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Background: Portal pressure (PP) results from the interplay of vasoconstrictors and vasodilators. Recently, we have shown that Kupffer cell (KC) activation increases PP. Aims: The role of the vasodilating compounds nitric oxide (NO) and carbon monoxide (CO) was studied. The hypothesis of the present study was that these vasodilators counteract the PP increase following KC activation. Methods: Livers of rats weighing 180-200 g were isolated and perfused. KCs were activated by zymosan A (cell wall particles from yeast; 150 μg/ml). The effects of NO and guanylate cyclase (GC) were evaluated by the NO synthase inhibitor NG-nitro-L-arginine methylester (L-NAME; 0.3 mM, and the GC inhibitor 4H-8-bromo-1,2,4-oxadiazolo(3,4-d)benz(b)(1,4)oxazin-1-one (NS-2028, 1.0 μM); the effects of the heme oxygenase (HO) derived compound CO were evaluated by direct administration of CO or inhibition of HO by zinc protoporphyrin IX (ZnPP IX, 1.0 μM). Results: In isolated perfused rat livers, administration of L-NAME or NS-2028 further raised PP increase following KC activation. This effect could be reduced by the cGMP analogue 8-Br-cGMP. Inhibition of HO caused marked amplification of PP increase in zymosan-treated organs. CO prevented this PP increase cGMP independently. Interestingly, KC activation and simultaneous inhibition of HO augmented the production of prostaglandins D2 and F2α and of thromboxane A2. Accordingly, indomethacin blunted the increase of PP in zymosan/ZnPP-treated livers. Conclusions: NO restricts the initial PP increase after KC activation by GC-mediated cGMP. CO from heme degradation limits the increase of PP after KC activation eicosanoid dependently, but cGMP independently. Copyright © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Refractory ascites is a frequent complication of advanced cirrhosis and is associated with hepatorenal syndrome and hepatic hydrothorax. Large volume paracentesis and pleurodesis are regarded as first-line treatments in patients who do not respond adequately to diuretics. These treatments, however, do not prevent recurrence and carry the risk of worsening of the circulatory dysfunction leading to hepatorenal syndrome. The transjugular intrahepatic portosystemic shunt (TIPS) has been proposed as an alternative to paracentesis. TIPS reduces the rate of ascites recurrence mainly due to the reduction in the filtration pressure. In addition, TIPS results in a positive effect on renal function, including hepatorenal syndrome, demonstrated by a rapid increase in urinary sodium excretion, urinary volume, and improvement in plasma creatinine concentration. Furthermore, plasma renin activity, aldosterone, and noradrenalin concentrations improve gradually after TIPS insertion suggesting a positive effect on systemic underfilling, the factor of hepatorenal syndrome. As demonstrated recently in two meta-analyses including five randomised studies, TIPS also improves survival when compared with paracentesis. However, the evidence is based on relatively few studies with only 305 patients included. The positive effects of the TIPS are opposed by an increased frequency and severity of episodes of hepatic encephalopathy which may be reduced by both patient selection and reduced shunt diameter. Based on the present knowledge the recommended hierarchy of treatments for refractory ascites may be reconsidered upgrading TIPS in suitable candidates. [ABSTRACT FROM AUTHOR]

Background/Aims: Cirrhotic patients show an increased risk of variceal bleeding upon bacterial infections. Kupffer cells (KC) constitute the first macrophage population to become activated by bacterial β-glucans and endotoxins derived from the gut. We therefore investigated whether and how KC activation increases portal pressure. Methods: KC in normal and fibrotic livers from bile duct ligated (BDL) rats were activated by the β-glucan component of zymosan in vivo and during isolated rat liver perfusion. Results: Activation of KC in normal livers resulted in a severalfold increase of portal pressure in vivo as well as in isolated perfused liver preparations. This increase and the accompanying 40-fold stimulation of hepatic prostaglandin F2α/D2 and thromboxane A2 (TxA2) production in isolated perfused livers were attenuated by KC blockade. The TxA2 synthase inhibitor furegrelate and the TxA2 receptor antagonist BM 13.177 reduced the increase of portal perfusion pressure supporting TxA2 as pivotal vasoconstrictor released by activated KC. Importantly, a more pronounced vasopressor response in fibrotic livers was related to a raise in KC density and a 10-fold increase of TxA2 production after KC activation. Conclusions: KC activated by β-glucans increase portal pressure through the release of TxA2. This vasopressor response is augmented in BDL induced fibrosis. [Copyright &y& Elsevier]

