Cardioprotective effects of (2S,3R,4S)-N'-benzyl-N"-cyano-N-(3,4-dihydro-2-dimethoxymethyl-3-hydroxy-2-methyl-6-nitro-2H-benzopyran-4-yl)-guanidine (KR-31372) in rats and dogs.
The cardioprotective effects of (2S,3R,4S)-N'-benzyl- N"-cyano-N-(3,4-dihydro-2-dimethoxymethyl-3-hydro- xy-2-methyl-6-nitro-2H-benzopyran-4-yl)-guanidine (KR-31372) were evaluated against ischemic/reperfusion injury in isolated rat hearts in vitro and in anesthetized rats and dogs in vivo. In isolated perfused rat hearts subjected to a 30-min global ischemia/30-min reperfusion, KR-31372 (1-10 microM) significantly improved severe contracture (end-diastolic pressure and time to contracture), markedly reduced reperfusion lactate dehydrogenase release, and enhanced the recovery of reperfusion contractile function (left ventricular developed pressure and double product) in a concentration-dependent manner compared with the vehicle-treated group. In anesthetized rats subjected to a 45-min coronary occlusion and a 90-min reperfusion, intravenous KR-31372 dose-dependently reduced infarct size from 58.6% to 48.5, 48.1 and 39.6% at 0.3, 1.0 and 3.0 mg/kg, respectively (p < 0.05). In anesthetized beagle dogs that underwent a 1.5-hour occlusion followed by a 5-hour reperfusion, KR-31372 (2 mg/kg, i.v.) markedly reduced infarct size from 57.0% in controls to 28.0% (p < 0.05). The cardioprotective effects of KR-31372 on contractile function in globally ischemic rat hearts and on reperfusion injury in anesthetized rats were significantly reversed by pretreatment with selective adenosine triphosphate-sensitive potassium (K(ATP)) channel blockers, sodium 5-hydroxydecanoate and glibenclamide. Taken together, these results indicate that KR-31372 possesses potent cardioprotective effects in rats and dogs and its effects may be mediated by activation of mitochondrial K(ATP) channels.
Lee
Byung Ho
BH
Medicinal Science Division, Korea Research Institute of Chemical Technology, Daejon, Korea. bhlee@krict.re.kr
Seo
Ho Won
HW
Yoo
Sung-Eun
SE
D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D002317:Cardiovascular Agents / Q000494:pharmacology*; D003326:Coronary Circulation; D003327:Coronary Disease / Q000188:drug therapy / Q000473:pathology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005905:Glyburide / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000473:pathology* / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy / Q000503:physiopathology
D001578:Benzopyrans; D002317:Cardiovascular Agents; D006146:Guanidines; D007004:Hypoglycemic Agents; C419651:KR 31372; C084684:BMS 180448; D007770:L-Lactate Dehydrogenase; D005905:Glyburide