Amrinone prevents the inhibition of muscle pyruvate dehydrogenase complex activity during sepsis

Abstract

A decreased proportion of active pyruvate dehydrogenase complex (PDH) in skeletal muscle has been implicated as an important factor in elevating plasma lactate concentrations in hypermetabolic sepsis. The mediators of the septic process responsible for the inhibition of PDH complex in muscle are unknown. To assess the role of tumor necrosis factor in mediating the effects of sepsis, the effect of daily injections of amrinone (5 mg/kg/day), which inhibits the release of tumor necrosis factor during sepsis, on the proportion of PDH in the active form (PDHa) was investigated in a model of chronic hypermetabolic sepsis. In skeletal muscle from untreated septic rats, PDHa was decreased 50%. Treatment of septic rats with amrinone for 5 days prevented the sepsis-induced decrease in PDHa. Sepsis caused a 2.5-fold elevation in plasma lactate concentrations. The maintenance of the PDH complex activity at control values following injection of amrinone in septic rats was associated with reduced lactate concentrations in plasma. Thus, amrinone prevented the sepsis-induced abnormalities in skeletal muscle PDH activity and plasma lactate concentrations.