OBJECTIVE We hypothesized that methylene blue, by inhibiting the activation of soluble guanylate cyclase mediated by nitric oxide, may reverse systemic hypotension, enhance myocardial function, and improve peripheral distribution of blood flow during endotoxic shock. METHODS Randomized, controlled, acute intervention study. METHODS University intensive care laboratory. METHODS Twenty-one healthy, anesthetized, mongrel dogs, weighing 26 +/- 4 kg. METHODS Groups 1 (n = 7) and 2 (n = 7) received endotoxin (2 mg/kg iv) alone combined with increasing doses of 2.5, 5, 10, and 20 mg/kg iv of methylene blue. Each dose was administrated for 30 mins with a free interval of 30 mins. Group 3 (n = 7) served as a control group, receiving the same doses of methylene blue in the absence of endotoxin. All animals were given normal saline to keep cardiac filling pressures constant. Blood flow probes were placed around the superior mesenteric, renal, and femoral arteries to measure regional blood flow by ultrasonic technique. Data were collected every 30 mins during the study. RESULTS After endotoxemia, methylene blue increased systemic and pulmonary arterial pressure and vascular resistances in a dose-dependent manner up to 10 mg/kg, but had no effect on cardiac index. At the highest dose, methylene blue decreased arterial pressure and systemic vascular resistance. At doses of methylene blue of < or = 10 mg/kg, mesenteric and femoral blood artery flow increased. At the highest dose of 20 mg/kg, femoral artery blood flow further increased, but mesenteric blood flow decreased. Renal artery blood flow was unaffected by methylene blue. In the absence of endotoxin, methylene blue at doses of 2.5 or 5 mg/kg did not alter mean arterial pressure, but reduced cardiac index, indicating an increase in systemic vascular resistance. In contrast, the higher doses of 10 or 20 mg/kg of methylene blue decreased mean arterial pressure and systemic vascular resistance. However, pulmonary arterial pressure and pulmonary vascular resistance increased in a dose-dependent manner. Mesenteric and renal artery blood flow decreased but femoral blood flow increased. As in the presence of endotoxin, methylene blue induced dose-related increases in oxygen uptake and oxygen extraction ratio, but did not alter oxygen delivery. Methylene blue largely attenuated the endotoxin-induced increase in plasma nitrite concentrations. CONCLUSIONS Low and moderate doses of methylene blue can significantly increase arterial blood pressure but not cardiac index during endotoxic shock. Methylene blue infusion may selectively increase mesenteric blood flow. High doses of methylene blue can worsen systemic hypotension, myocardial depression, and pulmonary hypertension after endotoxemia.