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1 Heart Foundation Research Center, Griffith University, Southport, Australia; Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
2 Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
* To whom correspondence should be addressed. E-mail: j.peart{at}griffith.edu.au.
Prolonged exposure to morphine exerts a profound cardioprotective phenotype in murine heart. In the present study, we examined mechanisms by which morphine generates this effect, exploring roles of Gi and Gs proteins, PKA, PKC and 
-adrenergic receptors (-AR) in acute and chronic opioid preconditioning. Perfused hearts from placebo, acute (AM, 10 µmol/L) or chronic morphine-treated (CM) mice (75mg pellet, 5 days) underwent 25min global ischemia with 45min reperfusion. Following reperfusion, placebo hearts exhibited marked contractile dysfunction (RPP, 40±4% baseline; EDP, 33±3 mmHg). In contrast, AM-treated hearts displayed significant recovery of RPP and EDP (60±3% and 23±4 mmHg, respectively, p<0.05 vs placebo). CM hearts demonstrated a complete return of diastolic function, and substantially greater recovery of contractile function (83±3%, p<0.05 vs placebo and AM). Pretreatment with Gi protein inhibitor, pertussis toxin, abolished AM protection while partially attenuating recovery afforded by CM (p<0.05 vs placebo). Treatment with Gs inhibitor, NF449, ineffective against AM preconditioning, abolished CM protection. Similarly, PKA blockade with protein kinase A Inhibitor (PKI) significantly attenuated the protective CM phenotype, while ineffective in AM hearts. Furthermore, PKC inhibition with chelerythrine was ineffective against CM preconditioning while eliminating AM protection. Additionally, while 1-AR blockade with CGP-20712A failed to alter recovery in CM hearts, the 2-AR antagonist, ICI118,551, significantly attenuated post-ischemic recovery. Neither -AR antagonist exerted any effect upon AM preconditioning. These data describe novel findings whereby CM preconditioning is mediated by a PKC independent pathway involving PKA, 2-ARs, and Gs proteins; while AM preconditioning is mediated via Gi proteins and PKC.
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