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


CONCLUSIONS
The results suggest that the protective effects of isoflurane against infarction during early reperfusion are mediated by Erk1/2, p70s6K, and eNOS in vivo.
Krolikowski
John G
JG
Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Weihrauch
Dorothee
D
Bienengraeber
Martin
M
Kersten
Judy R
JR
Warltier
David C
DC
Pagel
Paul S
PS
D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D019157:Ischemic Preconditioning, Myocardial; D007530:Isoflurane / Q000494:pharmacology*; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011817:Rabbits; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology
D018685:Anesthetics, Inhalation; D005419:Flavonoids; D007530:Isoflurane; D052250:Nitric Oxide Synthase Type III; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D048049:Extracellular Signal-Regulated MAP Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D019331:NG-Nitroarginine Methyl Ester; D020123:Sirolimus