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CARDIOVASCULAR ANESTHESIA

Noble Gases Without Anesthetic Properties Protect Myocardium Against Infarction by Activating Prosurvival Signaling Kinases and Inhibiting Mitochondrial Permeability Transition In Vivo

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

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

Address correspondence and reprint requests to Paul S. Pagel, MD, PhD, Clement J. Zablocki Veterans Affairs Medical Center, 5000 W. National Avenue, Milwaukee, WI 53295. Address e-mail to pspagel{at}mcw.edu.

BACKGROUND: The anesthetic noble gas, xenon, produces cardioprotection. We hypothesized that other noble gases without anesthetic properties [helium (He), neon (Ne), argon (Ar)] also produce cardioprotection, and further hypothesized that this beneficial effect is mediated by activation of prosurvival signaling kinases [including phosphatidylinositol-3-kinase, extracellular signal-regulated kinase, and 70-kDa ribosomal protein s6 kinase] and inhibition of mitochondrial permeability transition pore (mPTP) opening in vivo.

METHODS: Rabbits (n = 98) instrumented for hemodynamic measurement and subjected to a 30-min left anterior descending coronary artery (LAD) occlusion and 3 h reperfusion received 0.9% saline (control), three cycles of 70% He-, Ne-, or Ar-30% O₂ administered for 5 min interspersed with 5 min of 70% N₂–30% O₂ before LAD occlusion, or three cycles of brief (5 min) ischemia interspersed with 5 min reperfusion before prolonged LAD occlusion and reperfusion (ischemic preconditioning). Additional groups of rabbits received selective inhibitors of phosphatidylinositol-3-kinase (wortmannin; 0.6 mg/kg), extracellular signal-regulated kinase (PD 098059; 2 mg/kg), or 70-kDa ribosomal protein s6 kinase (rapamycin; 0.25 mg/kg) or mPTP opener atractyloside (5 mg/kg) in the absence or presence of He pretreatment.

RESULTS: He, Ne, Ar, and ischemic preconditioning significantly (P < 0.05) reduced myocardial infarct size [23% ± 4%, 20% ± 3%, 22% ± 2%, 17% ± 3% of the left ventricular area at risk (mean ± sd); triphenyltetrazolium chloride staining] versus control (45% ± 5%). Wortmannin, PD 098059, rapamycin, and atractyloside alone did not affect infarct size, but these drugs abolished He-induced cardioprotection.

CONCLUSIONS: The results indicate that noble gases without anesthetic properties produce cardioprotection by activating prosurvival signaling kinases and inhibiting mPTP opening in rabbits.

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