Objective: Nitric oxide (NO) has been proposed as a common mediator of tumor necrosis factor-α (TNFα)-induced vasodilation and myocardial dysfunction. Accordingly, we performed an extensive assessment of the influence of NO synthase inhibition on left ventricle (LV) and circulatory performance in conscious dogs at steady state and after establishment of TNFα mediated myodepression. Methods: Autonomically blocked, chronically instrumented dogs were studied at steady state and 6 h after initiation of a 1-h rhTNFα infusion (40 μg/kg). Ventricular performance was evaluated using the pressure-volume framework. Dogs were then treated with either N(G)-nitro-L-arginine methylester (L-NAME, 40 mg/kg bolus) or angiotensin II (250-500 ng/kg). Results: L-NAME, under control conditions or following recombinant human (rh)TNFα-induced ventricular dysfunction, produced marked increases in afterload with attendant increases in LV pressure, volume, and prolonged isovolumic relaxation without adversely influencing coronary blood flow. Regardless of whether the dogs received rhTNFα, L-NAME did not affect the slopes of the end-systolic pressure-volume and stroke-work (SW)-end-diastolic volume (EDV) relations (force-based measure of contractility), whereas the slope of the dP/dt(max)-EDV relation, a velocity dependent parameter of LV systolic function, declined. Overall ventricular performance, as seen by the circulation, was reduced by L-NAME in control as well as rhTNFα-treated dogs, evidenced by rightward shifts of the SW-EDV and dP/dt(max)-EDV relations. Similar findings were observed in the separate cohorts of dogs, at steady state and 6 h after rhTNFα, following angiotensin II at matched systolic pressure. Conclusions: Systemic NO synthase inhibition with L-NAME does not acutely reverse rhTNFα-induced myocardial dysfunction. The detrimental influence of L-NAME on LV size, relaxation, and velocity-based measures of contractility is likely attributable to its effects on increasing afterload. Copyright (C) 1999 Elsevier Science B.V.