KR-31762, a novel KATP channel opener, exerts cardioprotective effects by opening SarcKATP channels in rat models of ischemia/reperfusion-induced heart injury.
The cardioprotective effects of KR-31762, a newly synthesized K+(ATP) opener, were evaluated in rat models of ischemia/reperfusion (I/R) heart injury. In isolated rat hearts subjected to 30-min global ischemia followed by 30-min reperfusion, KR-31762 (3 and 10 microM) significantly increased the left ventricular developed pressure (LVDP) and double product (heart rate x LVDP) after 30-min reperfusion in a concentration-dependent manner, while decreasing the left ventricular end-diastolic pressure (LVEDP). KR-31762 also significantly increased the time to contracture (TTC) during ischemic period (20.0, 22.4 and 26.4 min for control, 3 and 10 microM, respectively), while decreasing the release of lactate dehydrogenase (LDH) from the heart during 30 min reperfusion (30.4, 14.3 and 19.7 U/g heart weight, respectively). All these parameters except LDH release were reversed by glyburide (1 microM), a nonselective blocker of K+(ATP) channel, but not by 5-hydroxydecanoate, a selective blocker of mitoK+(ATP) channel. In anesthetized rats subjected to 45-min occlusion of left anterior descending coronary artery followed by 90-min reperfusion, KR-31762 significantly decreased the infarct size (60.8, 40.5 and 37.8% for control, 0.3 and 1.0 mg/kg, iv, respectively). KR-31762 slightly relaxed the isolated rat aorta precontracted with methoxamine (IC(50): 23.5 microM). These results suggest that KR-31762 exerts potent cardioprotective effects through the opening of sarcolemmal K(ATP) channel in rat hearts with the minimal vasorelaxant effects.
Lee
Sung-Hun
SH
Department of Applied Biochemistry, Division of Life Science, College of Biomedical and Health Science, Konkuk University, 322 Danwol-Dong, Chungju, Korea.
Yang
Min-Kyu
MK
Lim
Jong-Hyun
JH
Seo
Ho-Won
HW
Yi
Kyu-Yang
KY
Yoo
Sung-Eun
SE
Lee
Byung-Ho
BH
Won
Hyung-Sik
HS
Lee
Chang-Soo
CS
Choi
Wahn-Soo
WS
Shin
Hwa-Sup
HS
D000818:Animals; D001011:Aorta / Q000187:drug effects; D001578:Benzopyrans / Q000494:pharmacology* / Q000627:therapeutic use; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D003652:Decanoic Acids / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005905:Glyburide / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006880:Hydroxy Acids / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D054086:KATP Channels / Q000819:agonists* / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D049990:Membrane Transport Modulators / Q000494:pharmacology* / Q000627:therapeutic use; D008729:Methoxamine / Q000494:pharmacology; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012508:Sarcolemma / Q000187:drug effects* / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects*; D017725:Ventricular Pressure / Q000187:drug effects
D001578:Benzopyrans; D002316:Cardiotonic Agents; D003652:Decanoic Acids; D006146:Guanidines; D006880:Hydroxy Acids; D007211:Indoles; D054086:KATP Channels; C529419:KR-31762; D049990:Membrane Transport Modulators; D026902:Potassium Channel Blockers; D014662:Vasoconstrictor Agents; C052853:5-hydroxydecanoic acid; C084684:BMS 180448; D007770:L-Lactate Dehydrogenase; D008729:Methoxamine; D005905:Glyburide