1 The effects of endotoxin on the vasoconstrictor responses to sympathetic nerve stimulation (SNS) were investigated in the rat isolated perfused mesenteric bed. 2 Rats received either saline (0.1 ml h(-1)) or endotoxin (2.5 mg kg(-1) h(-1)) intravenously for 4 h; the mesenteric beds were then isolated, perfused with Krebs and prepared for SNS (50 V, 3 ms, 7-40 Hz). 3 SNS caused a frequency-dependent vasoconstrictor response which was abolished by either tetrodotoxin (10(-7) M), prazosin (2.4 x 10(-7)M) or guanethidine (2.4 x 10(-7) M). 4 In mesenteric vascular beds removed from rats infused with endotoxin, there were markedly impaired vasoconstrictor responses to SNS, although responses to noradrenaline were not modified. 5 Removal of the endothelium with distilled water prevented endotoxin-induced impairment of vasoconstrictor responses to SNS, without modifying these responses in preparations from control rats. 6 Pretreatment with dexamethasone (3 mg kg(-1) i.p. Ih before commencing endotoxin or saline infusions) did not modify responses to SNS in control rats but prevented the effects of endotoxin. 7 Both L-NAME (10(-3) M) and indomethacin (10(-5) M) restored responses to SNS in preparations from endotoxin-treated rats without modifying these responses in control preparations. However, coadministration of L-NAME and indomethacin markedly augmented responses in both control and endotoxin-treated preparations. 8 The effects of L-NAME were reversed by addition of L-arginine (10(-3) M). 9 The data suggest that endotoxin impairs the release of noradrenaline and that this effect is secondary to increased production of nitric oxide and prostanoids, possibly by the endothelium.