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Background: Recent studies have shown the presence of vascular endothelial growth factor (VEGF)-dependent splanchnic angiogenesis in experimental models of portal hypertension, and the role of such neovascularisation on the development of both portosystemic collaterals and hyperdynamic splanchnic circulation. However, the mechanisms modulating angiogenesis in portal hypertension are unknown. Experimental evidence indicates that NAD(P)H oxidase is required for VEGF-induced angiogenesis. Interestingly, we have recently shown that splanchnic NAD(P)H oxidase activity is significantly increased in portal hypertensive rats. Therefore, it could be possible that activated NAD(P)H oxidases modulate angiogenesis in portal hypertension., Aim: To determine the effects of chronic NAD(P)H oxidase inhibition on angiogenesis and splanchnic haemodynamics in portal hypertensive rats., Methods: Partial portal vein-ligated and sham-operated rats were treated with the NAD(P)H oxidase inhibitor apocynin, or with vehicle for 5 days. Then, the expression of angiogenesis markers (western blotting), the formation of portosystemic collaterals (radioactive microspheres) and the production of superoxide anion (lucigenin-enhanced chemiluminescence) were determined. Mean arterial pressure, portal pressure, and superior mesenteric arterial blood flow and resistance were also measured., Results: In portal hypertensive rats, NAD(P)H oxidase blockade significantly decreased portosystemic collateral formation, and superior mesenteric arterial flow. It also reduced the splanchnic expression of VEGF, VEGF receptor-2 and CD31, and attenuated the increased production of superoxide, compared with vehicle., Conclusions: NAD(P)H oxidase plays an important role in experimental portal hypertension, modulating splanchnic angiogenesis, the formation of portosystemic collaterals and the development of splanchnic hyperdynamic circulation. These results suggest that NAD(P)H oxidase may represent a new target in the treatment of portal hypertension.

Background: Bacterial translocation (BT) plays a major role in the pathophysiological process of spontaneous infections in portal hypertension (PH) and cholestatic jaundice. The major mechanisms promoting BT in experimental animal models are the disruption of the intestinal ecological equilibrium and disruption of the intestinal mucosal barrier. The enzymes xanthine dehydrogenase (XD) and xanthine oxidase (XO) are often implicated as a significant source of oxidants which have a major impact on the impairment of intestinal barrier function., Aim: To investigate the incidence of BT in rats with PH and obstructive jaundice, and to evaluate the impact of XD and XO., Methods: Animals were subjected to sham laparotomy (SL), PH by calibrated stenosis of the portal vein, and common bile duct ligation (CBDL). They were fed either a standard pellet diet or a tungsten supplemented molybdenum-free diet. Four weeks after the operative procedure, intestinal colonisation and BT to portal vein, vena cava, mesenteric lymph nodes, liver, and spleen were determined. Intestinal XD and XO activity were measured enzymatically and histochemically., Results: Significant (p<0.01) intestinal bacterial overgrowth was present in all PH and CBDL groups compared with the SL group. In normally fed animals after SL, BT occurred in 12%. In PH and after CBDL, the rate of BT increased significantly (p<0.05) to 28% and 54% respectively. In the jejunum of normally fed animals subjected to PH or CBDL, a significant increase in XO was observed (p<0.01). Animals fed a tungsten supplemented diet showed a significant attenuation of BT to 14% in PH and 22% after CBDL (p<0. 05). Tungsten treatment completely suppressed jejunal XD and XO activities., Conclusions: Significant intestinal bacterial overgrowth, BT, and XD to XO conversion occurred in PH and after CBDL. XD and XO inactivation by a tungsten supplemented molybdenum-free diet significantly reduced the incidence of BT without affecting intestinal bacterial overgrowth. These data strongly support the hypothesis that increased XD to XO conversion may contribute to intestinal barrier failure in PH and after CBDL.

In eight patients with cirrhosis of the liver and portal hypertension an intravenous infusion of lysine vasopressin induced a rapid increase in the plasma level of the fibrinolytic proenzyme plasminogen activator. In contrast, triglycyl lysine vasopressin (glypressin; GVP), in a dose known to lower portal venous pressure, produced no fibrinolytic response. This lack of fibrinolytic response represents an advantage of GVP over lysine vasopressin in addition to its longer in vivo half-life and lower cardiotoxicity. Clinical trials of GVP in the treatment of bleeding oesophageal varices are needed.