Lipopolysaccharide inhibits acetylcholine- and nitric oxide-mediated vasodilation in vivo.

The bacterial endotoxin lipopolysaccharide (LPS) inhibits endothelium-dependent relaxation. At present, there is no evidence that this is due to a diminution in the vasorelaxant potencies of nitric oxide (NO) or related nitrosyl factors such as S-nitroso-cysteine (SNC). The aim of the present study was to determine whether the systemic administration of LPS reduces endothelium-dependent vasodilation in rats by diminishing the vasorelaxant potencies of NO or related nitrosyl factors. We examined the time course of effects of a low dose of LPS (2 mg/kg i.v.) on base-line mean arterial pressure and vascular resistances and the hemodynamic responses produced by i.v. injection of the endothelium-dependent vasodilator ACh, the NO donor sodium nitroprusside (SNP) and SNC in urethane-anesthetized rats. LPS produced a sustained fall in mean arterial pressure after 90-120 min due to a reduction in cardiac output. The vasodilator effects of ACh, SNP and SNC in the hindquarter bed were diminished 30 to 75 min after the administration of LPS. The vasodilator effects of ACh in this bed were unaffected 120 to 180 min after LPS. In contrast, the vasodilator effects of SNP were markedly augmented, whereas those of SNC were markedly diminished, 120 to 180 min after LPS. The vasodilator responses produced by ACh in the renal and mesenteric beds were diminished 30 to 75 min and 120 to 180 min, respectively, after LPS. The vasodilator actions of SNP and SNC were not substantially reduced in these beds. These results demonstrate that LPS inhibits ACh-induced vasodilation in vivo. In the hindquarter bed, this may involve loss of the vasodilator effectiveness of NO or related nitrosyl factors. In the renal and mesenteric beds, the loss of ACh-induced responses may be due to the LPS-induced inhibition of muscarinic receptor-mediated signal transduction mechanisms.