Vardenafil: a novel type 5 phosphodiesterase inhibitor reduces myocardial infarct size following ischemia/reperfusion injury via opening of mitochondrial KATP channels in rabbits

Abstract: cGMP and opening of mitochondrial KATP channel play an important role in preconditioning of the heart following ischemia/reperfusion (I/R) injury. We investigated the cardioprotective effect of vardenafil (VAR) (Levitra™), a highly selective and biochemically potent inhibitor of phosphodiesterase-5 (PDE-5) that enhances erectile function in men through up-regulation of cGMP. Rabbits were treated with VAR (0.014 mg/kg, iv) or volume-matched saline, 30 min prior to 30 min of sustained regional ischemia followed by 3 h of reperfusion. 5-hydroxydecanoate (5-HD, 5 mg/kg, iv) or HMR 1098 (HMR, 3 mg/kg, iv), the respective blockers of mitochondrial or sarcolemmal KATP channels were administered 10 min before I/R. Infarct size was measured by computer morphometry of tetrazolium stained sections. Vardenafil treatment caused decrease in mean arterial blood pressure from 93.5±2.6 to 82.2±1.5 mmHg and increase in heart rate from baseline value of 151±20 to 196±4.6 bpm (mean±standard error of mean (S.E.M.), P <0.05) within 5 min. The infarct size (% of risk area) was reduced from 33.8±1.3 in control rabbits to 14.3±2.2 (58% reduction, P <0.05). 5-HD abolished VAR-induced protection as demonstrated by increase in infarct size to 34.5±2.3 (P <0.05, N =6 per group). In contrast, HMR failed to block the protective effect of VAR (infarct size, 14.3±2.2 versus 16.3±1.0 in VAR + HMR, P >0.05). Neither inhibitors of the KATP channel influenced the infarct size in the control rabbits, as shown by infarct size of 34.9±1.1 and 33.3±1.4 in animals treated with 5-HD and HMR, respectively. For the first time, we demonstrate that VAR induces protective effect against I/R injury via opening of mitochondrial KATP channel. These results further support our hypothesis that the novel class of PDE-5 inhibitors induce protective effect in the ischemic heart, in addition to their well known clinical effects in the treatment of erectile dysfunction in men. [Copyright &y& Elsevier]