Cyclic AMP mediated arrhythmias induced in the ischaemic pig heart

Ligation of the anterior descending coronary artery two-thirds from its origin in the pig was found to precipitate ventricular arrhythmias and fibrillation, starting approximately 20 min post-ligation, which were associated with regional accumulation of myocardial cAMP in the ischaemic area. When the arrhythmias stopped, cyclic AMP levels in the ischaemic zone were decreased. Arrhythmias could then be induced by subepicardial infusion (10 microliter/min) close to the visible edge of ischaemia of cAMP analogues [N6-monobutyryl cAMP, N6,O2'-dibutyryl cAMP (5.10(-2) M each)] or agents which increase the myocardial contents of cAMP. These agents were: isoproterenol (10(-6) M), noradrenaline, adrenaline (10(-5) M each), glucagon, histamine (10(-3) M each), theophylline and caffeine (5.10(-2) M each). Also active were dopamine (10(-3) M), ouabain (10(-5) M) and aconitine (10(-6) M). The arrhythmias induced by infusion of catecholamines were dependent on Ca2+ and were abolished by beta-adrenoceptor blocking agents (pindolol, 10(-6) M) and calcium antagonists (isoptin, D 600, 10(-4) M each). Infusion of 150 mM sodium chloride or 100 mM sodium butyrate did not precipitate arrhythmias. It is concluded that myocardial cAMP may play an important role in the genesis of ventricular arrhythmias in the ischaemic heart, probably by augmenting the slow calcium inward current.