Bacterial translocation up-regulates GTP-cyclohydrolase I in mesenteric vasculature of cirrhotic rats.
In cirrhosis, arterial vasodilation and the associated hemodynamic disturbances are most prominent in the mesenteric circulation, and its severity has been linked to bacterial translocation (BT) and endotoxemia. Synthesis of nitric oxide (NO), the main vasodilator implicated, is dependent on the essential cofactor tetrahydrobiopterin (BH(4)). The key enzyme involved in BH(4) synthesis is GTP-cyclohydrolase I (GTPCH-I), which is stimulated by endotoxin. Therefore, we investigated GTPCH-I activity and BH(4) biosynthesis in the mesenteric vasculature of cirrhotic rats with ascites, as well as their relationship with BT and endotoxemia, serum NO, and mean arterial pressure (MAP). GTPCH-I activity and BH(4) content in mesenteric vasculature was determined by high-performance liquid chromatography. BT was assessed by standard bacteriologic culture of mesenteric lymph nodes (MLNs). Serum endotoxin was measured by a kinetic turbidimetric limulus amebocyte lysate assay, and serum NO metabolite (NOx) concentrations were assessed by chemiluminescence. BT was associated with local lymphatic and systemic appearance of endotoxin and was accompanied by increases in serum NOx levels. GTPCH-I activity and BH(4) content in mesenteric vasculature were both increased in animals with BT and correlated significantly (r = 0.69, P <.01). Both GTPCH-I activity and BH(4) levels significantly correlated with serum endotoxin and NOx levels (r = 0.69 and 0.54, 0.81 and 0.53, P <.05). MAP (a marker of systemic vasodilatation) correlated with endotoxemia (r = 0.58, P <.03) and with GTPCH-I activity (r = 0.69, P <.01). In conclusion, in cirrhotic animals BT appears to lead to endotoxemia, stimulation of GTPCH-I, increased BH(4) synthesis, and further enhancement of vascular NO production that leads to aggravation of vasodilatation.
Wiest
Reiner
R
Hepatic Hemodynamic Laboratory, Veterans Administration Medical Center, West Haven, CT 06515, USA.
Cadelina
Gregory
G
Milstien
Sheldon
S
McCuskey
Robert S
RS
Garcia-Tsao
Guadalupe
G
Groszmann
Roberto J
RJ
D000818:Animals; D018988:Bacterial Translocation; D001708:Biopterins / Q000031:analogs & derivatives* / Q000096:biosynthesis; D001794:Blood Pressure; D019446:Endotoxemia / Q000209:etiology; D006136:GTP Cyclohydrolase / Q000096:biosynthesis* / Q000097:blood; D008106:Liver Cirrhosis, Experimental / Q000201:enzymology*; D008297:Male; D008638:Mesenteric Arteries / Q000201:enzymology*; D009569:Nitric Oxide / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation
D001708:Biopterins; D009569:Nitric Oxide; D006136:GTP Cyclohydrolase; C003402:sapropterin