The effects of tumor necrosis factor-alpha on systolic and diastolic function in rat ventricular myocytes

The proinflammatory cytokine tumor necrosis factor-alpha (TNF-α) is associated with myocardial dysfunction observed in sepsis and septic shock. There are two fundamental components to this dysfunction. (1) systolic dysfunction; and (2) diastolic dysfunction. The aim of these experiments was to determine if any aspect of whole-heart dysfunction could be explained by alterations to global intracellular calcium ([Ca(2+)](i)), contractility, and [Ca(2+)](i) handling, by TNF-α, at the level of the individual rat myocyte. We took an integrative approach to simultaneously measure [Ca(2+)](i), contractility and sarcolemmal Ca fluxes using the Ca indicator fluo-3, video edge detection, and the perforated patch technique, respectively. All experiments were performed at 37°C. The effects of 50 ng/mL TNF-α were immediate and sustained. The amplitude of systolic [Ca(2+)](i) was reduced by 31% and systolic shortening by 19%. Diastolic [Ca(2+)](i), myocyte length and relaxation rate were not affected, nor were the activity of the [Ca(2+)](i) removal mechanisms. The reduction in systolic [Ca(2+)](i) was associated with a 14% reduction in sarcoplasmic reticulum (SR) content and a 11% decrease in peak L-type Ca current (I(C)(a-L)). Ca influx was decreased by 7% associated with a more rapid I(C)(a-L) inactivation. These data show that at the level of the myocyte, TNF-α reduces SR Ca which underlies a reduction in systolic [Ca(2+)](i) and thence shortening. Although these findings correlate well with aspects of systolic myocardial dysfunction seen in sepsis, in this model, acutely, TNF-α does not appear to provide a cellular mechanism for sepsis-related diastolic myocardial dysfunction.