Protein kinase C plays an essential role in sildenafil-induced cardioprotection in rabbits

Division of Cardiology, Department of Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298 Submitted 3 November 2003 ; accepted in final form 8 December 2003 Sildenafil citrate (Viagra) is the most widely used pharmacological drug for treating erectile dysfunction in men. It has potent cardioprotective effects against ischemia-reperfusion injury via nitric oxide and opening of mitochondrial ATP-sensitive K + channels. We further investigated the role of protein kinase C (PKC)-dependent signaling pathway in sildenafil-induced cardioprotection. Rabbits were treated (orally) with sildenafil citrate (1.4 mg/kg) 30 min before index ischemia for 30 min and reperfusion for 3 h. The PKC inhibitor chelerythrine (5 mg/kg iv) was given 5 min before sildenafil. Infarct size (% of risk area) reduced from 33.65 ± 2.17 in the vehicle (saline) group to 15.07 ± 0.63 in sildenafil-treated groups, a 45% reduction compared with vehicle (mean ± SE, P < 0.05). Chelerythrine abolished sildenafil-induced protection, as demonstrated by increase in infarct size to 31.14 ± 2.4 ( P < 0.05). Chelerythrine alone had an infarct size of 33.5 ± 2.5, which was not significantly different compared with DMSO-treated group (36.8 ± 1.7, P > 0.05). Western blot analysis demonstrated translocation of PKC- , - , and - isoforms from cytosol to membrane after treatment with sildenafil. However, no change in the PKC- and - isoforms was observed. These data provide direct evidence of an essential role of PKC, and potentially PKC- , - , and - , in sildenafil-induced cardioprotection in the rabbit heart. chelerythrine Address for reprint requests and other correspondence: R. C. Kukreja, Box 281, Div. of Cardiology, Medical College of Virginia, Virginia Commonwealth Univ., Richmond, VA 23298 (E-mail: rakesh{at}hsc.vcu.edu ).