Inhibition of apoptotic protein p53 lowers the threshold of isoflurane-induced cardioprotection during early reperfusion in rabbits

• Published in: Anesthesia and analgesia Vol. 103; no. 6; pp. 1400 - 1405
• Main Authors: VENKATAPURAM, Suneetha, CHEN WANG, KROLIKOWSKI, John G, WEIHRAUCH, Dorothee, KERSTEN, Judy R, WARLTIER, David C, PRATT, Phillip F, PAGEL, Paul S
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott 01.12.2006
• Subjects: Anesthesia; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Benzothiazoles - pharmacology; Biological and medical sciences; Glycogen Synthase Kinases - physiology; Ischemic Preconditioning, Myocardial; Isoflurane - pharmacology; Male; Medical sciences; Mitochondrial Membrane Transport Proteins - physiology; Myocardial Infarction - prevention & control; Myocardial Reperfusion Injury - prevention & control; Phosphatidylinositol 3-Kinases - physiology; Phosphorylation; Rabbits; Toluene - analogs & derivatives; Toluene - pharmacology; Tumor Suppressor Protein p53 - antagonists & inhibitors; Volatile compound; Vertebrata; Mammalia; Reperfusion; General anesthetic; Animal; Cardioprotective agent; Rabbit; Anesthesia; Lagomorpha; Isoflurane; Halogen Organic compounds
• ISSN: 0003-2999; 1526-7598
• DOI: 10.1213/01.ane.0000240903.63832.d8e

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