Beta-Arrestin2 Regulates The Rapid Component Of Delayed Rectifier K+ Currents And Cardiac Action Potential Of Guinea Pig Cardiomyocytes After Adrenergic Stimulation

A decrease in the rapid component of delayed rectifier potassium current (IKr) during chronic heart failure (CHF) prolongs action potential (AP), and plays a key role in the pathogenesis of ventricular arrhythmias. beta-Arrestin2 has been shown to restore the inotropic reserve of beta-adrenergic regulation, but little or nothing is known about its effect on intrinsic channel. This study investigated the role of beta-arrestin2 in the regulation of cardiac hERG/IKr potassium channel and AP during chronic adrenergic stimulation. Single left ventricular myocytes were isolated from guinea pig heart, and were transfected with adenovirus encoding beta-arrestin2, or beta-arrestin2 siRNA or an empty adenovirus. Cell cultures containing 10 nM isoproterenol, 1 nM phenylephrine or vehicle alone (control medium) were electro-physiologically examined after 48 h of incubation. Action potential duration at 50 and 90 % of repolarization (APD(50) and APD(90)) were measured using whole-cell patch-clamp recording. Sustained adrenergic stimulation significantly reduced the density of the IKr current (p < 0.001). beta-Arrestin2 expression in cell cultures treated with isoproterenol or phenylephrine was significantly downregulated after adrenergic stimulation (p < 0.001). Overexpression of beta-arrestin2 significantly attenuated isoproterenol or phenylephrine-induced reduction in IKr current. It also prevented the phenylephrine-induced prolongation of AP (p < 0.05 for APD(50) and p < 0.001 for APD(90)), but did not significantly affect AP profile after exposure of the cardiomyocytes to isoproterenol (p > 0.05). Therefore, Increased levels of beta-Arrestin2 weaken dysregulation of IKr current and prevent excessive AP prolongation, making it an effective anti-arrhythmic strategy.