GSK3beta inhibition and K(ATP) channel opening mediate acute opioid-induced cardioprotection at reperfusion.
Both glycogen synthase kinase 3beta (GSK3beta) and the ATP-dependant potassium channel (K(ATP)) mediate opioid-induced cardioprotection (OIC). However, whether direct K(ATP) channel openers induce cardioprotection prior to reperfusion and their signaling cascade position with respect to GSK3beta inhibition is unknown. Therefore, we investigated the role of K(ATP) channel opening at reperfusion in OIC, and the interaction between the GSK signaling axis and K(ATP) 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 K(ATP) antagonist, HMR-1098 (6 mg/kg), or the putative mitochondrial K(ATP) antagonist, 5-HD (10 mg/kg). The putative sK(ATP) channel opener, P-1075 (1microg/kg) or the putative mK(ATP) 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 sK(ATP) and mK(ATP) channel are involved in acute OIC and the GSK signaling axis regulates cardioprotection via K(ATP) channel opening.
Gross
Eric R
ER
Medical College of Wisconsin, Dept. of Pharmacology and Toxicology, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
Hsu
Anna K
AK
Gross
Garrett J
GJ
D000701:Analgesics, Opioid / Q000494:pharmacology* / Q000627:therapeutic use; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D001578:Benzopyrans / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006146:Guanidines / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D009020:Morphine / Q000494:pharmacology* / Q000627:therapeutic use; D009203:Myocardial Infarction / Q000201:enzymology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012508:Sarcolemma / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D000077191:Wortmannin
D000701:Analgesics, Opioid; D000730:Androstadienes; D001549:Benzamides; D001578:Benzopyrans; D002316:Cardiotonic Agents; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D006146:Guanidines; D007093:Imidazoles; D007211:Indoles; D008301:Maleimides; D009020:Morphine; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D000077191:Wortmannin; C428117:BMS 191095; C417521:SB 216763; C117780:mitochondrial K(ATP) channel; C083877:BW 373U86; C073896:N-cyano-N'-(1,1-dimethylpropyl)-N''-(3-pyridinyl)guanidine; C410297:HMR 1098; C000605508:Gsk3b protein, rat