Characterization and functional role of rapid- and slow-activating delayed rectifier K+ currents in atrioventricular node cells of guinea pigs

The atrioventricular (AV) node is the only conduction pathway where electrical impulse can pass from atria to ventricles and exhibits spontaneous automaticity. This study examined the function of the rapid- and slow-activating delayed rectifier K+ currents (I-Kr and I-Ks) in the regulation of AV node automaticity. Isolated AV node cells from guinea pigs were current- and voltage-clamped to record the action potentials and the I-Kr and I-Ks current. The expression of I-Kr or I-Ks was confirmed in the AV node cells by immunocytochemistry, and the positive signals of both channels were localized mainly on the cell membrane. The basal spontaneous automaticity was equally reduced by E4031 and HMR-1556, selective blockers of I-Kr and I-Ks, respectively. The nonselective beta-adrenoceptor agonist isoproterenol markedly increased the firing rate of action potentials. In the presence of isoproterenol, the firing rate of action potentials was more effectively reduced by the I-Ks inhibitor HMR-1556 than by the I-Kr inhibitor E4031. Both E4031 and HMR-1556 prolonged the action potential duration and depolarized the maximum diastolic potential under basal and beta-adrenoceptor-stimulated conditions. I-Kr was not significantly influenced by beta-adrenoceptor stimulation, but I-Ks was concentration-dependently enhanced by isoproterenol (EC50: 15 nM), with a significant negative voltage shift in the channel activation. These findings suggest that both the I-Kr and I-Ks channels might exert similar effects on regulating the repolarization process of AV node action potentials under basal conditions; however, when the beta-adrenoceptor is activated, I-Ks modulation may become more important.