The aim of this study was to investigate vascular actions of SIN-1 in comparison with those of other nitrovasodilators in rabbit femoral arteries. SIN-1 induced relaxations that were unaltered by endothelium removal, inhibition of nitric oxide (NO) synthase and inhibition of the formation of oxygen reactive species such as anion superoxide, hydrogen peroxide and hydroxyl radical. Oxyhemoglobin reduced the relaxation caused by SIN-1 and exogenous NO. Exogenous NO and nitroglycerin relaxations were endothelium-independent. However, those produced by sodium nitroprusside were increased in endothelium denuded segments. Preincubation of segments with nitroglycerin (100 mM) produced a marked tolerance, whereas this effect did not occur when preincubation was done with SIN-1 (100 mM). To analyze the in vivo tolerance, rabbits were chronically treated with SIN-1 or nitroglycerin (15 mg/kg every 8 h, s.c.). Chronic treatment with SIN-1 for 5 days did not reduce relaxation response. However, 3 days of treatment with nitroglycerin induced a marked reduction of relaxations. Chronic treatment with nitroglycerin did not modify the relaxation caused by SIN-1, i.e., there was no cross-tolerance between the two drugs. These results suggest that the endothelium-independent relaxation elicited by SIN-1 is not modulated by endothelial NO or free radicals, and does not produce tolerance after its prolonged administration as occurs with nitroglycerin.