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CARDIOVASCULAR ANESTHESIA

Extracellular Signal-Regulated Kinases Trigger Isoflurane Preconditioning Concomitant with Upregulation of Hypoxia-Inducible Factor-1 and Vascular Endothelial Growth Factor Expression in Rats

From the Departments of Anesthesiology, Medicine (Division of Cardiovascular Diseases), and Pharmacology and Toxicology, the Medical College of Wisconsin and the Clement J. Zablocki Veterans Affairs Medical Center; Department of Biomedical Engineering, Marquette University, Milwaukee, Wisconsin.

Address correspondence and reprint requests to Paul S. Pagel MD PhD, Medical College of Wisconsin, MEB-M4280, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226. Address e-mail to pspagel{at}mcw.edu.

INTRODUCTION: Extracellular signal-related kinases 1 and 2 (Erk1/2) are mitogen-activated protein kinases that have been implicated in anesthetic preconditioning; but whether Erk1/2 triggers or mediates this beneficial effect and the mechanisms by which Erk1/2 produces cardioprotection are unknown. We tested the hypothesis that isoflurane preconditioning is triggered by Erk1/2 concomitant with upregulation of hypoxia-inducible factor 1 (HIF-1) and vascular endothelial growth factor (VEGF) expression in rats instrumented for hemodynamic measurement and subjected to a 30-min coronary artery occlusion and 2-h reperfusion.

METHODS: Rats randomly received IV 0.9% saline (control) or isoflurane (1.0 minimum alveolar concentration administered for 30 min and discontinued 15 min [memory period] before coronary occlusion) in the absence or presence of the selective Erk1/2 inhibitor PD 098059 (1 mg/kg in dimethylsulfoxide administered IV either 3 min before exposure to isoflurane [trigger] or 3 min after discontinuation of the drug [mediator]). Additional rabbits were pretreated with dimethylsulfoxide alone. Left ventricular tissue samples were obtained at selected intervals from additional groups of rats for Western immunoblot analysis of phospho-Erk1/2, HIF-1, and VEGF protein expression.

RESULTS: Isoflurane significantly (P < 0.05) reduced infarct size (41% ± 8% of the left ventricular area at risk; triphenyltetrazolium chloride staining) as compared with control (59% ± 4%). PD 098059 administered before, but not after, isoflurane abolished this cardioprotection (61% ± 5% and 42% ± 9%, respectively). Isoflurane-induced increases in phospho-Erk1/2, HIF-1, and VEGF expression were also inhibited by PD 098059 pretreatment.

CONCLUSIONS: The results indicate that Erk1/2 triggers isoflurane preconditioning concomitant with HIF-1 and VEGF upregulation in vivo.

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