Endotoxin impairs the response of rabbit mesenteric artery to electrical stimulation via a prejunctional mechanism.

1. The effect of E. coli lipopolysaccharide (LPS) on sympathetic neuro-effector transmission was studied in the rabbit mesenteric artery. The experiments were performed on artery rings isolated 5 or 20 h after intravenous treatment with LPS or saline as well as on artery rings isolated from non-treated rabbits (for assessment of the effect of in vitro preincubation with LPS). In most experiments, neural elements in the arteries were stimulated electrically (10 V, 2 ms, 1-32 Hz). 2. Preincubation with LPS (10 micrograms ml-1) for 5 or 20 h had no effect on the contraction responses of endothelium-intact artery rings to electrical stimulation. In contrast, in vivo intravenous pretreatment with LPS (10 micrograms) led to an inhibition of the contraction; LPS elicited this effect when injected 20 h, but not 5 h, before the experiment. The effect of LPS was eliminated in artery rings isolated from animals receiving an inhibitor of protein synthesis (actinomycin D or cycloheximide) before treatment with LPS. LPS (injected 20 h before the experiment) had no effect on the concentration-response curves for exogenous noradrenaline and tyramine in endothelium-intact artery rings. 3. The inhibition of electrically induced contractions produced by LPS treatment in endothelium-intact artery rings was attenuated by atropine and yohimbine, but not by phentolamine. Yohimbine plus atropine restored the depressed contraction to the normal level. Clonidine and acetylcholine mimicked the effect of LPS in endothelium-intact artery rings isolated from saline-treated animals. 4. When steady-state contractions were induced by 5 min of stimulation at 16 Hz, acetylcholine or clonidine reduced the contraction in endothelium-denuded artery rings from both saline-treated rabbits and animals receiving LPS 20 h before the experiment. The reduction produced by acetylcholine or clonidine of the contraction in artery rings from LPS-treated rabbits was significantly greater than in artery rings from saline-treated animals.5. These results suggest that treatment of rabbits with LPS inhibits noradrenaline release from sympathetic nerve endings via increased sensitivity of both prejunctional inhibitory muscarinic receptors and x2-adrenoceptors in mesenteric arteries. They also suggest that the effect of LPS is independent of endothelial cells but linked to protein synthesis.