Background: Slow delayed rectifier potassium current (I) is an important component of repolarization reserve during sympathetic nerve excitement. However, little is known about age-related functional changes of I and its involvement in age-dependent arrhythmogenesis.
Objective: The purpose of this study was to investigate age-related alteration of the I response to β-adrenergic receptor (βAR) 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 density in ventricular cardiomyocytes between young and old guinea pigs. However, in contrast to I potentiation in young hearts, isoproterenol (ISO) evoked an acute inhibition on I in a concentration-dependent manner in old guinea pig hearts. The βAR antagonist, but not βAR 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 channel and βAR, 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, Gβγ inhibitor gallein, PLC inhibitor U73122, or protein kinase C inhibitor Bis-1 prevented the reduction of I 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: βAR activation acutely induces an inhibitory I response in aging guinea pig hearts through βAR-Gi signaling, which contributes to increased susceptibility to arrhythmogenesis in aging hearts.
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