Opioid-Induced Cardioprotection Occurs via Glycogen Synthase Kinase β Inhibition During Reperfusion in Intact Rat Hearts

ABSTRACT—Glycogen synthase kinase (GSK) inhibition produced by ischemic preconditioning has been previously shown to be regulated through phosphatidylinositol-3 kinase (PI3K). Therefore, we determined whether opioid-induced cardioprotection (OIC) occurs during reperfusion by altering GSK phosphoryla...

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Bibliographic Details
Published in:	Circulation research 2004-04, Vol.94 (7), p.960-966
Main Authors:	Gross, Eric R, Hsu, Anna K, Gross, Garrett J
Format:	Article
Language:	eng
Subjects:	Aminophenols - pharmacology Androstadienes - pharmacology Animals Benzamides - pharmacology Biological and medical sciences Cardiotonic Agents - pharmacology Cardiotonic Agents - therapeutic use Chromones - pharmacology Fundamental and applied biological sciences. Psychology Glycogen Synthase Kinase 3 - antagonists & inhibitors Glycogen Synthase Kinase 3 - physiology Glycogen Synthase Kinase 3 beta Indoles - pharmacology Male Maleimides - pharmacology Morphine - pharmacology Morpholines - pharmacology Myocardial Infarction - metabolism Myocardial Infarction - pathology Narcotic Antagonists - pharmacology Nuclear Receptor Subfamily 1, Group F, Member 3 Phosphatidylinositol 3-Kinases - antagonists & inhibitors Phosphatidylinositol 3-Kinases - physiology Piperazines - pharmacology Premedication Rats Rats, Sprague-Dawley Receptors, Opioid, delta - drug effects Receptors, Retinoic Acid - antagonists & inhibitors Receptors, Retinoic Acid - physiology Receptors, Thyroid Hormone - antagonists & inhibitors Receptors, Thyroid Hormone - physiology Signal Transduction - drug effects Sirolimus - pharmacology Vertebrates: cardiovascular system
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Summary:	ABSTRACT—Glycogen synthase kinase (GSK) inhibition produced by ischemic preconditioning has been previously shown to be regulated through phosphatidylinositol-3 kinase (PI3K). Therefore, we determined whether opioid-induced cardioprotection (OIC) occurs during reperfusion by altering GSK phosphorylation through PI3K and target of rapamycin (TOR). Furthermore, we determined if selective GSK inhibitors, SB216763(SB21) or SB415286(SB41), emulate OIC. Rats were treated with the nonselective opioid agonist, morphine (MOR, 0.3 mg/kg), the δ-selective opioid agonist BW373U86 (BW, 1 mg/kg), or the GSK inhibitors, SB21 (0.6 mg/kg) or SB41(1.0 mg/kg), either 10 minutes before ischemia or 5 minutes before reperfusion. Five minutes before opioid or SB21 treatment, some rats received either the PI3K inhibitor wortmannin (15 μg/kg) or LY294002 (0.3 mg/kg) or the TOR inhibitor rapamycin (3 μg/kg). After 30 minutes of ischemia followed by 2 hours of reperfusion, infarct size was assessed. MOR, BW, SB41, and SB21 reduced infarct size compared with vehicle when administered before ischemia (42.9±2.6, 40.3±2.3, 46.6±1.6, 42.2±1.8 versus 60.0±1.1%, respectively; P
ISSN:	0009-7330 1524-4571