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Grenoble, France

Ramond A.,Laboratoire HP | Ramond A.,French Institute of Health and Medical Research | Godin-Ribuot D.,Laboratoire HP | Godin-Ribuot D.,French Institute of Health and Medical Research | And 13 more authors.
Fundamental and Clinical Pharmacology | Year: 2013

We have previously shown that chronic intermittent hypoxia (IH), a component of the obstructive sleep apnea syndrome, increases heart sensitivity to infarction. We investigate here the deleterious mechanisms potentially involved in the IH-induced infarction aggravation, investigating the role of oxidative stress. Male Wistar rats were subjected to chronic IH or normoxia (N). IH consisted of repetitive 1-min cycles (30s with inspired O2 fraction 5% followed by 30s normoxia) and was applied for 8h during daytime, for 14days. After the 14-day exposure, mean arterial blood pressure (MABP) was higher in the hypoxic compared with the normoxic group. Infarct size, measured on isolated hearts after ischemia-reperfusion, was significantly increased in IH compared with normoxic group (36.0±2.8% vs. 21.8±3.1% for tempol corresponding control groups and 40.3±3.5% vs. 29.4±3.7% for melatonin corresponding control groups). Tempol or melatonin administration during the 14-day IH exposure prevented both IH-induced increase in MABP and infarction aggravation (24.8±2.8% vs. 25.9±4.0% for tempol-treated groups and 32.3±3.2% vs. 34.5±4.2% for melatonin-treated groups). Myocardial oxidative stress was induced by IH, as measured by dihydroethidium (DHE) level and p47-phox expression (the cytosolic protein required for the activation of the NADPH oxidase). This effect was abolished by tempol and melatonin treatments, which were able to normalize DHE level and NADPH expression. In conclusion, oxidative stress appears to mediate the deleterious cardiovascular effects of IH and, in particular, the increased myocardial susceptibility to infarction. © 2011 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.

Joyeux-Faure M.,Laboratoire HP | Joyeux-Faure M.,French Institute of Health and Medical Research | Durand M.,Grenoble University Hospital Center | Bedague D.,Grenoble University Hospital Center | And 10 more authors.
Fundamental and Clinical Pharmacology | Year: 2012

Cardiac surgery and cardiopulmonary bypass (CPB) induce ischemia-reperfusion and subsequent cellular injury with inflammatory reaction. Clinical and experimental studies suggest that recombinant human erythropoietin (EPO) independently of its erythropoietic effect may be used as a cytoprotective agent against ischemic injury. We tested the hypothesis that one large dose of EPO administered shortly before CPB prevents the elevation of cardiac and cerebral ischemic blood markers as well as the systemic inflammatory response induced by cardiac surgery with CBP through this randomized double-blind placebo-controlled pilot trial. Fifty patients scheduled for coronary artery bypass graft (CABG) surgery with CPB were randomly allocated to EPO or control groups. EPO (800IU/kg intravenously) or placebo (saline) was administered before CPB. The primary end point was to study the effect of EPO administration on several blood markers of myocardial and cerebral ischemia in relation to CABG with CPB. In both groups, surgery increased plasma concentrations of cardiac (troponin T, NT-proBNP, and creatine kinase MB) and cerebral (S100β protein) markers ischemic as well as the pro-inflammatory marker interleukin-6. Compared with the placebo, EPO administration before CPB did not prevent an increase of all these markers following CPB. In conclusion, one large dose of EPO, given shortly before CPB, did not protect against cardiac and cerebral ischemia and inflammatory response occurring during CABG surgery with CPB. Although the long-term clinical implications remain unknown, the findings do not support use of EPO at this dose as a cytoprotective agent in patients undergoing cardiac surgery. © 2011 Société Française de Pharmacologie et de Thérapeutique.

Tonini J.,Laboratoire HP | Tonini J.,French Institute of Health and Medical Research | Tonini J.,Grenoble University Hospital Center | Michallet A.-S.,Laboratoire HP | And 17 more authors.
Respiratory Physiology and Neurobiology | Year: 2011

Reduced exercise tolerance has been reported in obstructive sleep apnea syndrome (OSAS) patients, although the associated hypertension, obesity and/or metabolic disorder may underlie this reduction. Therefore, we evaluated the effects of chronic intermittent hypoxia (CIH) in 12 healthy subjects on exercise capacity, cardio-respiratory responses, and substrate oxidation during maximal and sub-maximal exercise. Subjects were exposed to 30 cycles of hypoxia-reoxygenation per hour for 14 nights. Although exercise capacity was unaltered PETCO 2 was reduced and V̇E/V̇CO2 increased during both maximal and submaximal exercise tests, indicating a hyperventilatory response. Maximal heart rate was lower and diastolic arterial blood pressure (DBP) was higher in the 1st min of recovery after submaximal exercise. Subjects reached maximal lipid oxidation at a higher power output and had decreased blood lactate for a given power output. This suggests that although the metabolic adaptations to CIH in healthy subjects may improve exercise performance, the cardio-pulmonary modifications are similar to those observed in OSAS patients and could limit exercise capacity. © 2011 Elsevier B.V.

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