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 β-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 β-adrenoceptor–stimulated conditions. I_Kr was not significantly influenced by β-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 β-adrenoceptor is activated, I_Ks modulation may become more important.