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Pro-inflammatory factors such as the adipokine leptin and cytokine tumor necrosis factor-α (TNFα) have been implicated in the onset of myocardial dysfunction in ischemia–reperfusion injury, sepsis, heart failure, viral myocarditis and cardiac allograft rejection. Although circulating TNFα and leptin levels are both elevated under a variety of inflammatory conditions, it remains unknown whether TNFα and leptin depress cardiac contractile function independently or synergistically. We examined the effect of acute (30 min) and short-term (24 h) exposure of TNFα, leptin or both on cardiac contractile function in adult rat ventricular myocytes. Contractile properties were evaluated using an Ionoptix Softedge system including peak shortening (PS), maximal velocity of shortening/relengthening (±dL/dt), time-to-PS (TPS) and time-to-90% relengthening (TR90). Both TNFα (0.5–500 pg/ml) and leptin (1–100 nm) exerted concentration-dependent inhibitions in PS and ±dL/dt following a 30-min exposure. TNFα but not leptin prolonged TR90. Interestingly, TNFα-induced depression of cell shortening was masked by leptin and vice versa. Following a 24-h incubation, both TNFα 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 TNFα, leptin or both. In summary, this study demonstrated that the inhibitory effect on cardiac contraction by TNFα and leptin may mask each other and share a common mechanism(s), probably dependent on NO.