Hassoun 2008 Crit Care Med

Hassoun SM, Marechal X, Montaigne D, Bouazza Y, Decoster B, Lancel S, Neviere R (2008) Prevention of endotoxin-induced sarcoplasmic reticulum calcium leak improves mitochondrial and myocardial dysfunction. Crit Care Med 36:2590-6.

» PMID: 18679108

Hassoun SM, Marechal X, Montaigne D, Bouazza Y, Decoster B, Lancel S, Neviere R (2008) Crit Care Med

Abstract: OBJECTIVE: Growing evidence suggests that mitochondria function is impaired in sepsis. Here, we tested the hypothesis that lipopolysaccharide would induce mitochondrial Ca²⁺ overload and oxygen utilization abnormalities as consequences of sarcoplasmic reticulum Ca²⁺ handling derangements that are typically observed in sepsis. As lipopolysaccharide-induced sarcoplasmic reticulum dysfunction was mainly characterized by reduced sarcoplasmic reticulum Ca²⁺ uptake and Ca²⁺ leak, we tested whether dantrolene, a sarco(endo)plasmic reticulum calcium ATPase 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/intravenously). Assessment of contractile function and Ca²⁺ handling was performed 4 hr after lipopolysaccharide. The relative contribution of the different Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ uptake and increased sarcoplasmic reticulum Ca²⁺ leak. Functional sarcoplasmic reticulum changes were associated with modification in the status of phospholamban phosphorylation whereas SERCA was unchanged. Rises in mitochondrial Ca²⁺ 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 Ca2+ 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 Ca²⁺ handling dysfunction is an early event during endotoxemia that could be responsible for, or contribute to, mitochondrial Ca²⁺ overload, metabolic failure, and cardiac dysfunction.

• O2k-Network Lab: FR Lille Neviere R, FR Lille Lancel Steve

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Organism: Rat  Tissue;cell: Heart  Preparation: Isolated mitochondria 

HRR: Oxygraph-2k