title: 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.
abstract: 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.
authors.affiliation: Medicinal Science Division, Korea Research Institute of Chemical Technology, Daejon, Korea. bhlee@krict.re.kr
authors.forename: Byung Ho
authors.initials: BH
authors.lastname: Lee
authors.forename: Ho Won
authors.initials: HW
authors.lastname: Seo
authors.forename: Sung-Eun
authors.initials: SE
authors.lastname: Yoo
mesh_terms: 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
chemical_list: D001578:Benzopyrans; D002317:Cardiovascular Agents; D006146:Guanidines; D007004:Hypoglycemic Agents; C419651:KR 31372; C084684:BMS 180448; D007770:L-Lactate Dehydrogenase; D005905:Glyburide