Bacterial translocation in cirrhotic rats stimulates eNOS-derived NO production and impairs mesenteric vascular contractility

Nitric oxide (NO) has been implicated in the arterial vasodilation and asso ciated vascular hyporesponsiveness to vasoconstrictors observed in liver ci rrhosis. Bacteria, potent activators of NO and TNF-alpha synthesis, are fou nd in the mesenteric lymph nodes (MLNs) of ascitic cirrhotic rats. Here, we investigated the impact of bacterial translocation (BT) to MLNs on TNF-alp ha production, vascular NO release, and contractility in the mesenteric vas culature of ascitic cirrhotic rats. Vascular response to the alpha-adrenoag onist methoxamine, which is diminished in the superior mesenteric arterial beds of cirrhotic rats, is further blunted in the presence of BT. BT promot ed vascular NO release in cirrhotic rats, an effect that depended on pressu re-induced shear stress and was blocked by the NO inhibitor N-omega-nitro-L -arginine. Removing the endothelium had the same effect. Endothelial NO syn thase (eNOS), but not the inducible isoform (iNOS), was present in mesenter ic vasculature of cirrhotic rats with and without BT, and its expression wa s enhanced compared with controls. TNF-alpha was induced in MLNs by BT and accumulated in parallel in the serum. This TNF-alpha production was associa ted with elevated levels of tetrahydrobiopterin (BH4), a TNF-alpha-stimulat ed cofactor and enhancer of eNOS-derived NO biosynthesis and NOS activity i n mesenteric vasculature. These findings establish a link between BT to MLN s and increased TNF-alpha production and elevated BH4 levels enhancing eNOS -derived NO overproduction, further impairing contractility in the cirrhoti c mesenteric vasculature.