title: In vivo pharmacology of Ro 46-2005, the first synthetic nonpeptide endothelin receptor antagonist: implications for endothelin physiology.
abstract: Ro 46-2005 is a small-molecular-weight nonpeptide antagonist of the endothelin (ET), ETA and ETB 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.
authors.affiliation: Pharma Division, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Clozel
authors.forename: V
authors.initials: V
authors.lastname: Breu
authors.forename: G A
authors.initials: GA
authors.lastname: Gray
authors.forename: B M
authors.initials: BM
authors.lastname: Löffler
mesh_terms: D000758:Anesthesia; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology*; D000096926:Benzenesulfonamides
chemical_list: D001120:Arginine; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide; D011743:Pyrimidines; D013449:Sulfonamides; C083751:Ro 46-2005; D000096926:Benzenesulfonamides