title: Effects of anipamil, a long acting analog of verapamil, in pigs subjected to myocardial ischemia.
abstract: In this study we examined the cardiovascular and possible antiarrhythmic actions of anipamil, a long acting analog of verapamil. Initial dose-response studies for anipamil (0.25-6.0 mg/kg, i.v.) in pentobarbitone-anesthetized pigs (n = 4) were conducted to determine the effects of the drug on EKG and hemodynamic measures. In this initial study anipamil was found to produce a dose-dependent reduction in blood pressure, left-ventricular pressure and its derivative (dP/dtmax), cardiac output, and increase in heart rate. These results were used as a basis from which to choose doses for a second study to assess antiarrhythmic actions of anipamil against arrhythmias induced by regional myocardial ischemia. The antiarrhythmic effects of the two doses were compared with verapamil when the latter was given at a dose producing cardiovascular effects mid-way between those produced by the two doses of anipamil. Anesthetized pigs were randomly assigned to receive one of three drug treatments, or vehicle control, prior to occlusion of the left-anterior descending coronary artery. Antiarrhythmic effectiveness of low (1.0 mg/kg + 0.10 mg/kg/min infusion, n = 8) and high (5.0 mg/kg + 0.50 mg/kg/min infusion, n = 12) dose anipamil was compared to that of verapamil (0.5 mg/kg + 0.60 mg/kg/min infusion, n = 8) in a vehicle controlled study (n = 15). Arrhythmic events (VPB, VT and VF incidence) were monitored and grouped according to their time of occurrence after occlusion. Thus phase 1a arrhythmias occurred 0-5 min after initiation of occlusion, phase 1b, 5-30 min, and phase 2, 0.5-4 hr after occlusion. This study showed that during phase 1a there was a low incidence of arrhythmias in all groups except the one receiving 5 mg/kg anipamil where the group incidence of VT was 58% as compared to 20% in controls (n = 15). Most ventricular arrhythmias occurred in all groups during phase 1b. In this phase verapamil abolished VF and reduced VT, as compared with controls. Anipamil (high and low doses) tended to reduce VT but not VF. In the period 0.5 to 4 hours post occlusion (phase 2) all three drug treatments were associated with fewer arrhythmias but this only reached statistical significance with verapamil. Thus verapamil was more efficacious than anipamil at providing antiarrhythmic protection against both early and late onset arrhythmias. Anipamil may have been proarrhythmic in the early phase of arrhythmias and only moderately antiarrhythmic, if at all, in the later phase.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Department of Pharmacology & Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, Canada.
authors.forename: M K
authors.initials: MK
authors.lastname: Pugsley
authors.forename: C R
authors.initials: CR
authors.lastname: Ries
authors.forename: L J
authors.initials: LJ
authors.lastname: Guppy
authors.forename: C J
authors.initials: CJ
authors.lastname: Harvie
authors.forename: M J
authors.initials: MJ
authors.lastname: Walker
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D017202:Myocardial Ischemia / Q000097:blood / Q000503:physiopathology*; D011437:Propylamines / Q000494:pharmacology*; D013552:Swine; D013997:Time Factors; D014700:Verapamil / Q000494:pharmacology
chemical_list: D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D011437:Propylamines; C045313:anipamil; D014700:Verapamil