Mechanisms of action of beta-adrenergic agents on the arrhythmogenic transient inward current in rabbit Purkinje fibers

Abstract

Catecholamines increase the amplitudes of oscillatory afterpotentials (OAP) and peak magnitude of the transient inward current ( I ti) responsible for OAP. The objectives of this study were to determine whether β-adrenoceptor stimulation can induce I ti, and to determine the mechanism by which β-adrenoceptor stimulation increases the magnitude of I ti. Experiments were performed using standard two electrode voltage-clamp techniques in isolated rabbit Purkinje fibers. Holding potential was either −50 or −80 mV. The I ti was elicited by repolarizing steps, following 1.5 or 3 s activating steps to potentials near 0 mV. Isoproterenol (ISO) failed to induce the I ti at concentrations from 10 −8 to 10 −6 m. However, ISO (10 −7 m) significantly increased peak magnitude of spontaneously occurring I ti ( P < 0.05), or I ti induced by acetylstrophanthidin (AS) ( P < 0.05). ISO also shifted the minimum activation voltage 10 mV more negative ( P < 0.05). The currentvoltage relationship demonstrated that ISO significantly increased the range of potentials over which I ti≥5 nA occurred, but did not significantly shift the voltage at which maximum peak current was observed. Effects of ISO on I ti were blocked by 10 −7 m propranolol or atenolol. Mn 2+ (2 m m) or verapamil (2 μ m) blocked the slow inward current ( I si) more than 80% before substantially decreasing peak I ti. Either agent blocked stimulation of I si but not I ti by ISO at 10 −7 m. In contrast, quinacrine (20 μ m), an inhibitor of Na +Ca 2+ exchange, abolished stimulation of I ti by ISO while having no significant effect on I si. Our results indicate that β-adrenoceptor stimulation cannot induce I ti in rabbit Purkinje fibers, but can enhance the I ti induced by other means, by stimulating Na +Ca 2+ exchange.