Abstract-We assessed the clinical and pharmacological profile of the orally active V 1 vascular vasopressin (AVP) receptor nonpeptide antagonist SR49059 (SR) during the osmotic stimulation of AVP release in hypertensive patients. In a double-blind crossover-versus-placebo study, 24 untreated stage I or II essential hypertensive patients (12 whites and 12 blacks) received a single 300 mg oral dose of SR 2 hours before the stimulation of AVP secretion with a 5% hypertonic saline infusion. Hemodynamic, humoral, and hormonal parameters were monitored for up to 28 hours after drug administration. SR did not alter blood pressure or heart rate before the saline infusion and did not reduce the blood pressure increment induced by the hypertonic saline infusion. However, the blood pressure peak at the end of the hypertonic saline infusion was slightly lower in the presence of SR (Pϭ0.04). Heart rate was significantly faster between 4 and 6 hours after SR administration (Pϭ0.02). The rise in plasma sodium and osmolality triggered by the saline infusion was not modified by SR, but AVP release was slightly greater in the presence of SR (PϽ0.0003). AVP-induced aggregation of blood platelets in vitro was significantly reduced by SR, with a peak effect 2 hours after drug administration that coincided with the SR peak plasma concentration. Plasma renin activity and aldosterone before and after the saline infusion were not modified by SR. Urine volume and osmolality were not altered by SR administration. SR effects were similar in the 2 ethnic groups as well as in salt-sensitive versus salt-resistant patients. In a situation of AVP osmotic release and volume expansion in hypertensive patients, a single oral dose of the V 1 vascular AVP receptor nonpeptide antagonist SR49059, which is able to block AVP-induced platelet aggregation, exerts a transient vasodilation effect that is not associated with a sustained blood pressure reduction. SR49059 is a pure V 1 vascular receptor antagonist that is devoid of V 2 renal receptor actions. (Hypertension. 1999;34:1293-1300.)Key Words: vasopressins Ⅲ nonpeptide antagonist Ⅲ vasopressins Ⅲ hypertension, essential Ⅲ osmoregulation T he neurohypophysial hormone arginine vasopressin (AVP) is involved in the regulation of body fluid osmolality, blood volume, blood pressure, cell contraction, cell proliferation, and adrenocorticotropic hormone secretion via the stimulation of specific receptors currently classified into V 1 vascular (V 1 R), V 2 renal (V 2 R), and V 3 pituitary (V 3 R) subtypes with distinct pharmacological profiles and intracellular second messengers. 1 AVP has been shown to be one of the most powerful in vitro vasoconstrictor substances, 2 and its vasoconstrictor and mitogenic actions may contribute to the pathogenesis of arterial hypertension, heart failure, and atherosclerosis. 3,4 AVP plays a role in the maintenance of blood pressure in several conditions, including upright posture, dehydration, hemorrhage, adrenal insufficiency, and cardiac failure, and during surgery. 5,6 An...
