Vardenafil: a novel type 5 phosphodiesterase inhibitor reduces myocardial infarct size following ischemia/reperfusion injury via opening of mitochondrial K(ATP) channels in rabbits.
cGMP and opening of mitochondrial K(ATP) 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 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 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 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.
Salloum
Fadi N
FN
Division of Cardiology, Department of Internal Medicine, Box 980281, Virginia Commonwealth University, 1101 East Marshall Street, Room 7-046, Richmond, VA 23298-0281, USA.
Ockaili
Ramzi A
RA
Wittkamp
Michael
M
Marwaha
Vijay R
VR
Kukreja
Rakesh C
RC
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D006439:Hemodynamics; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D008929:Mitochondria, Heart / Q000502:physiology*; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D010879:Piperazines / Q000494:pharmacology*; D015221:Potassium Channels; D011817:Rabbits; D011897:Random Allocation; D015427:Reperfusion Injury; D013450:Sulfones / Q000494:pharmacology; D014227:Triazines / Q000494:pharmacology; D000069058:Vardenafil Dihydrochloride
D002316:Cardiotonic Agents; D007093:Imidazoles; D010879:Piperazines; D015221:Potassium Channels; D013450:Sulfones; D014227:Triazines; D000069058:Vardenafil Dihydrochloride; D000255:Adenosine Triphosphate