JOURNAL HOME CME HOME THIS MONTH PAST ISSUES ETOC COLLECTIONS AUTHORS REVIEWERS EDITORIAL BOARD FEEDBACK RSS HELP
		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Venkatapuram, S. Articles by Pagel, P. S. Search for Related Content PubMed PubMed Citation Articles by Venkatapuram, S. Articles by Pagel, P. S. Related Collections Resuscitation Cardiovascular Pharmacology

---

CARDIOVASCULAR ANESTHESIA

Inhibition of Apoptotic Protein p53 Lowers the Threshold of Isoflurane-Induced Cardioprotection During Early Reperfusion in Rabbits

Suneetha Venkatapuram, MD, Chen Wang, MD^*, John G. Krolikowski, BA^*, Dorothee Weihrauch, DVM, PhD^*, Judy R. Kersten, MD^*, David C. Warltier, MD, PhD^*, Phillip F. Pratt, Jr, PhD^*, and Paul S. Pagel, MD, PhD^*

From the *Departments of Anesthesiology, Pharmacology and Toxicology, and Medicine (Division of Cardiovascular Diseases), Medical College of Wisconsin and The Clement J. Zablocki Veterans Affairs Medical Center; and 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: Exposure to isoflurane before and during early reperfusion protects against myocardial infarction by activating phosphatidylinositol-3-kinase (PI3K)-mediated signaling. The apoptotic protein, p53, is regulated by PI3K, and inhibition of p53 protects against ischemic injury. We tested the hypothesis that p53 inhibition lowers the threshold of isoflurane-induced postconditioning in vivo.

METHODS: Rabbits (n = 73) instrumented for hemodynamic measurement and subjected to a 30-min left anterior descending coronary artery occlusion and 3-h reperfusion received 0.9% saline (control), isoflurane (0.5 or 1.0 minimum alveolar concentration [MAC]) administered for 3 min before and 2 min after reperfusion, the p53 inhibitor pifithrin- (1.5 or 3.0 mg/kg), or 0.5 MAC isoflurane plus 1.5 mg/kg pifithrin-. Other rabbits received 3.0 mg/kg pifithrin- or 0.5 MAC isoflurane plus 1.5 mg/kg pifithrin- after pretreatment with the selective PI3K inhibitor wortmannin (0.6 mg/kg) or the mitochondrial permeability transition pore opener atractyloside (5 mg/kg).

RESULTS: Isoflurane (1.0 but not 0.5 MAC), pifithrin- (3.0 but not 1.5 mg/kg), and the combination of 0.5 MAC isoflurane plus 1.5 mg/kg pifithrin- significantly (P < 0.05) reduced infarct size (21% ± 4%, 43% ± 7%, 22% ± 4%, 45% ± 4%, and 28% ± 3% [mean ± sd], respectively, of left ventricular area at risk; triphenyltetrazolium chloride staining) when compared with control (45% ± 2%). Atractyloside, but not wortmannin, abolished 3.0 mg/kg pifithrin--induced cardioprotection, whereas atractyloside and wortmannin blocked reductions in infarct size produced by 0.5 MAC isoflurane plus 1.5 mg/kg pifithrin-.

CONCLUSION: The results indicate that inhibition of the apoptotic protein p53 lowers the threshold of isoflurane-induced cardioprotection during early reperfusion in vivo.

Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999