Arrhythmogenic effects of isoproterenol-activated Cl − current in guinea-pig ventricular myocytes

Abstract

Possible arrhythmogenic effects of the isoproterenol-activated Cl current were examined in isolated guinea-pig ventricular myocytes under various intra- and extracellular Cl − concentrations. Experiments were carried out with external K + concentration ([K +] o) decreased to 2 or 3 m m. Under symmetrical concentrations of Cl − in intra- and extra-cellular solutions (E Cl=0 mV), 1 μ m isoproterenol (ISP) depolarized resting membrane potential (RMP) by 6.2±1.1 mV and slowed repolarization with induction of early afterdepolarizations (EADs) in 9 out of 9 cells. EADs appeared at voltages positive to −40 mV, where L-type Ca 2+ current is assumed to be activated. When Cl − concentrations were settled near physiological conditions (E Cl=−40–50 mV), ISP depolarized RMP by 2.8±0.4 mV and elicited abnormal repolarization with occasional EADs in 6 out of 19 cells. When E Cl was set to −80 mV, however, ISP depolarized RMP by only 0.5±0.5 mV without induction of abnormal activities. Thus, depolarizing effects of ISP and incidence of repolarization abnormalities including EADs were increased as E Cl shifted to more positive potential levels. At [K +] o=4 m m, no abnormal activities were observed when E Cl was around −50 mV ( 0 8 ), and 6 out of 6 cells showed abnormal activities when E Cl was set to 0 mV. ISP-elicited abnormal activities were abolished by 1 m m DNDS (4,4′-dinitrostilbene-2,2′-disulphonic acid), a blocker for Cl − channels. We suggest that during conditions of hypokalemia or decreased K + conductance, ISP-activated Cl − current may contribute to the genesis of arrhythmias through facilitation of membrane depolarization and abnormal automaticity in combination with the concomitantly enhanced Ca 2+ current by ISP.