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Sepsis or septic shock occurs frequently in sick and injured patients and is associated with a significant mortality. Myocardial contractile dysfunction has been proposed to be a major determinant of sepsis-related mortality. This study was directed to examine the role of Na+/H+ exchange activity in myocardial defects after sepsis or after sepsis complicated by a previous burn injury.Laboratory study.University research laboratory.Sprague-Dawley rats (300–350 g, males).Cardiac function, cellular Na+ and Ca2+, myocardial pH, and high-energy phosphates were examined in perfused hearts harvested after sepsis alone (intratracheal Streptococcus pneumoniae, 0.4 mL of 1 × 107 CFU/mL), after sepsis complicated by previous burn injury (40% total body surface area), and after amiloride (a selective inhibitor of Na+/H+ exchange) treatment of either sepsis alone or sepsis plus burn.The ratio of Na+ signal from the intracellular compartment (Na+i) compared with an external standard (monitored by 23Na-NMR spectroscopy, TmDOTP−4 shift reagent) increased by 70% in sepsis alone and by 41% in sepsis complicated by previous burn injury compared with shams. Cardiac adenosine triphosphate and intracellular pH (31P nuclear magnetic resonance spectroscopy) were unchanged by sepsis or sepsis plus burn. Left ventricular pressure and maximal change in pressure over time were reduced after sepsis or after sepsis plus burn injury. Amiloride treatment in either sepsis or sepsis complicated by a previous burn injury prevented myocardial Na+ and Ca2+ accumulation, attenuated sepsis-related lactic acidosis, and improved left ventricular function.Our results suggest that sepsis-related cardiac dysfunction is mediated, in part, by Na+/H+ exchange activity, and inhibition of Na+/H+ exchange activity improves cardiac function after sepsis alone or sepsis complicated by a previous injury.