N-acetylcysteine enhances endothelium-dependent vasorelaxation in the isolated rat mesenteric artery

Study hypothesis: Previous studies have suggested that N-acetylcysteine (NAC) may confer additional protection in acetaminophen (APAP) overdose by improving hepatic microcirculation. We hypothesize that NAC enhances release of nitric oxide (NO) from the vasculature. Methods: Sprague-Dawley rat superior mesenteric artery rings were suspended in oxygenated Krebs-Henseleit tissue baths and contracted with U-46619 (a thromboxane A(2)-mimetic). In part 1, the effect of NAC on endothelial cell (EC) release of NO was assessed by measurement of vasorelaxation induced by acetylcholine (ACh, an EC-dependent vasorelaxor) in the presence and absence of NAG. In part 2, the effect of glutathione (a major component of NAC hepatoprotection) was examined by measuring ACh-induced vasorelaxation in rings from rat treated with L-buthionine sulfoxamine (BSO, a glutathione synthesis inhibitor). Data were analyzed by repeated-measures ANOVA. Results: Addition of 15 to 30 mmol/l NAC after ring contraction had no direct vasodilatory effect. By contrast, pretreatment of rings with NAC(15 mmol/L) enhanced vasorelaxation induced by ACh (95.0%+/-7.9% versus 62.3%+/-7.6% for control; ACh dose, 1 mu mol/L; P<.001) or by A23187, a receptor-independent, NO-mediated vasodilator (91.6%+/-9.6% versus 68.3%+/-12.1% for control; A23187 dose, 1 mu mol/L; P<.001). In rings from BSO-treated rats, NAC also enhanced vasorelaxation (76.5%+/-7.1%; P<.001 versus control), but to a lesser degree than in nontreated rats. Conclusion: NAC enhances endothelium-dependent vasodilation in an isolated rat mesenteric artery ring preparation. In addition to its antioxidant effects, NAC may decrease APAP hepatotoxicity by stimulating NO production and improving microvascular circulation.