Lipopolysaccharide-induced impairment of nitric oxide-mediated vasorelaxation and protective effects of nitric oxide synthesis inhibitors in isolated rat mesenteric arteries.

Isolated rat mesenteric arteries were incubated with lipopolysaccharide (LPS) for 6 h and then mounted in an organ bath to investigate their responses to various relaxants. Exposure to LPS moderately reduced acetylcholine (ACh)-induced endothelium-dependent relaxation (EDR), and markedly reduced sodium nitroprusside (SNP)-induced endothelium-independent relaxation (EIR). It did not affect ACh-induced EDR under treatment with a nitric oxide synthase (NOS) inhibitor, which is mediated by an endothelium-derived hyperpolarizing factor (EDHF), and forskolin-induced EIR. N-(3-(Aminomethyl)benzyl)acetamidine (1400 W), an inducible nitric oxide synthase (iNOS) inhibitor, actinomycin D, an RNA polymerase inhibitor, cycloheximide, a protein synthesis inhibitor, and dexamethazone reduced the nitric oxide (NO) production and reversed the reduced ACh-induced EDR and SNP-induced EIR. In LPS-treated mesenteric artery, L-arginine-induced relaxation was not affected by removal of endothelium, indicating muscular inducible nitric oxide synthase (iNOS) induction. Pre-exposure to SNP (NO donor) also moderately reduced ACh-induced EDR and markedly reduced SNP-induced EIR with little effect on ACh-induced EDHF-mediated EDR. In conclusion, in vitro exposure to LPS desensitized vascular smooth muscle cells to endogenous and exogenous NO by overproduction of muscular iNOS-derived NO, and an iNOS inhibitor and iNOS induction inhibitors prevented the LPS-induced desensitization.