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(Hypertension. 2000;35:726.)
© 2000 American Heart Association, Inc.

Scientific Contributions

ET_B Receptor Blockade Potentiates the Pressor Response to Big Endothelin-1 But Not Big Endothelin-2 in the Anesthetized Rabbit

Jean-Philippe Gratton; Giles A. Rae; Ghassan Bkaily; Pedro D’Orléans-Juste

From the Department of Pharmacology (J.-P.G.), Yale University School of Medicine, Boyer Center for Molecular Medicine, New Haven, Ct; the Department of Pharmacology (G.A.R.), Centro de Ciencias Biologicas, Universidade Federal de Santa Catarina, Florianopolis, Brazil; and the Department of Anatomy and Cell Biology (G.B.) and the Department of Pharmacology (P.D’O.-J.), Medical School, Université de Sherbrooke, Sherbrooke, Québec, Canada.

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

Abstract—The precursor of endothelin-1, big endothelin-1, is considered to be a more reliable marker of systemic production of vasoactive peptide. However, it is largely unclear whether ET_B receptor–dependent clearance and endothelium-derived relaxing factors affect the precursor in a similar manner to mature ET-1. These ET_B-dependent modulations of big ET-1 and big ET-2 pressor properties were therefore studied in the anesthetized rabbit. When injected into the left cardiac ventricle, ET-1 and ET-2 (0.01 to 1 nmol/kg) each induced biphasic responses (a depressor followed by a pressor response), whereas big ET-1 and big ET-2 (0.1 to 3 nmol/kg) caused only protracted pressor responses. The highest dose of big ET-1 caused significantly greater responses than ET-1, ET-2, or big ET-2. A selective ET_A receptor antagonist, BQ-123 (1 mg/kg), markedly reduced pressor responses to all 4 peptides, whereas blockade of ET_B receptors with BQ-788 (0.25 mg/kg) sharply potentiated the responses to ET-1, ET-2, and big ET-1, but not to big ET-2. Indomethacin (10 mg/kg) sharply potentiated the pressor response to ET-1 (1 nmol/kg), but not big ET-1, at all time points. In control animals, ET-1, but not big ET-1, also triggered an indomethacin-sensitive increase in circulating prostacyclin. Finally, systemically administered big ET-1, but not big ET-2, induced a phosphoramidon-sensitive increase in plasma IR-ET. Our results suggest a significant limiting role of ET_B receptors on pressor responses to big ET-1. In contrast, the same receptor entities do not modulate the hemodynamic properties of the ET-2 precursor, given that, unlike big ET-1, it is poorly converted in the pulmonary or systemic circulation in anesthetized rabbits.

Key Words: endothelin • endothelium-derived relaxing factor • endothelin-converting enzyme • prostacyclin • chromatography • receptors

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