Effects of sildenafil on cardiac repolarization

Objectives: Sudden death has occasionally been reported in patients taking sildenafil. The objective of this study was to investigate the effect of sildenafil on cardiac repolarization. Methods: We used conventional microelectrode recording technique in isolated guinea pig papillary muscles and canine Purkinje fibers, whole-cell patch clamp techniques in guinea pig ventricular myocytes, and in vivo ECG measurements in guinea pigs. Results: Action potential duration at 90% repolarization (APD(90)) was not affected by sildenafil in the therapeutic ranges (less than or equal to 1 muM), but shortened by higher concentration (greater than or equal to10 muM) in both guinea pig papillary muscles and canine Purkinje fibers. (D)-Sotalol prolonged APD(90) in the same preparations with concentrations greater than or equal to1 muM in a reverse frequency-dependent manner. Co-administration of sildenafil (10 and 30 muM) abolished the APD-prolonging effects of (D)-sotalol (30 muM) and amiodarone (100 muM). Sildenafil, with concentrations up to 30 muM, had no significant effect on both the rapid (I-kappar) and the slow (I-kappas) components of the delayed rectifier potassium currents in guinea pig ventricular myocytes. Sildenafil dose-dependently blocked L-type Ca2+ current (I-Ca,I-L) but had no effect on persistent Na+ current in guinea pig ventricular myocytes. ECG recordings in intact guinea pigs revealed significant shortening of QTc interval by sildenafil (10 and 30 mg/kg orally). The QT-prolonging effects by (D,L)-sotalol (50 mg/kg) and amiodarone (100 mg/kg) were abolished by sildenafil (30 mg/kg). Conclusions: Sildenafil does not prolong cardiac repolarization. Instead, in supra-therapeutic concentrations, it accelerates cardiac repolarization, presumably through its blocking effect on I-Ca,I-L. (C) 2002 Elsevier Science B.V. All rights reserved.