In the isolated perfused mesenteric vascular bed, porcine endothelin (ET) and sarafotoxin S6b produced direct vasoconstriction and potentiated nerve stimulation-induced vasoconstriction. ET also enhanced the vasoconstrictor response to exogenous norepinephrine (NE). Basal or stimulated endogenous NE release was not affected either by ET or sarafotoxin S6b. Qualitatively similar responses to ET and sarafotoxin S6b were always observed, although, in many cases, the response to ET was greater and longer lasting than to sarafotoxin S6b. These results indicate that vasoconstrictor responses to ET or sarafotoxin S6b are mediated primarily by postsynaptic mechanisms. No initial vasodilator response to ET or sarafotoxin S6b was observed in this mesenteric vascular preparation.