Catecholamine/cyclic AMP/Ca2+ induces arrhythmias in the healthy pig heart

Agents known to increase cAMP levels in the myocardium were infused subepicardially (focal infusion, 10 microliters/min) in healthy pigs (open chest). Noradrenaline (NA) (10(-5) M), adrenaline (10(-5) M), and isoproterenol (10(-6) M) (in 0.9% NaCl) induced arrhythmias infrequently, but in the presence of Ca2+ (2.5 X 10(-3) M CaCl2) they consistently induced arrhythmias--most commonly ventricular tachycardia--within 60 sec that were readily reversible on termination of infusion. N6,O2'-dibutyryl-cAMP (dbcAMP) and N6-monobutyryl-cAMP (mbcAMP) (5 X 10(-2) M each) produced arrhythmias lasting up to 1 hr with rather slow (up to 20 min) onset. Arrhythmias were induced by 8-Br-cAMP (5 X 10(-2) M) in the presence of inhibitor of cyclic nucleotide phosphodiesterase (3 X 10(-4) M Ro 7-2956) within 30 min. The NA/Ca2+ arrhythmias were abolished by isoptin, D 600, MnCl2 (each 10(-4) M) and beta adrenoceptor blockade (10(-5) M pindolol, 10(-4) propranolol; 10(-4) M D-propranolol was ineffective) but were not suppressed by tetrodotoxin (up to 10(-5) M). Arrhythmias induced by dbcAMP or mbcAMP were abolished by isoptin (10(-4) M) and MnCl2 (5 X 10(-4) M) but not propranolol (10(-4) M). The NA/Ca2+ arrhythmias were also abolished by carbamylcholine (10(-6) M). Acetylcholine (10(-4) M) was less effective. Arrhythmias were not precipitated by 0.9% NaCl, 2.5 X 10(-3) M CaCl2/0.9% NaCl, 5 X 10(-2) M N6-monobutyryl-2'-deoxy-cAMP (deoxy-mbcAMP) or 10(-1) M sodium butyrate. Analysis of myocardial tissue obtained from the NA/Ca2+ infusion site showed that cAMP was increased when ventricular tachycardia ensued. We conclude that the catecholamine/cAMP/Ca2+ system may play an important role in the genesis of arrhythimas, possibly by inducing automaticity in ventricular fibers through slow Ca2+ channels