KATP opener-induced delayed cardioprotection: involvement of sarcolemmal and mitochondrial KATP channels, free radicals and MEK1/2

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Gross, Eric R.
Peart, Jason N.
Hsu, Anna K.
Grover, Gary J.
Gross, Garrett J.
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2003
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Abstract

Previous studies have demonstrated the importance of the sarcolemmal and/or the mitochondrial KATP channel (sKATP and mKATP, respectively) in mediating delayed cardioprotection induced by opioids, bradykinin, adenosine or the KATP-channel opener (KCO), diazoxide. However, the ability of other KCOs, such as the putative sKCO P-1075 or the putative mKCO BMS-191095, to induce delayed cardioprotection has not been tested. In this study, rats were randomly divided and treated with P-1075 (1 姯kg), BMS-191095 (BMS, 1 mg/kg), diazoxide (3.5 mg/kg) or vehicle. Selective blockers were also administered 5 min prior to KCO or vehicle. These included the sKATP antagonist (HMR-1098 (HMR, 6 mg/kg)), the mKATP antagonist (5-hydroxydecanoic acid (5-HD, 10 mg/kg)), the oxygen radical scavenger (N-2-mecaptopropionyl-glycine (2-MPG, 20 mg/kg)) or the MEK1/2 inhibitor (PD-98059 (PD, 1 mg/kg)). Twenty-four hours later, rats were subjected to 30-min ischemia and 2-h reperfusion, followed by infarct size assessment. P-1075, BMS or diazoxide treatment produced similar reductions in infarct size as compared to vehicle (37.2 ᠲ.3%, 40.7 ᠱ.5%, 35.6 ᠳ.6%* vs. 59.8 ᠱ.8%, P < 0.05, respectively). HMR administration before P-1075 and diazoxide abolished delayed cardioprotection, but not BMS-induced infarct size reduction (56.1 ᠱ.1%, 54.9 ᠳ.3%, 41.0 ᠱ.7%*, respectively). Administration of 5-HD, 2-MPG or PD prior to the three KATP openers abolished delayed cardioprotection. These data imply BMS-191095 has a selective mitochondrial site of action, perhaps the mKATP channel, whereas diazoxide and P-1075 affect both the sKATP and mKATP channels. All three KCO also require an initial oxygen-derived free radical (OFR) burst and MEK1/2 activation to trigger delayed cardioprotection.

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Journal of Molecular and Cellular Cardiology

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35

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8

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Cardiovascular medicine and haematology

Medical physiology

Biochemistry and cell biology

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