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

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Title Cardioprotective effects of acute and chronic opioid treatment are mediated via different signaling pathways
Author Peart, Jason Nigel John; Gross, Garrett J.
Journal Name American Journal of Physiology - Heart and Circulatory Physiology
Year Published 2006
Place of publication Bethesda MD USA
Publisher American Physiological Society
Abstract 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 Gi and Gs proteins, PKA, PKC, and β-adrenergic receptors (β-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 Gi protein inhibitor pertussis toxin abolished AM protection while partially attenuating CM recovery (P < 0.05 vs. placebo). Treatment with Gs 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 β1-AR blockade with CGP-20712A failed to alter recovery in CM hearts, the β2-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, β2-AR, and Gs proteins, whereas AM preconditioning is mediated via Gi proteins and PKC.
Peer Reviewed Yes
Published Yes
Alternative URI
Copyright Statement Self-archiving of the author-manuscript version is not yet supported by this journal. Please refer to the journal link for access to the definitive, published version or contact the author[s] for more information.
Volume 291
Issue Number 4
Page from H1746
Page to H1753
ISSN 0363-6135
Date Accessioned 2006-06-30
Date Available 2015-02-04T04:26:41Z
Language en_US
Research Centre Menzies Health Institute Qld; Heart Foundation Research Centre
Faculty Griffith Health Faculty
Subject PRE2009-Clinical Pharmacology and Therapeutics
Publication Type Journal Articles (Refereed Article)
Publication Type Code c1a

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