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1 Transitional Year Residency Program, St Joseph's Medical Center, Milwaukee, Wisconsin, United States; Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
2 Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
3 Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States; , United States
* To whom correspondence should be addressed. E-mail: ggross{at}mcw.edu.
Previous studies in our laboratory suggest acute inhibition of glycogen synthase kinase 3 (GSK) by SB216763 (SB21) is cardioprotective when administered just prior to reperfusion. However, it is unknown whether the GSK inhibitor, SB21, administered 24 hours prior to ischemia is cardioprotective and whether the mechanism involves KATP channels and the mitochondrial permeability transition pore (MPTP). Male Sprague-Dawley rats were administered the GSK inhibitor, SB21 (0.6mg/kg), or vehicle 24 hours prior to ischemia. Subsequently, rats were acutely anesthetized with Inactin and underwent 30 minutes of ischemia and 2 hours of reperfusion followed by infarct size determination. Subsets of rats received either the sarcolemmal KATP channel blocker, HMR-1098 (6mg/kg), the mitochondrial KATP channel blocker, 5-HD (10mg/kg), or the MPTP opener, atractyloside (5mg/kg), either 5 minutes prior to SB21 administration or 5 minutes prior to reperfusion 24 hours later. SB21 reduced infarct size compared to vehicle (44±2* versus 61±2%, respectively, *P<0.01). 5-HD administered either prior to SB21 treatment or 5 minutes prior to reperfusion the following day abrogated SB21-induced protection (54±4, 61±2%, respectively). HMR-1098 did not effect SB21-induced infarct size reduction when administered prior to SB21 treatment (43±1*%), however, HMR-1098 partially abrogated SB21-induced infarct size reduction when administered just prior to reperfusion 24 hours later (52±1%). MPTP opening either prior to SB21 administration or 5 minutes prior to reperfusion abrogated the infarct size reduction produced by SB21 (61±2, 62±2%, respectively). Hence, GSK inhibition reduces infarct size when given 24 hours prior to administration via opening KATP channels and MPTP closure.
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