Investigates the role of hepatic stellate cells (HSC) in the physiopathology of portal hypertension. Structure of HSC; Functions and activation of HSC; Conditions that influence the contractility of activated myofibroblastic HSC; Impact of endothelin-1 on smooth muscle and endothelial cells.

Offers information on idiopathic portal hypertension (IPH) and noncirrhotic portal fibrosis (NCPF). Difference between IPH and NCPF; Etiology of the diseases; Pathological mechanisms involved in IPH and NCPF; Signs and symptoms of IPH and NCPF.

Analyzes the role of intrahepatic modulation of portal pressure in portal hypertension. Description of the intrahepatic vasculature; Measurement of intrahepatic blood flow; Modulation of intrahepatic vascular resistance.

Hyperdynamic circulation as well as increased hepatic resistance contribute to portal hypertension in cirrhosis of the liver [1]. Hyperdynamic circulation with increased cardiac output, heart rate and plasma volume and decreased arterial blood pressure and systemic vasodilatation is pivotal for the hyperdynamic circulation. This has prompted intense research of a number of endogenous neurohumoral mediators with vasodilating properties (NO, natriuretic peptides, glucagon, etc.) [2, 3]. [ABSTRACT FROM AUTHOR]

Tackles the role of nitric oxide in portal hypertension. Correlation between intrahepatic resistance and blood flow; Physiological and morphological changes occurring in chronic liver diseases; Influence of an increase in systemic and splanchnic blood flow on the hyperdynamic circulatory state associated with portal hypertension.

The article offers information on a study on the effect of amiloride on portal hypertension in rat liver cirrhosis. It involved induction of liver cirrhosis via bile duct ligation (BDL) or thioacetamide (TAA) administration. Results revealed that portal pressure in rat liver cirrhosis is lowered by amiloride by inhibiting intrahepatic vasocontraction.

Abstract: Aims: In liver cirrhosis, inflammation triggers portal hypertension. Kupffer cells (KC) produce vasoconstrictors upon activation by bacterial constituents. Here, we hypothesize that the anti-inflammatory action of the cannabinoid receptor 2 (CB2) agonists JWH-133 and GP 1a attenuate portal hypertension. Main methods: In vivo measurements of portal pressures and non-recirculating liver perfusions were performed in rats 4weeks after bile duct ligation (BDL). Zymosan (150μg/ml, isolated liver perfusion) or LPS (4mg/kgb.w., in vivo) was infused to activate the KC in the absence or presence of JWH-133 (10mg/kgb.w.), GP 1a (2.5mg/kgb.w.) or ZnPP IX (1μM). Isolated KC were treated with Zymosan (0.5mg/ml) in addition to JWH-133 (5μM). The thromboxane (TX) B2 levels in the perfusate and KC media were determined by ELISA. Heme oxygenase-1 (HO-1) and CB2 were analyzed by Western blot or confocal microscopy. Key findings: JWH-133 or GP 1a pre-treatment attenuated portal pressures following KC activation in all experimental settings. In parallel, HO-1 expression increased with JWH-133 pre-treatment. However, the inhibition of HO-1 enhanced portal hypertension, indicating the functional role of this novel pathway. In isolated KC, the expression of CB2 and HO-1 increased with Zymosan, LPS and JWH-133 treatment while TXB2 production following KC activation was attenuated by JWH-133 pre-treatment. Significance: JWH-133 or GP 1a treatment attenuates portal hypertension. HO-1 induction by JWH-133 plays a functional role. Therefore, the administration of JWH-133 or GP 1a represents a promising new treatment option for portal hypertension triggered by microbiological products. [Copyright &y& Elsevier]