title: Ro 40-5967, a novel calcium channel antagonist, protects against ventricular fibrillation.
abstract: Ro 40-5967 is a new calcium channel antagonist that binds at the same membrane sites as verapamil, yet has minimal negative inotropic effects. The effects of Ro 40-5967 on the susceptibility to ventricular fibrillation were investigated and compared to diltiazem. Ventricular fibrillation (VF) was induced in 40 mongrel dogs with healed myocardial infarctions by a 2-min coronary occlusion during exercise. Twenty-four animals were found to be susceptible to VF and were given the treatments described below. Pretreatment with Ro 40-5967 (n = 17, 1000 micrograms/kg i.v.) significantly (P < 0.001) reduced the incidence of VF (13 of 17 protected) during the exercise plus ischemia test. Diltiazem (n = 8, 1000 micrograms/kg) completely suppressed VF. Lower doses of diltiazem and Ro 40-5967 did not prevent VF. The hemodynamic effects of Ro 40-5967 were also compared to diltiazem and verapamil. Diltiazem and verapamil, but not Ro 40-5967, increased P-R interval in a dose-dependent manner. Even when reflex tachycardia was controlled by beta-adrenoceptor blockade, Ro 40-5967 still exerted only minimal effects on P-R interval. Verapamil, but neither Ro 40-5967 nor diltiazem, provoked a dose-dependent negative inotropic response. All three drugs elicited large increases in coronary blood flow. These data support the hypothesis that calcium entry may play a critical role in the development of malignant arrhythmias during ischemia. Further, Ro 40-5967 can protect against ventricular fibrillation without significant negative inotropic or dromotropic effects.
authors: Department of Physiology, Ohio State University, Columbus 43210.
authors: G E
authors: GE
authors: Billman
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001665:Binding Sites; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D004110:Diltiazem / Q000494:pharmacology; D004198:Disease Susceptibility; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D020748:Mibefradil; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000503:physiopathology; D017202:Myocardial Ischemia / Q000503:physiopathology; D005082:Physical Exertion; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D014693:Ventricular Fibrillation / Q000517:prevention & control*; D014700:Verapamil / Q000494:pharmacology
chemical_list: D001562:Benzimidazoles; D002121:Calcium Channel Blockers; D013764:Tetrahydronaphthalenes; D020748:Mibefradil; D014700:Verapamil; D004110:Diltiazem