Faculty Collaboration Database

Inhibition of apoptotic protein p53 lowers the threshold of isoflurane-induced cardioprotection during early reperfusion in rabbits. Anesth Analg 2006 Dec;103(6):1400-5

Date

11/24/2006

Pubmed ID

17122210

DOI

10.1213/01.ane.0000240903.63832.d8e

Scopus ID

2-s2.0-33845671313 (requires institutional sign-in at Scopus site)   35 Citations

Abstract

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-alpha (1.5 or 3.0 mg/kg), or 0.5 MAC isoflurane plus 1.5 mg/kg pifithrin-alpha. Other rabbits received 3.0 mg/kg pifithrin-alpha or 0.5 MAC isoflurane plus 1.5 mg/kg pifithrin-alpha 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-alpha (3.0 but not 1.5 mg/kg), and the combination of 0.5 MAC isoflurane plus 1.5 mg/kg pifithrin-alpha 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-alpha-induced cardioprotection, whereas atractyloside and wortmannin blocked reductions in infarct size produced by 0.5 MAC isoflurane plus 1.5 mg/kg pifithrin-alpha.

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

Author List

Venkatapuram S, Wang C, Krolikowski JG, Weihrauch D, Kersten JR, Warltier DC, Pratt PF Jr, Pagel PS

Author

Dorothee Weihrauch DVM, PhD Research Scientist II in the Anesthesiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Benzothiazoles
Glycogen Synthase Kinases
Ischemic Preconditioning, Myocardial
Isoflurane
Male
Mitochondrial Membrane Transport Proteins
Myocardial Infarction
Myocardial Reperfusion Injury
Phosphatidylinositol 3-Kinases
Phosphorylation
Rabbits
Toluene
Tumor Suppressor Protein p53