In Vivo Pharmacology of Ro 46-2005, The First Synthetic Nonpeptide Endothelin Receptor Antagonist: Implications for Endothelin Physiology

Abstract

Summary: Ro 46-2005 is a small-molecular-weight nonpeptide antagonist of the endothelin (ET) ET_A and ET_B receptors, chemically derived from a class of compounds identified by systematic screening of chemicals. In vivo, Ro 46-2005 inhibited the depressor and, only at high doses (100 mg/kg i.v.) the pressor effect of ET-1. However, much lower doses (1 to 10 mg/kg i.v.) were sufficient to inhibit the pressor effect of the precursor big ET-1. As intravenous big ET-1 injection potentially reproduces better than ET-1 injection the physiological pattern of release of ET-1, we propose that intravenous big ET-1 should be used to evaluate the effects of antagonists on the constricting endothelin receptors.