The vasorelaxant activity of the omega-3 fatty acids-docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids-in comparison with other known vasodilators-sodium nitroprusside, nitroglycerin, papaverine, and D600-were studied in the isolated rat aorta. The relaxant responses of these vasodilators and fatty acids at concentrations of 1-100 muM were assessed in aortic rings contracted with norepinephrine (NE 10(-6) M) or with KCl (30 mM). Cyclic nucleotide enhancers (sodium nitroprusside, nitroglycerin, papaverine) were more effective in producing relaxation, regardless of the contractile mechanism, i.e., alpha adrenoceptor stimulation or depolarization. In contrast, the omega-3 fatty acids produced augmented relaxation in NE-contracted vessels. Relaxations produced by DHA (15 +/- 2% to 45 +/- 10%) were similar to D600 (16 +/- 2% to 60 +/- 7%) in NE-contracted rings, but not in KCl contracted rings. The responses to D600 and DHA in KCl contracted vessels were 79 +/- 2% to 104 +/- 3% and 5 +/- 1% to 21 +/- 3%, respectively. In another set of experiments, the effects of omega-3 fatty acids in the presence of albumin were examined; no significant differences in the induced relaxant responses were noted. These results suggest that the mechanisms of vascular relaxation, such as cyclic nucleotide elevation and calcium antagonism of potential-operated channels, are different from those induced by the omega-3 fatty acids.