Prevention of endotoxin-induced sarcoplasmic reticulum calcium leak improves mitochondrial and myocardial dysfunction.

Author(s): Sidi H, Xavier M, David M, Youcef B, Brigitte D, Steve L, Remi N

Affiliation(s): From the Department of Physiology (EA 2689), (HS, MX, MD, BY, DB, LS, NR), University of Lille 2, IFR 114 (IMPRT), Lille, France; Department of Anesthesiology and Intensive Care, CHRU, Lille, France; and Department of Echocardiography (MD), Cardiology Hospital, CHRU, Lille, France.

Publication date & source: 2008-08-01, Crit Care Med., [Epub ahead of print]

Publication type:

OBJECTIVE:: Growing evidence suggests that mitochondria function is impaired in sepsis. Here, we tested the hypothesis that lipopolysaccharide would induce mitochondrial Ca overload and oxygen utilization abnormalities as consequences of sarcoplasmic reticulum Ca handling derangements that are typically observed in sepsis. As lipopolysaccharide-induced sarcoplasmic reticulum dysfunction was mainly characterized by reduced sarcoplasmic reticulum Ca uptake and Ca leak, we tested whether dantrolene, a sarcoplasmic reticulum Ca leak inhibitor, would prevent mitochondrial and cardiac contractile dysfunction. DESIGN:: Randomized controlled trial. SETTING:: Experimental laboratory. SUBJECTS:: Male Sprague Dawley rats. INTERVENTIONS:: Sepsis was induced by injection of endotoxin lipopolysaccharide (10 mg/kg; iv). Assessment of contractile function and Ca handling was performed 4 hr after lipopolysaccharide. The relative contribution of the different Ca transporters to relaxation in intact cardiomyocytes was studied during successive electrically evoked twitches and caffeine stimulation. Sarcoplasmic reticulum vesicles and mitochondria from ventricles of rats treated or not with lipopolysaccharide were prepared to evaluate Ca uptake-release and oxygen fluxes, respectively. Effects of dantrolene (10 mg/kg) treatment in rats were evaluated in sarcoplasmic reticulum vesicles, mitochondria, and isolated hearts. MEASUREMENTS AND MAIN RESULTS:: Lipopolysaccharide challenge elicited cardiac contractile dysfunction that was accompanied by severe derangements in sarcoplasmic reticulum function, i.e., reduced Ca uptake and increased sarcoplasmic reticulum Ca leak. Functional sarcoplasmic reticulum changes were associated with modification in the status of phospholamban phosphorylation whereas SERCA was unchanged. Rises in mitochondrial Ca content observed in lipopolysaccharide-treated rats coincided with derangements in mitochondrial oxygen efficacy, i.e., reduced respiratory control ratio. Administration of dantrolene in lipopolysaccharide-treated rats prevented mitochondrial Ca overload and mitochondrial oxygen utilization abnormalities. Moreover, dantrolene treatment in lipopolysaccharide rats improved heart mitochondrial redox state and myocardial dysfunction. CONCLUSION:: These experiments suggest that sarcoplasmic reticulum Ca handling dysfunction is an early event during endotoxemia that could be responsible for, or contribute to mitochondrial Ca overload, metabolic failure, and cardiac dysfunction.