Interaction between tumor necrosis factor-α and leptin-induced inhibition of cardiac contractile function in isolated ventricular myocytes

Pro-inflammatory factors such as the adipokine leptin and cytokine tumor necrosis factor-alpha (TNF alpha) have been implicated in the onset of myocardial dysfunction in ischemia-reperfusion injury, sepsis, heart failure, viral myocarditis and cardiac allograft rejection. Although circulating TNF alpha and leptin levels are both elevated under a variety of inflammatory conditions, it remains unknown whether TNF alpha and leptin depress cardiac contractile function independently or synergistically. We examined the effect of acute (30 min) and short-term (24 h) exposure of TNF alpha, leptin or both on cardiac contractile function in Lull rat ventricular tnyocytes. Contractile properties were evaluated using an lonoptix Softedge System including peak shortening (PS), maximal velocity of shortening/relengthening (+/- dL/dt), time-to-PS (TPS) and tithe-to-90% relengthening (TR90). Both TNF alpha (0.5-500 pg/ml) and leptin (1-100 nm) exerted concentration-dependent inhibitions to PS and +/- dL/dt following a 30-min exposure. TNF alpha but not leptin prolonged TR90. Interestingly, TNF alpha-induced depression of cell shortening was masked by leptin and vice versa. Following a 24-h incubation, both TNF alpha and leptin significantly inhibited PS and +/- dL/dt without affecting TPS and TR90. There was no additive or synergistic response by the two pro-inflammatory factors. The nitric oxide synthase inhibitor L-NMMA abolished depression of myocyte shortening elicited by TNF alpha, leptin or both. In summary, this study demonstrated that the inhibitory effect on cardiac contraction by TNF alpha and leptin may mask each other and share a common mechanism(s), probably dependent on NO. (c) 2005 Elsevier Ltd. All rights reserved.