Tumor necrosis factor-alpha (TNF-alpha) is a primary mediator in the pathogenesis of tissue injury, and high circulating levels of TNF-alpha are found in a variety of pathological conditions. In open-chest anesthetized dogs, the effects of intracoronary recombinant human TNF-alpha (rTNF-alpha; 100 ng/kg for 60 min) on myocardial microvascular transport of a small hydrophilic indicator was examined by the single-injection, residue-detection method. Intracoronary infusion of rTNF-alpha increased myocardial microvascular transport after 120 min. This increase was preceded by a sustained decline in cardiac output and was associated with the appearance of areas with myocardial necrosis in the regional left ventricular wall. The myocardial plasma flow rate and maximum plasma flow rate in response to a 30-s coronary occlusion were not influenced by rTNF-alpha, although a decrease in the myocardial plasma flow rate was observed after 180 min. Circulating neutrophil counts were increased by rTNF-alpha, but the increase in myocardial capillary permeability could not be ascribed to regional neutrophil infiltration. We conclude that picomolar levels of rTNF-alpha can influence the movement of small hydrophilic molecules across the myocardial microvascular barrier in vivo and induce a prolonged decrease in cardiac performance. These effects may be important elements in myocardial pathophysiology.