Inhibitory G-protein–mediated modulation of slow delayed rectifier potassium channels contributes to increased susceptibility to arrhythmogenesis in aging heart

BACKGROUND Slow delayed rectifier potassium current (I-Ks) is an important component of repolarization reserve during sympathetic nerve excitement. However, little is known about age-related functional changes of I-Ks and its involvement in age-dependent arrhythmogenesis. OBJECTIVE The purpose of this study was to investigate age-related alteration of the I-Ks response to beta-adrenergic receptor (beta AR) activation. METHODS Dunkin-Hartley guinea pigs were used. Whole-cell patch-clamp recording was used to record K+ currents. Optical mapping of membrane potential was performed in ex vivo heart. RESULTS There was no difference in I-Ks density in ventricular cardiomyocytes between young and old guinea pigs. However, in contrast to I-Ks potentiation in young hearts, isoproterenol (ISO) evoked an acute inhibition on IKs in a concentration-dependent manner in old guinea pig hearts. The beta(2)AR antagonist, but not beta(1)AR antagonist, reversed the inhibitory response. Preincubation of cardiomyocytes with the inhibitory G protein (Gi) inhibitor pertussis toxin (PTX) also reversed the inhibitory response. In HEK293 cells cotransfected with cloned I-Ks channel and beta(2)AR, ISO enhanced the current but reduced it when cells were cotransfected with Gi2, and PTX restored the ISO-induced excitatory response. Moreover, in aging cardiomyocytes, G beta gamma inhibitor gallein, PLC inhibitor U73122, or protein kinase C inhibitor Bis-1 prevented the reduction of I-Ks by ISO. Furthermore, cardiac-specific Gi2 overexpression in young guinea pigs predisposed the heart to ventricular tachyarrhythmias. PTX pretreatment protected the hearts from ventricular arrhythmias. CONCLUSION beta AR activation acutely induces an inhibitory I-Ks response in aging guinea pig hearts through beta(2)AR-Gi signaling, which contributes to increased susceptibility to arrhythmogenesis in aging hearts.