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(Hypertension. 1997;30:1121-1127.)
© 1997 American Heart Association, Inc.

Articles

Effects of SR 49059, a New Orally Active and Specific Vasopressin V₁ Receptor Antagonist, on Vasopressin-Induced Vasoconstriction in Humans

Roger Weber; Antoinette Pechère-Bertschi; Daniel Hayoz; Vjekoslav Gerc; Rémi Brouard; Jean-Paul Lahmy; Hans R. Brunner; Michel Burnier

From the Division of Hypertension and Vascular Medicine, and Policlinique Médicale Universitaire, Lausanne, Switzerland, and Sanofi Recherche, Montpellier, France.

Abstract We have evaluated the efficacy of SR 49059, a new orally active and specific vasopressin V₁ receptor antagonist (arginine-vasopressin [AVP]), in the blockade of the vascular effects of exogenous AVP in healthy subjects. In preliminary experiments, two procedures to measure the V₁ vascular effects of AVP were assessed. First, the AVP-induced changes in skin blood flow were investigated by the injection of increasing doses of AVP intradermally, with or without a previous local vasodilation with calcitonin gene–related peptide (CGRP). In a second protocol, AVP was infused intra-arterially, and the changes in radial artery diameter and blood flow were measured. The intradermal injection of AVP caused significant decreases in skin blood flow, and the use of CGRP increased the sensitivity of the method by a factor of 10² to 10³. AVP infused intra-arterially caused dose-dependent decreases in the radial artery diameter and blood flow. In the main study, the potency and efficacy of SR 49059 to block the AVP-induced changes in skin blood flow were assessed in 12 healthy men with a double-blind, triple crossover study design. The subjects were randomized to receive a placebo orally and 30 mg and 300 mg of the antagonist at a 1-week interval. The subjects were then further randomized to evaluate the efficacy of the same doses of the antagonist to block the vasoconstriction of the radial artery induced by an intra-arterial infusion of AVP. SR 49059 inhibits, dose-dependently and significantly, the AVP-induced changes in skin blood flow, with a peak effect occurring between 2 and 6 hours after injection. In addition, the 300-mg dose of SR 49059 completely blocked the vasoconstriction of the radial artery induced by AVP. In conclusion, skin blood-flow measurement, after intradermal injection of AVP on a skin area vasodilated with CGRP, is an effective method to investigate the V₁ vascular effect of AVP in humans. SR 49059 is a potent and specific antagonist of V₁ receptors, which blocks the AVP-induced vasoconstriction.

Key Words: vasopressin • blood flow • calcitonin gene–related peptide • radial artery

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