Inhibition of the rapid component of the delayed rectifier potassium current in ventricular myocytes by angiotensin II via the AT1receptor

Background and purpose: There is increasing evidence that angiotensin II (Ang II) is associated with the occurrence of ventricular arrhythmias. However, little is known about the electrophysiological effects of Ang II on ventricular repolarization. The rapid component of the delayed rectifier K+ current (IKr) plays a critical role in cardiac repolarization. Hence, the aim of this study was to assess the effect of Ang II on IKr in guinea-pig ventricular myocytes. Experimental approach: The whole-cell patch-clamp technique was used to record IKr in native cardiocytes and in human embryonic kidney (HEK) 293 cells, co-transfected with human ether-a-go-go-related gene (hERG) encoding the α-subunit of IKr and the human Ang II type 1 (AT1) receptor gene. Key results: Ang II decreased the amplitude of IKr in a concentration-dependent manner with an IC50 of 8.9 nM. Action potential durations at 50% (APD50) and 90% (APD90) repolarization were prolonged 20% and 16%, respectively by Ang II (100 nM). Ang II-induced inhibition of the IKr was abolished by the AT1 receptor blocker, losartan (1 μM). Ang II decreased hERG current in HEK293 cells and significantly delayed channel activation, deactivation and recovery from inactivation. Moreover, PKC inhibitors, stausporine and Bis-1, significantly attenuated Ang II-induced inhibition of IKr. Conclusions and implications: Ang II produces an inhibitory effect on IKr/hERG currents via AT1 receptors linked to the PKC pathway in ventricular myocytes. This is a potential mechanism by which elevated levels of Ang II are involved in the occurrence of arrhythmias in cardiac hypertrophy and failure.