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GSK3β inhibition and KATP channel opening mediate acute opioid-induced cardioprotection at reperfusion

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Abstract

Both glycogen synthase kinase 3β (GSK3β) and the ATP-dependant potassium channel (KATP) mediate opioid-induced cardioprotection (OIC). However, whether direct KATP channel openers induce cardioprotection prior to reperfusion and their signaling cascade position with respect to GSK3β inhibition is unknown. Therefore, we investigated the role of KATP channel opening at reperfusion in OIC, and the interaction between the GSK signaling axis and KATP channels in cardioprotection.Male Sprague-Dawley rats underwent 30 minutes ischemia with 2 hours of reperfusion and infarct size was determined. Rats given the nonselective opioid agonist, morphine (0.3 mg/kg), or the selective delta opioid agonist, BW373U86 (1.0 mg/kg), 5 minutes prior to reperfusion reduced infarct size (40.3±1.6*, 39.7±1.9* versus 60.0±1.1%, respectively, * P<0.001%). This protection was abrogated with prior administration of the putative sarcolemmal KATP antagonist, HMR-1098 (6 mg/kg), or the putative mitochondrial KATP antagonist, 5-HD (10 mg/kg). The putative sKATP channel opener, P-1075 (1μg/kg) or the putative mKATP channel opener, BMS-191095 (1 mg/kg) given 5 minutes prior to reperfusion also reduced infarct size (41.8±2.4*, 43.4±1.4*) and protection was abrogated by prior administration of the PI3k inhibitor wortmannin (60.0±1.7, 64.0±2.6%, respectively, * P<0.001). Cardioprotection afforded by the GSK inhibitor SB216763 (0.6 mg/kg) given 5 minutes prior to reperfusion was also partially blocked by either HMR or 5-HD and completely blocked when HMR and 5-HD were given in combination (40.8±1.6*, 50.4±1.6^; 49.4±1.7^, 61.6±1.6%, respectively, * or ^ P<0.001). These data indicate that both the sKATP and mKATP channel are involved in acute OIC and the GSK signaling axis regulates cardioprotection via KATP channel opening.

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  1. Medical College of Wisconsin, Dept. of Pharmacology and Toxicology, 8701 Watertown Plank Road, Milwaukee (WI), 53226, USA

    E. R. Gross PhD, A. K. Hsu BS & G. J. Gross PhD

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  1. E. R. Gross PhD
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Gross, E.R., Hsu, A.K. & Gross, G.J. GSK3β inhibition and KATP channel opening mediate acute opioid-induced cardioprotection at reperfusion. Basic Res Cardiol 102, 341–349 (2007). https://doi.org/10.1007/s00395-007-0651-6

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  • DOI: https://doi.org/10.1007/s00395-007-0651-6

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