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

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^-7m propranolol or atenolol. Mn²⁺ (2 mm) or verapamil (2 μm) 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^-7m. In contrast, quinacrine (20 μm), an inhibitor of Na⁺Ca²⁺ 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⁺Ca²⁺ exchange.