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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.

AbstractThe 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.
AuthorsMin-Kyu Yang, Sung-Hun Lee, Ho-Won Seo, Kyu-Yang Yi, Sung-Eun Yoo, Byung-Ho Lee, Hun-Jong Chung, Hyung-Sik Won, Chang-Soo Lee, Suk-Hyung Kwon, Wahn-Soo Choi, Hwa-Sup Shin (Affiliation: Department of Applied Biochemistry, Division of Life Science, College of Biomedical and Health Science, Konkuk University, Korea.)
JournalJournal of pharmacological sciences (J Pharmacol Sci) Vol. 109 Issue 2 Pg. 222-32 (Feb 2009) ISSN: 1347-8613 [Print] Japan
PMID19234365 (Publication Type: In Vitro, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Benzopyrans
  • Cardiotonic Agents
  • Indoles
  • KATP Channels
  • KR-31761
  • Potassium Channels
  • mitochondrial K(ATP) channel
Topics
  • Animals
  • Benzopyrans (therapeutic use)
  • Cardiotonic Agents (therapeutic use)
  • Disease Models, Animal
  • Indoles (therapeutic use)
  • KATP Channels (agonists)
  • Male
  • Mitochondria, Heart (drug effects)
  • Potassium Channels (agonists)
  • Rats
  • Rats, Sprague-Dawley
  • Reperfusion Injury (drug therapy)
  • Sarcolemma (drug effects)
  • Vasodilation (drug effects)

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