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

cGMP and opening of mitochondrial K-ATP, channel play an important role in preconditioning of the heart following ischemia/reper-fusion (I/R) injury. We investigated the cardioprotective effect of vardenafil (VAR) (Levitra(TM)), a highly selective biochemically potent inhibitor of phosphodicsterase-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/kv, iv) or HMR 1098 (HMR 3 mg/kg, iv), the respective blockers of mitochondrial or sarcoleninial K-ATP 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 front 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-inducccl 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 K-ATP, 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 K-ATP 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. (c) 2005 Elsevier Ltd. All rights reserved.