title: Effects of Ro 40-5967, a novel calcium antagonist, on myocardial function during ischemia induced by lowering coronary perfusion pressure in dogs: comparison with verapamil.
abstract: Ro 40-5967 is a structurally novel calcium antagonist that binds to the verapamil binding site but has very weak negative inotropic effects compared to verapamil. The goals of the present study were to assess the effects of Ro 40-5967 on myocardial function during ischemia, and to compare them to those of verapamil. For this purpose, in anesthetized dogs where the circumflex coronary artery was cannulated and perfused at controlled pressure, myocardial function was measured using piezo electric crystals implanted into the endocardium. Myocardial distribution of coronary blood flow was assessed using radioactive microspheres. Ischemia was produced by lowering perfusion pressure from 100 to 15 mm Hg in steps. During ischemia, Ro 40-5967 partially prevented the decrease of segmental shortening (p less than 0.01) and increased coronary flow, especially in the endocardium (p less than 0.01). In contrast, verapamil did not improve myocardial function during ischemia. The protective effect of Ro 40-5967 could be partially explained by the decrease of arterial pressure and heart rate induced by Ro 40-5967. However, Ro 40-5967 injected directly inside the coronary artery did not induce systemic effects, but still had protective effects (p less than 0.05). Verapamil injected intracoronary produced severe cardiac depression. We conclude that in the present model during ischemia Ro 40-5967 has no negative inotropic effects, and in contrast to verapamil can improve the myocardial function.
authors: Pharmaceutical Research Department, F. Hoffmann-La Roche & Co., Ltd., Basel, Switzerland.
authors: J P
authors: JP
authors: Clozel
authors: L
authors: L
authors: Banken
authors: W
authors: W
authors: Osterrieder
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects*; D003327:Coronary Disease / Q000188:drug therapy / Q000503:physiopathology*; D004285:Dogs; D006321:Heart / Q000503:physiopathology*; D007275:Injections, Intravenous; D020748:Mibefradil; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology*
chemical_list: D001562:Benzimidazoles; D002121:Calcium Channel Blockers; D013764:Tetrahydronaphthalenes; D020748:Mibefradil; D014700:Verapamil