Effects of the nonpeptide V-1 vasopressin receptor antagonist SR49059 in hypertensive patients

We assessed the clinical and pharmacological profile of the orally active V -1 vascular vasopressin (AVP) receptor nonpeptide antagonist SR49059 (SR) d uring the osmotic stimulation of AVP release in hypertensive patients. In a double-blind crossover-versus-placebo study, 24 untreated stage I or IT es sential hypertensive patients (12 whites and 12 blacks) received a single 3 00 mg oral dose of SR 2 hours before the stimulation of AVP secretion with a 5% hypertonic saline infusion, Hemodynamic, humoral, and hormonal paramet ers 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 infusi on. However, the blood pressure peak at the end of the hypertonic saline in fusion was slightly lower in the presence of SR (P=0.04). Heart rate was si gnificantly faster between 4 and 6 hours after SR administration (P=0.02), The rise in plasma sodium and osmolality triggered by the saline infusion w as not modified by SR, but AVP release was slightly greater in the presence of SR (P<0.0003). AVP-induced aggregation of blood platelets in vitro was significantly reduced by SR, with a peak effect 2 hours after drug administ ration that coincided with the SR peak plasma concentration. Plasma renin a ctivity and aldosterone before and after the saline infusion were not modif ied by SR, Urine volume and osmolality were not altered by SR administratio n. SR effects were similar in the 2 ethnic groups as well as in salt-sensit ive versus salt-resistant patients. In a situation of AVP osmotic release a nd volume expansion in hypertensive patients, a single oral dose of the V-1 vascular AVP receptor nonpeptide antagonist SR49059, which is able to bloc k AVP-induced platelet aggregation, exerts a transient vasodilation effect that is not associated with a sustained blood pressure reduction. SR49059 i s a pure V-1 vascular receptor antagonist that is devoid of V-2 renal recep tor actions.