with circulatory shock, the physiological role of vasopressin V1a receptors in blood pressure (BP) homeostasis is ill-defined. In this study, we investigated the functional roles of the V1a receptor in cardiovascular homeostasis using gene targeting. The basal BP of conscious mutant mice lacking the V1a receptor gene (V1a ؊/؊ ) was significantly (P < 0.001) lower compared to the wild-type mice (V1a ؉/؉ ) without a notable change in heart rate. There was no significant alteration in cardiac functions as assessed by echocardiogram in the mutant mice. AVP-induced vasopressor responses were abolished in the mutant mice; rather, AVP caused a decrease in BP, which occurred in part through V2 receptor-mediated release of nitric oxide from the vascular endothelium. Arterial baroreceptor reflexes were markedly impaired in mutant mice, consistent with a loss of V1a receptors in the central area of baroreflex control. Notably, mutant mice showed a significant 9% reduction in circulating blood volume. Furthermore, mutant mice had normal plasma AVP levels and a normal AVP secretory response, but had significantly lower adrenocortical responsiveness to adrenocorticotropic hormone. Taken together, these results indicate that the V1a receptor plays an important role in normal resting arterial BP regulation mainly by its regulation of circulating blood volume and baroreflex sensitivity.knockout mouse ͉ adrenal cortex T he neurohypophyseal hormone arginine vasopressin (AVP) is involved in a plethora of physiological regulatory processes that occur via stimulation of specific V1a, V1b, and V2 receptors (1). These receptors have distinct pharmacological profiles and couple with specific intracellular second messengers (1). Vasopressin plays a prominent role in the cardiovascular system and influences arterial blood pressure (BP) at multiple sites in a complex fashion. The role of AVP has been well characterized in the regulation of BP in pathophysiological conditions such as severe hypovolemia͞hypotension episodes (2). However, its contribution to BP homeostasis in normal physiological situations is ill-defined (3). Vasopressin is a potent stimulator of vascular smooth muscle contraction in vitro, and V1a receptors mediate its vasoconstrictor effect (3). However, a relatively large amount of vasopressin is required to raise BP in vivo under normal physiological conditions (4); this is thought to be because vasopressin also acts on the brain, decreasing cardiac output by inhibiting sympathetic efferent activity and potentiating baroreflexes (5). AVP has been shown to enhance baroreflex function via activation of V1 receptors in the area postrema (6-8). In addition, vasopressin causes vasodilatation in some blood vessels, perhaps via rele...

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