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(Hypertension. 1997;30:1204-1209.)
© 1997 American Heart Association, Inc.

Articles

ET_B Receptor and Nitric Oxide Synthase Blockade Induce BQ-123–Sensitive Pressor Effects in the Rabbit

Jean-Philippe Gratton; Ghislain Cournoyer; Bernd-Michael Löffler; Pierre Sirois; Pedro D'Orléans-Juste

From the Department of Pharmacology (J.P.-G., G.C., P.S., P.D.-J.), Medical School, Université de Sherbrooke, Québec, Canada, and Pharma Division (B.-M.L.), Preclinical Research, F. Hoffmann–La Roche Ltd, Basel, Switzerland.

Correspondence to Pedro D'Orléans-Juste, PhD, Department of Pharmacology, Medical School, Université de Sherbrooke, Sherbrooke (Québec) J1H 5N4, Canada. E-mail labpdj{at}courrier.usherb.ca

Abstract Endothelin-1 (0.25 nmol/kg, injected into the left cardiac ventricle) induces a protracted increase of mean arterial pressure that is significantly reduced by the selective ET_A receptor antagonist BQ-123 (1 and 10 mg/kg) in the anesthetized rabbit. The sole administration of the selective ET_B antagonist BQ-788 (0.25 mg/kg) induces a pressor response abolished by BQ-123 (1 mg/kg). Concomitant to the increase in mean arterial pressure, BQ-788 induces a significant increase in plasma levels of endothelin-1 and its precursor big endothelin-1. The nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME; 10 mg/kg) also increases arterial blood pressure, and the response is reduced dose-dependently by BQ-123 (1 and 10 mg/kg). In addition, the administration of BQ-788 in the presence of L-NAME induced a further increase in arterial blood pressure. The duration of the pressor response to L-NAME is also significantly reduced by an endothelin-converting enzyme inhibitor, phosphoramidon (10 mg/kg). Finally, L-NAME induces an increase in plasma levels of big endothelin-1 but not endothelin-1. Our results illustrate that blockade of either nitric oxide synthase or ET_B receptors triggers a raise in plasma levels of endothelin-1 or its precursor. These later moieties are suggested to be significantly involved, through the activation of ET_A receptors, in the pressor effects of L-NAME and BQ-788 in the anesthetized rabbit.

Key Words: receptors, endothelin • arterial pressure • rabbits • endothelin-1 • endothelin-converting enzyme • nitric oxide

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