Role of Erk1/2, p70s6K, and eNOS in isoflurane-induced cardioprotection during early reperfusion in 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 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.

• Authors: John G Krolikowski, Dorothee Weihrauch, Martin Bienengraeber, Judy R Kersten, David C Warltier, Paul S Pagel
• Journal: Canadian journal of anaesthesia = Journal canadien d'anesthesie (Can J Anaesth) Vol. 53 Issue 2 Pg. 174-82 (Feb 2006) ISSN: 0832-610X [Print] United States
• PMID: 16434759 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anesthetics, Inhalation
• Flavonoids
• Isoflurane
• Nitric Oxide Synthase Type III
• Ribosomal Protein S6 Kinases, 70-kDa
• Extracellular Signal-Regulated MAP Kinases
• 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
• NG-Nitroarginine Methyl Ester
• Sirolimus

Topics

• Anesthetics, Inhalation (pharmacology)
• Animals
• Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors, metabolism)
• Flavonoids (pharmacology)
• Ischemic Preconditioning, Myocardial
• Isoflurane (pharmacology)
• Male
• Myocardial Reperfusion Injury (metabolism, prevention & control)
• NG-Nitroarginine Methyl Ester (pharmacology)
• Nitric Oxide Synthase Type III (antagonists & inhibitors, metabolism)
• Rabbits
• Ribosomal Protein S6 Kinases, 70-kDa (antagonists & inhibitors, metabolism)
• Sirolimus (pharmacology)