KR-31761, a novel K+(ATP)-channel opener, exerts cardioprotective effects by opening both mitochondrial K+(ATP) and Sarcolemmal K+(ATP) channels in rat models of ischemia/reperfusion-induced heart injury.
The cardioprotective effects of KR-31761, 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/30-min reperfusion, KR-31761 perfused prior to ischemia significantly increased both the left ventricular developed pressure (% of predrug LVDP: 17.8, 45.1, 54.2, and 62.6 for the control, 1 microM, 3 microM, and 10 microM, respectively) and double product (DP: heart rate x LVDP; % of predrug DP: 17.5, 44.9, 56.2, and 64.5 for the control, 1 microM, 3 microM, and 10 microM, respectively) at 30-min reperfusion while decreasing the left ventricular end-diastolic pressure (LVEDP). KR-31761 (10 microM) significantly increased the time to contracture during the ischemic period, whereas it concentration-dependently decreased the lactate dehydrogenase release during reperfusion. All these parameters were significantly reversed by 5-hydroxydecanoate (5-HD, 100 microM) and glyburide (1 microM), selective and nonselective blockers of the mitochondrial K+(ATP) (mitoK+(ATP)) channel and K+(ATP) channel, respectively. In anesthetized rats subjected to 30-min occlusion of left anterior descending coronary artery/2.5-h reperfusion, KR-31761 administered 15 min before the onset of ischemia significantly decreased the infarct size (72.2%, 55.1%, and 47.1% for the control, 0.3 mg/kg, i.v., and 1.0 mg/kg, i.v., respectively); and these effects were completely and almost completely abolished by 5-HD (10 mg/kg, i.v.) and HMR-1098, a selective blocker of sarcolemmal K+(ATP) (sarcK+(ATP)) channel (6 mg/kg, i.v.) administered 5 min prior to KR-31761 (72.3% and 67.9%, respectively). KR-31761 only slightly relaxed methoxamine-precontracted rat aorta (IC50: > 30.0 microM). These results suggest that KR-31761 exerts potent cardioprotective effects through the opening of both mitoK+(ATP) and sarcK+(ATP) channels in rat hearts with a minimal vasorelaxant effect.
Yang
Min-Kyu
MK
Department of Applied Biochemistry, Division of Life Science, College of Biomedical and Health Science, Konkuk University, Korea.
Lee
Sung-Hun
SH
Seo
Ho-Won
HW
Yi
Kyu-Yang
KY
Yoo
Sung-Eun
SE
Lee
Byung-Ho
BH
Chung
Hun-Jong
HJ
Won
Hyung-Sik
HS
Lee
Chang-Soo
CS
Kwon
Suk-Hyung
SH
Choi
Wahn-Soo
WS
Shin
Hwa-Sup
HS
D000818:Animals; D001578:Benzopyrans / Q000627:therapeutic use*; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D004195:Disease Models, Animal; D066298:In Vitro Techniques; D007211:Indoles / Q000627:therapeutic use*; D054086:KATP Channels / Q000819:agonists*; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects; D015221:Potassium Channels / Q000819:agonists*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy*; D012508:Sarcolemma / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
D001578:Benzopyrans; D002316:Cardiotonic Agents; D007211:Indoles; D054086:KATP Channels; C540303:KR-31761; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel