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 associated vascular hyporesponsiveness to vasoconstrictors observed in liver cirrhosis. Bacteria, potent activators of NO and TNF-alpha synthesis, are found in the mesenteric lymph nodes (MLNs) of ascitic cirrhotic rats. Here, we investigated the impact of bacterial translocation (BT) to MLNs on TNF-alpha production, vascular NO release, and contractility in the mesenteric vasculature of ascitic cirrhotic rats. Vascular response to the alpha-adrenoagonist methoxamine, which is diminished in the superior mesenteric arterial beds of cirrhotic rats, is further blunted in the presence of BT. BT promoted vascular NO release in cirrhotic rats, an effect that depended on pressure-induced shear stress and was blocked by the NO inhibitor N(omega)-nitro-L-arginine. Removing the endothelium had the same effect. Endothelial NO synthase (eNOS), but not the inducible isoform (iNOS), was present in mesenteric vasculature of cirrhotic rats with and without BT, and its expression was enhanced compared with controls. TNF-alpha was induced in MLNs by BT and accumulated in parallel in the serum. This TNF-alpha production was associated with elevated levels of tetrahydrobiopterin (BH(4)), a TNF-alpha-stimulated cofactor and enhancer of eNOS-derived NO biosynthesis and NOS activity in mesenteric vasculature. These findings establish a link between BT to MLNs and increased TNF-alpha production and elevated BH(4) levels enhancing eNOS-derived NO overproduction, further impairing contractility in the cirrhotic mesenteric vasculature.
Wiest
R
R
Hepatic Hemodynamic Laboratory, Veterans Administration Medical Center, West Haven, Connecticut 06516, USA.
Das
S
S
Cadelina
G
G
Garcia-Tsao
G
G
Milstien
S
S
Groszmann
R J
RJ
D000818:Animals; D018988:Bacterial Translocation; D004305:Dose-Response Relationship, Drug; D008106:Liver Cirrhosis, Experimental / Q000382:microbiology; D008198:Lymph Nodes / Q000378:metabolism; D008297:Male; D008638:Mesenteric Arteries / Q000378:metabolism*; D008729:Methoxamine / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D010477:Perfusion; D011312:Pressure; D020033:Protein Isoforms; D051381:Rats; D017207:Rats, Sprague-Dawley; D013314:Stress, Mechanical; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014661:Vasoconstriction; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D020033:Protein Isoforms; D014409:Tumor Necrosis Factor-alpha; D014662:Vasoconstrictor Agents; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D008729:Methoxamine