KR-31762, a novel KATP channel opener, exerts cardioprotective effects by opening SarcKATP channels in rat models of ischemia/reperfusion-induced heart injury.

Publisher: Pharmaceutical Society of Korea Country of Publication: Korea (South) NLM ID: 8000036 Publication Model: Print-Electronic Cited Medium: Print ISSN: 0253-6269 (Print) Linking ISSN: 02536269 NLM ISO Abbreviation: Arch Pharm Res Subsets: MEDLINE

Original Publication: Seoul, Pharmaceutical Society of Korea.

Benzopyrans/*pharmacology ; Cardiotonic Agents/*pharmacology ; Indoles/*pharmacology ; KATP Channels/*agonists ; Membrane Transport Modulators/*pharmacology ; Myocardial Infarction/*prevention & control ; Myocardial Reperfusion Injury/*prevention & control ; Myocardium/*metabolism ; Sarcolemma/*drug effects ; Ventricular Function, Left/*drug effects; Animals ; Aorta/drug effects ; Benzopyrans/therapeutic use ; Cardiotonic Agents/therapeutic use ; Decanoic Acids/pharmacology ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Glyburide/pharmacology ; Guanidines/pharmacology ; Heart Rate/drug effects ; Hydroxy Acids/pharmacology ; Indoles/therapeutic use ; KATP Channels/metabolism ; L-Lactate Dehydrogenase/metabolism ; Male ; Membrane Transport Modulators/therapeutic use ; Methoxamine/pharmacology ; Myocardial Infarction/metabolism ; Myocardial Infarction/pathology ; Myocardial Infarction/physiopathology ; Myocardial Reperfusion Injury/metabolism ; Myocardial Reperfusion Injury/pathology ; Myocardial Reperfusion Injury/physiopathology ; Myocardium/enzymology ; Myocardium/pathology ; Potassium Channel Blockers/pharmacology ; Rats ; Rats, Sprague-Dawley ; Sarcolemma/metabolism ; Vasoconstrictor Agents/pharmacology ; Vasodilation/drug effects ; Ventricular Pressure/drug effects

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.

0 (Benzopyrans)
0 (Cardiotonic Agents)
0 (Decanoic Acids)
0 (Guanidines)
0 (Hydroxy Acids)
0 (Indoles)
0 (KATP Channels)
0 (KR-31762)
0 (Membrane Transport Modulators)
0 (Potassium Channel Blockers)
0 (Vasoconstrictor Agents)
624-00-0 (5-hydroxydecanoic acid)
9B1I77MS94 (BMS 180448)
EC 1.1.1.27 (L-Lactate Dehydrogenase)
HUQ1KC1YLI (Methoxamine)
SX6K58TVWC (Glyburide)

Date Created: 20080502 Date Completed: 20080611 Latest Revision: 20171116

20221213

10.1007/s12272-001-1182-9

18449506