title: Sildenafil and vardenafil but not nitroglycerin limit myocardial infarction through opening of mitochondrial K(ATP) channels when administered at reperfusion following ischemia in rabbits.
abstract: Phosphodiesterase-5 (PDE-5) inhibitors including sildenafil and vardenafil induce powerful preconditioning-like cardioprotective effect against ischemia/reperfusion injury through opening of mitochondrial K(ATP) channels in the heart. The goal of these studies was to demonstrate the protective effect of sildenafil and vardenafil on reperfusion injury and to compare it with the antianginal vasodilator nitroglycerin (NTG). In addition, we determined the role of mitochondrial K(ATP) channels in protection. Adult male New Zealand white rabbits were anesthetized and subjected to ischemia by 30 min of coronary artery occlusion followed by 3 h of reperfusion. Seven groups were studied. 1-Controls; 2-Sildenafil (total dose: 0.71 mg/kg; i.v.) infused for 65 min starting 5 min before reperfusion; 3-Sildenafil+5-hydroxydecanoate (5-HD, blocker of mitochondrial K(ATP) channel, total dose: 5 mg/kg) administered as 2 bolus injections; 4-Vardenafil (total dose: 0.014 mg/kg; iv) administered as in group 2; 5-Vardenafil+5-HD administered as in group 3; 6-5-HD administered as two bolus injections and 7-Nitroglycerin (NTG, total dose: 2 microg kg(-1) min(-1)) administered as in group 2. Infarct size was reduced in sildenafil (19.19+/-1.3%) as well as vardenafil (17.0+/-2.0%) treated groups as compared to controls (33.8+/-1.7%). However, NTG failed to confer similar cardioprotection (31.5+/-0.8%). 5-HD blocked the cardioprotective effects of sildenafil and vardenafil as shown by an increase in infarct size (34.0+/-1.1% and 28.3+/-1.9%, respectively). Both sildenafil and vardenafil protect the ischemic myocardium against reperfusion injury through a mechanism dependent on mitochondrial K(ATP) channel opening.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Box 980281, Virginia Commonwealth University, 1101 East Mashall Street, Room 7-046, Richmond, VA 23298-0281, USA.
authors.forename: Fadi N
authors.initials: FN
authors.lastname: Salloum
authors.forename: Yuko
authors.initials: Y
authors.lastname: Takenoshita
authors.forename: Ramzi A
authors.initials: RA
authors.lastname: Ockaili
authors.forename: Vladimir P
authors.initials: VP
authors.lastname: Daoud
authors.forename: Eric
authors.initials: E
authors.lastname: Chou
authors.forename: Kazu-ichi
authors.initials: K
authors.lastname: Yoshida
authors.forename: Rakesh C
authors.initials: RC
authors.lastname: Kukreja
mesh_terms: D000818:Animals; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D008929:Mitochondria, Heart / Q000378:metabolism / Q000473:pathology; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D005996:Nitroglycerin / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D015221:Potassium Channels / Q000378:metabolism*; D011687:Purines / Q000494:pharmacology; D011817:Rabbits; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology*; D014227:Triazines / Q000494:pharmacology; D000069058:Vardenafil Dihydrochloride; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D007093:Imidazoles; D010879:Piperazines; D015221:Potassium Channels; D011687:Purines; D013450:Sulfones; D014227:Triazines; D014665:Vasodilator Agents; C117780:mitochondrial K(ATP) channel; D000069058:Vardenafil Dihydrochloride; D000068677:Sildenafil Citrate; D005996:Nitroglycerin