Effects of sildenafil on cardiac repolarization.
OBJECTIVE
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 (< or =1 microM), but shortened by higher concentration (> or =10 microM) in both guinea pig papillary muscles and canine Purkinje fibers. D-Sotalol prolonged APD(90) in the same preparations with concentrations > or =1 microM in a reverse frequency-dependent manner. Co-administration of sildenafil (10 and 30 microM) abolished the APD-prolonging effects of D-sotalol (30 microM) and amiodarone (100 microM). Sildenafil, with concentrations up to 30 microM, had no significant effect on both the rapid (I(Kr)) and the slow (I(Ks)) components of the delayed rectifier potassium currents in guinea pig ventricular myocytes. Sildenafil dose-dependently blocked L-type Ca(2+) current (I(Ca,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,L).
Chiang
Chern-En
CE
Division of Cardiology, Taipei Veterans General Hospital and National Yang-Ming University, 201, Sec 2, Shih-Pai Road, 112, Taipei, Taiwan. cechiang@vghtpe.gov.tw
Luk
Hsiang-Ning
HN
Wang
Tsui-Min
TM
Ding
Philip Yu-An
PY
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000037:antagonists & inhibitors; D002118:Calcium / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006168:Guinea Pigs; D006329:Heart Conduction System / Q000187:drug effects*; D008297:Male; D010210:Papillary Muscles / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism; D011687:Purines; D011690:Purkinje Fibers / Q000187:drug effects; D000068677:Sildenafil Citrate; D012964:Sodium / Q000378:metabolism; D013450:Sulfones; D014665:Vasodilator Agents / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D012964:Sodium; D000068677:Sildenafil Citrate; D011188:Potassium; D002118:Calcium