Extracellular signal-regulated kinases trigger isoflurane preconditioning concomitant with upregulation of hypoxia-inducible factor-1alpha and vascular endothelial growth factor expression in rats.
BACKGROUND
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 1alpha (HIF-1alpha) 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-1alpha, 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-1alpha, and VEGF expression were also inhibited by PD 098059 pretreatment.


CONCLUSIONS
The results indicate that Erk1/2 triggers isoflurane preconditioning concomitant with HIF-1alpha and VEGF upregulation in vivo.
Wang
Chen
C
Department of Anesthesiology, Medical College of Wisconsin and Clement J. Zablocki Veterans Affairs Medical Center, MEB-M4280, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226, USA.
Weihrauch
Dorothee
D
Schwabe
David A
DA
Bienengraeber
Martin
M
Warltier
David C
DC
Kersten
Judy R
JR
Pratt
Phillip F
PF
Pagel
Paul S
PS
D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D005786:Gene Expression Regulation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000502:physiology; D019157:Ischemic Preconditioning, Myocardial; D007530:Isoflurane / Q000494:pharmacology*; D008297:Male; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000502:physiology
D018685:Anesthetics, Inhalation; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D007530:Isoflurane; D048049:Extracellular Signal-Regulated MAP Kinases