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This Article Full Text Full Text (PDF) All Versions of this Article: 291/4/H1746    most recent 00233.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (9) Citing Articles via Google Scholar Google Scholar Articles by Peart, J. N. Articles by Gross, G. J. Search for Related Content PubMed PubMed Citation Articles by Peart, J. N. Articles by Gross, G. J.

Cardioprotective effects of acute and chronic opioid treatment are mediated via different signaling pathways

¹Heart Foundation Research Center, Griffith University, Brisbane, Queensland, Australia; and ²Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin

Submitted 6 March 2006 ; accepted in final form 30 April 2006

A 5-day exposure to morphine exerts a profound cardioprotective phenotype in murine hearts. In the present study, we examined mechanisms by which morphine generates this effect, exploring the roles of G_i and G_s proteins, PKA, PKC, and -adrenergic receptors (-AR) in acute and chronic opioid preconditioning. Langendorff-perfused hearts from placebo, acute morphine (AM; 10 µmol/l)-, or chronic morphine (CM)-treated mice (75-mg pellet, 5 days) underwent 25-min ischemia and 45-min reperfusion. After reperfusion, placebo-treated hearts exhibited marked contractile and diastolic dysfunction [rate-pressure product (RPP), 40 ± 4% baseline; end-diastolic pressure (EDP), 33 ± 3 mmHg], whereas AM hearts showed significant improvement in recovery of RPP and EDP (60 ± 3% and 23 ± 4 mmHg, respectively; P < 0.05 vs. placebo). Furthermore, CM hearts demonstrated a complete return of diastolic function and significantly greater recovery of contractile function (83 ± 3%, P < 0.05 vs. both placebo and AM). Pretreatment with G_i protein inhibitor pertussis toxin abolished AM protection while partially attenuating CM recovery (P < 0.05 vs. placebo). Treatment with G_s inhibitor NF-449 did not affect AM preconditioning yet completely abrogated CM preconditioning. Similarly, PKA inhibition significantly attenuated the ischemia-tolerant state afforded by CM, whereas it was ineffective in AM hearts. PKC inhibition with chelerythrine was ineffective in CM hearts while completely abrogating AM preconditioning. Moreover, whereas ₁-AR blockade with CGP-20712A failed to alter recovery in CM hearts, the ₂-AR antagonist ICI-118,551 significantly attenuated postischemic recovery. These data describe novel findings whereby CM preconditioning is mediated by a PKC-independent pathway involving PKA, ₂-AR, and G_s proteins, whereas AM preconditioning is mediated via G_i proteins and PKC.

ischemia-reperfusion; G protein-coupled receptors; rate-pressure product; end-diastolic pressure; morphine

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