Noble gases without anesthetic properties protect myocardium against infarction by activating prosurvival signaling kinases and inhibiting mitochondrial permeability transition in vivo.

Abstract

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.

• Authors: Paul S Pagel, John G Krolikowski, Yon Hee Shim, Suneetha Venkatapuram, Judy R Kersten, Dorothee Weihrauch, David C Warltier, Phillip F Pratt Jr
• Journal: Anesthesia and analgesia (Anesth Analg) Vol. 105 Issue 3 Pg. 562-9 (Sep 2007) ISSN: 1526-7598 [Electronic] United States
• PMID: 17717207 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Androstadienes
• Cardiotonic Agents
• Flavonoids
• Mitochondrial Membrane Transport Proteins
• Mitochondrial Permeability Transition Pore
• Noble Gases
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors
• Atractyloside
• Helium
• Neon
• Argon
• Protein Kinases
• Ribosomal Protein S6 Kinases, 70-kDa
• Extracellular Signal-Regulated MAP Kinases
• 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
• Sirolimus
• Wortmannin

Topics

• Androstadienes (pharmacology)
• Animals
• Argon (pharmacology)
• Atractyloside (pharmacology)
• Cardiotonic Agents (pharmacology, therapeutic use)
• Disease Models, Animal
• Enzyme Activation
• Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors, metabolism)
• Flavonoids (pharmacology)
• Heart Ventricles (drug effects, pathology)
• Helium (pharmacology)
• Ischemic Preconditioning, Myocardial
• Male
• Mitochondria, Heart (drug effects, metabolism, pathology)
• Mitochondrial Membrane Transport Proteins (antagonists & inhibitors, metabolism)
• Mitochondrial Permeability Transition Pore
• Myocardial Infarction (etiology, metabolism, pathology, prevention & control)
• Myocardial Ischemia (complications, drug therapy, metabolism)
• Myocardial Reperfusion Injury (etiology, metabolism, pathology, prevention & control)
• Myocardium (enzymology, metabolism, pathology)
• Neon (pharmacology)
• Noble Gases (pharmacology, therapeutic use)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors (pharmacology)
• Protein Kinases (metabolism)
• Rabbits
• Ribosomal Protein S6 Kinases, 70-kDa (antagonists & inhibitors, metabolism)
• Signal Transduction (drug effects)
• Sirolimus (pharmacology)
• Wortmannin