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Canadian Journal of Anesthesia

, Volume 53, Issue 2, pp 174–182 | Cite as

Le rôle des Erk1/2, p70s6K et eNOS dans la cardioprotection induite par ľisoflurane pendant la reperfusion in vivo précoce

  • John G. Krolikowski
  • Dorothee Weihrauch
  • Martin Bienengraeber
  • Judy R. Kersten
  • David C. Warltier
  • Paul S. Pagel
Article

Résumé

Objectif

Ľadministration ďisoflurane pendant la reperfusion précoce qui suit une occlusion prolongée de ľartère coronaire diminue la taille de ľinfarctus myocardique en activant la transduction du signal de la phosphatidylinositol-3-kinase (PI3K). Les kinases extracellulaires reliées au signal (Erk1/2) représentent un mécanisme redondant par lequel le signalement des éléments en aval à partir de PI3K, incluant la s6 kinase de protéines ribosomales 70-kDA (p70s6K) et ľoxyde nitrique synthase endothéliale (eNOS), peuvent être activés pour réduire la lésion de reperfusion. Nous avons testé ľhypothèse que les Erk1/2, p70s6K et eNOS assuraient la médiation du postconditionnement induit par ľisoflurane dans des myocardes de lapin in vivo.

Méthode

Des lapins anesthésiés aux barbituriques (n = 78), instrumentés pour la mesure de ľhémodynamique générale, ont été soumis à une occlusion coronaire de 30 min, suivie de trois heures de reperfusion. Répartis au hasard, ils ont reçu une solution salée à 0,9 % (témoin), ľinhibiteur de Erk1/2, PD 098059 (2 mg·kg-1), ľinhibiteur de p70s6K, la rapamycine (0,25 mg·kg-1), ľinhibiteur non sélectif de ľoxyde nitrique synthase (NOS) ľester méthylique N-nitro-L-arginine (L-NAME; 10 mg·kg-1), ľantagoniste sélectif de la NOS inductible, le chlorhydrate ďaminoguanidine (AG, 300 mg·kg-1) ou ľinhibiteur sélectif de NOS neuronal, le 7-nitro-indazole (7-NI, 50 mg·kg-1) en présence ou non ďune concentration alvéolaire minimale de 1,0 ďisoflurane administrée pendant trois minutes avant et deux minutes après la reperfusion.

Résultats

Ľexposition brève à une concentration alvéolaire minimale de 1,0 ďisoflurane a réduit (P < 0,05) la taille de ľinfarctus (21 ± 4 % [moyenne ± ET] de ľaire du ventricule gauche à risque, respectivement; coloration au triphényltétrazolium) comparativement au témoin (41 ± 5 %). Les PD 098059, rapamycine et L-NAME, mais non les AG ou 7-NI, ont aboli la protection produite par ľisoflurane.

Conclusion

Le résultat suggère que les effets protecteurs de ľisoflurane contre ľinfarctus pendant la reperfusion précoce dépendent de la médiation des Erk1/2, p70s6K et eNOS in vivo.

Role of Erk1/2, p70s6K, and eNOS in isofluraneinduced cardioprotection during early reperfusionin vivo

Abstract

Purpose

Administration of isoflurane during early reperfusion after prolonged coronary artery occlusion decreases myocardial infarct size by activating phosphatidylinositol-3-kinase (PI3K) signal transduction. The extracellular signal-related kinases (Erk1/2) represent a redundant mechanism by which signaling elements downstream from PI3K, including 70-kDA ribosomal protein s6 kinase (p70s6K) and endothelial nitric oxide synthase (eNOS), may be activated to reduce reperfusion injury. We tested the hypothesis Erk1/2, p70s6K, and eNOS mediate isoflurane-induced postconditioning in rabbit myocardiumin vivo.

Methods

Barbiturate-anesthetized rabbits (n = 78) instrumented for measurement of systemic hemodynamics were subjected to a 30-min coronary occlusion followed by three hours reperfusion. Rabbits were randomly assigned to receive 0.9% saline (control), the Erk1/2 inhibitor PD 098059 (2 mg·kg-1), the p70s6K inhibitor rapamycin (0.25 mg·kg-1), the nonselective nitric oxide synthase (NOS) inhibitor N-nitro-L-arginine methyl ester (L-NAME; 10 mg·kg-1), the selective inducible NOS antagonist aminoguanidine hydrochloride (AG, 300 mg·kg-1), or the selective neuronal NOS inhibitor 7-nitroindazole (7-NI, 50 mg·kg-1) in the presence or absence of 1.0 minimum alveolar concentration isoflurane administered for three minutes before and two minutes after reperfusion.

Results

Brief exposure to 1.0 minimum alveolar concentration isoflurane reduced (P < 0.05) infarct size (21 ± 4% [mean ± SD] of left ventricle area at risk, respectively; triphenyltetrazolium staining) as compared to control (41 ± 5%). PD 098059, rapamycin, and L-NAME, but not AG nor 7-NI, abolished the protection produced by isoflurane.

Conclusion

The results suggest that the protective effects of isoflurane against infarction during early reperfusion are mediated by Erk1/2, p70s6K, and eNOSin vivo.

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Copyright information

© Canadian Anesthesiologists 2006

Authors and Affiliations

  • John G. Krolikowski
    • 1
  • Dorothee Weihrauch
    • 1
  • Martin Bienengraeber
    • 1
    • 2
  • Judy R. Kersten
    • 1
    • 2
  • David C. Warltier
    • 1
    • 2
    • 3
    • 4
  • Paul S. Pagel
    • 1
    • 2
  1. 1.Departments of AnesthesiologyMedical College of Wisconsin and the Clement J. Zablocki Veterans Affairs Medical CenterMilwaukeeUSA
  2. 2.Department of Pharmacology and ToxicologyMedical College of Wisconsin and the Clement J. Zablocki Veterans Affairs Medical CenterMilwaukeeUSA
  3. 3.Department of Medicine (Division of Cardiovascular Diseases)Medical College of Wisconsin and the Clement J. Zablocki Veterans Affairs Medical CenterMilwaukeeUSA
  4. 4.Department of Biomedical EngineeringMarquette UniversityMilwaukeeUSA

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