The effect of nicotine on adrenergic and sensory nerves was examined in tail artery ring segments and isolated perfused mesenteric vascular bed. Nicotine by itself (3 x 10(-5) and 3 x 10(-4) M) had no vasoconstrictor effect on the perfused mesentery. However, in the presence of guanethidine (5 x 10(-6) M) and methoxamine (5 x 10(-6) M), nicotine (5 x 10(-5) and 10(-4) M) caused vasodilation of 20 +/- 4 and 26 +/- 6%, respectively. The relaxation produced by nicotine was attenuated in the presence of capsaicin (3 x 10(-7) M) to desensitize sensory nerves. Higher concentrations of nicotine (3 x 10(-4) and 10(-3) M) also produced a relaxation of the mesenteric artery by 49 +/- 7 and 73 +/- 11%, respectively, an effect that was insensitive to capsaicin. The nicotinic antagonist hexamethonium (10(-5) M) blocked the relaxation produced by both low and high concentrations of nicotine. Removal of the endothelium by saponin (50 mg/ml) did not change the effect of nicotine, nor did the cyclooxygenase inhibitor indomethacin (10(-6) M). In tail artery ring segments, nicotine had no effect by itself. Nicotine (10(-5) to 10(-3) M) did not potentiate contractile responses evoked by transmural nerve stimulation, rather relaxation was produced with concentrations above 10(-4) M. These data suggest that at low concentrations nicotine activates capsaicin-sensitive sensory nerves via an action on nicotinic receptors. At higher concentrations nicotine relaxes vascular smooth muscle directly, an effect which is independent of sensory nerves.(ABSTRACT TRUNCATED AT 250 WORDS)