flunarizine and Coronary-Disease

Spontaneous sustained ventricular tachycardia (VT) occurring 16-24 hours after left anterior descending (LAD) coronary artery occlusion in the canine heart is most likely based on abnormal automaticity. In vitro, it has been demonstrated that the rate of the arrhythmia and the effect of overdrive pacing depends on the maximal diastolic potential (MDP). The MDP is also of importance in understanding the effect of antiarrhythmic drugs. To study 1) the possible presence of different responses to overdrive pacing and 2) the relation between the response to overdrive pacing and the effect of different antiarrhythmic drugs in the intact heart, we investigated the effect of 1) (prolonged) pacing and 2) lidocaine (3 mg/kg), verapamil (0.4-1.0 mg/kg), or flunarizine (2 mg/kg) during VT.. In 21 conscious dogs with chronic atrioventricular block, 60 sustained VTs were observed 1 day after LAD occlusion. During VT, pacing with interstimulus intervals of 400, 300, and 200 msec for 15, 60, and 120 seconds was done on 40 VTs. Based on their response to pacing, VTs were divided into a pacing-suppressible (PS group) and a pacing-nonsuppressible group (PNS group). The mean cycle length in the PS group was significantly longer (410 +/- 50 msec) than in the PNS group (360 +/- 35 msec, p less than or equal to 0.01). Suppression was directly related to the rate and duration of pacing. Spontaneous recurrence of VTs was observed after 26 +/- 45 seconds. Lidocaine and verapamil increased cycle length of the suppressible VTs and terminated them, whereas flunarizine had no effect. Except for verapamil, which increased cycle length of the VTs, no effects were seen in the PNS group.. In conscious dogs showing sustained VTs 16-24 hours after LAD occlusion, 1) the slower VTs can be suppressed by pacing, verapamil, and lidocaine but not by flunarizine, and 2) the faster VTs are not affected by pacing, lidocaine, and flunarizine, and are only slowed by verapamil. These findings are compatible with in vitro findings of abnormal automaticity, with the slower VTs originating from a higher MDP than the faster VTs.

Topics: Animals; Arterial Occlusive Diseases; Cardiac Pacing, Artificial; Coronary Disease; Dogs; Electrocardiography; Electrophysiology; Female; Flunarizine; Lidocaine; Male; Tachycardia; Time Factors; Verapamil

The effect of flunarizine, a calcium entry-blocker, on the ischemic myocardial metabolism of the open-chest dog heart was examined and compared to that of diltiazem. During ischemia, initiated by ligating the left anterior descending coronary artery, the metabolism of the myocardium switched from aerobic to anaerobic; the levels of glycogen, fructose-1,6-diphosphate (FDP), adenosinetriphosphate and creatinephosphate decreased, and the levels of glucose-6-phosphate (G6P), fructose-6-phosphate (F6P), lactate, adenosine diphosphate and adenosine monophosphate increased during 3 min of ischemia. The calculated energy charge potential decreased, and the [( G6P] + [F6P]/[FDP] ratio and the lactate/pyruvate ratio were increased by ischemia. Flunarizine (0.3 or 1 mg/kg) or diltiazem (0.1 mg/kg) was injected i.v. 5 min before the start of ischemia. Pretreatment with either flunarizine or diltiazem reduced the decrease in the energy charge potential and the increase in the [( G6P] + [F6P]/[FDP] ratio during ischemia. Flunarizine (1 mg/kg) and diltiazem (0.1 mg/kg) reduced the accumulation of lactate due to ischemia, leading to a decrease in the lactate/pyruvate ratio. Flunarizine and diltiazem may lessen the influence of ischemia on the myocardial tissue.

Topics: Adenine Nucleotides; Animals; Blood Pressure; Coronary Circulation; Coronary Disease; Diltiazem; Dogs; Female; Flunarizine; Fructose; Glucose; Glucosephosphates; Glycogen; Heart Rate; Male; Myocardium; Phosphocreatine

In male rats, anaesthetized with pentobarbitone, ligation of the main left coronary artery causes an early phase of ventricular arrhythmias which last about 30 min. In approximately 60% of control animals, ventricular fibrillation occurs but since spontaneous reversion to sinus rhythm may occur, mortality is of the order of 30%. When administered intravenously 15 min prior to ligation, verapamil (0.01 and 0.05 mg kg-1), prenylamine (0.5 mg kg-1), flunarizine (0.1, 0.25, 0.5 and 1.0 mg kg-1) and cinnarizine (0.25, 0.5 and 1.0 mg kg-1) protected against these arrhythmias. Higher doses of verapamil (0.1 and 0.5 mg kg-1), prenylamine (5 mg kg-1) and flunarizine (2.5 mg kg-1) did not afford a similar protection and mortality was increased to or above control values. Death was due in prenylamine-treated rats to atrioventricular block leading to asystole whereas in those administered verapamil or flunarizine it was a consequence of persistent ventricular fibrillation. Prior to ligation, a sustained fall in mean arterial blood pressure was observed only following the administration of the highest doses of prenylamine, flunarizine and cinnarizine. Heart rate was reduced by administration of only the highest dose of prenylamine. These studies show that although the four calcium antagonists studied, i.e. verapamil, prenylamine, flunarizine and cinnarizine do suppress ischaemia-induced arrhythmias, this protective effect may be limited to a narrow concentration range.

Topics: Anesthesia; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Blood Pressure; Calcium Channel Blockers; Cinnarizine; Coronary Disease; Flunarizine; Heart Rate; Male; Prenylamine; Rats; Rats, Inbred Strains; Verapamil

We tested the effects of the calcium antagonists lanthanum, diltiazem, and flunarizine on the development of atherosclerosis in rabbits fed a 2% cholesterol diet. The drugs were given orally and were well tolerated. In the cholesterol control animals, 52.2% of the thoracic aortic intimal surface was Sudan IV positive. This was reduced by 37% (p less than 0.05) with lanthanum, 37% (p less than 0.05) with diltiazem, and 34% (p less than or equal to 0.06) with flunarizine. In all cholesterol-fed animals, the intramural, but not subepicardial, coronary arteries were severely diseased. The extent and distribution of this disease were not altered by the various drug interventions. Thus, the calcium antagonists lanthanum, diltiazem, and flunarizine suppress atherogenesis of the rabbit aorta but have no effect on the extent or distribution of atherosclerosis in the intramural coronary arteries.

Topics: Animals; Aortic Diseases; Arteriosclerosis; Calcium Channel Blockers; Cholesterol, Dietary; Cinnarizine; Coronary Disease; Diltiazem; Female; Flunarizine; Lanthanum; Organ Size; Rabbits