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Role of Erk1/2, p70s6K, and eNOS in isoflurane-induced cardioprotection during early reperfusion in vivo. Can J Anaesth 2006 Feb;53(2):174-82



Pubmed ID





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 myocardium in 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 x kg(-1)), the p70s6K inhibitor rapamycin (0.25 mg x kg(-1)), the nonselective nitric oxide synthase (NOS) inhibitor N-nitro-L-arginine methyl ester (L-NAME; 10 mg x kg(-1)), the selective inducible NOS antagonist aminoguanidine hydrochloride (AG, 300 mg x kg(-1)), or the selective neuronal NOS inhibitor 7-nitroindazole (7-NI, 50 mg x 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 eNOS in vivo.

Author List

Krolikowski JG, Weihrauch D, Bienengraeber M, Kersten JR, Warltier DC, Pagel PS


Paul S. Pagel MD, PhD Professor in the Anesthesiology department at Medical College of Wisconsin
Dorothee Weihrauch DVM, PhD Professor in the Anesthesiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Anesthetics, Inhalation
Extracellular Signal-Regulated MAP Kinases
Ischemic Preconditioning, Myocardial
Myocardial Reperfusion Injury
NG-Nitroarginine Methyl Ester
Nitric Oxide Synthase Type III
Ribosomal Protein S6 Kinases, 70-kDa
jenkins-FCD Prod-468 69a93cef3257f26b866d455c1d2b2d0f28382f14