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11, 12-Epoxyeicosatrienoic acid (11,12-EET), a potent vasodilator produced by the endothelium, acts on calcium-activated potassium channels and shares biological activities with the heme oxygenase/ carbon monoxide (HO/CO) system. We examined whether activation of HO mediates the dilator action of 11,12-EET, and that of the other EETs, on rat mesenteric arteries. Dose-response curves ([10.sup.-9] to [10.sup.-6]M) to 5,6-EET, 8,9-EET, 11,12-EET, 14,15-EET, and Ach ([10.sup.-9] to [10.sup.-4]M) were evaluated in preconstricted ([10.sup.-6] mol/l phenylephrine) mesenteric arteries ( Epoxygenase; carbon monoxide; endothelial cell; mesenteric artery

Background & Aims: In patients with cirrhosis, the clinical benefit of the treatment with human albumin for ascites is debated, and no data are available regarding refractory ascites. In this study, in patients with cirrhosis and refractory ascites, we assessed the effect of long‐term albumin administration on emergent hospitalization and mortality. Methods: Seventy patients with cirrhosis and refractory ascites, followed at the Unit of Internal Medicine and Hepatology, University and General Hospital of Padova, Italy, were included into the study. Forty‐five patients were non‐randomly assigned to receive long‐term administration of human albumin at the doses of 20 g twice per week (n = 45), in addition to standard medical of care (SOC), and compared to those followed according to SOC. Patients were followed up to the end of the study, liver transplantation or death. Results: The cumulative incidence of 24‐month mortality was significantly lower in patients treated with albumin than in the group of patients treated with SOC (41.6% vs 65.5%; P = 0.032). The period free of emergent hospitalization was significantly longer in patients treated with long‐term administration of albumin (P = 0.008). Analysing separately the causes of inpatient admission, patients treated with albumin showed a reduction in the incidence of overt hepatic encephalopathy, ascites, spontaneous bacterial peritonitis (SBP) and non‐SBP infections. In addition, a non‐significant trend towards a reduced probability of hepatorenal syndrome was observed. Conclusion: In patients with cirrhosis and refractory ascites, long‐term treatment with albumin improves survival and reduces the probability of emergent hospitalizations. See Editorial on Page 45 [ABSTRACT FROM AUTHOR]

Background: We investigated the effect of green tea extract (GTE) in arterial hypertension with high oxidative stress. Angiotensin (Ang) II induces endothelial dysfunction (ED) that is crucial for the development of atherosclerosis and hypertension. Methods: Male Sprague-Dawley rats, 13 weeks old, randomly assigned to drinking water with or without GTE (6 mg/mL) received a vehicle, a high (700 μg/kg/d) or a low (350 μg/kg/d) Ang II dose for 13 days, by osmotic mini-pumps. Blood pressure (BP) was measured with telemetry. After sacrifice, left ventricular (LV) mass index, small mesenteric artery media-to-lumen ratio, and concentration–response curves of phenylephrine-precontracted arteries to acetylcholine were evaluated. The effect of the superoxide dismutase (SOD-1) analog tempol on artery responses to acetylcholine was assessed. Oxidative stress was measured by plasma hydroperoxides and nitrotyrosine levels. The mRNA of heme oxygenase 1 (HO-1), NADPH oxidase endothelial p22phox subunit, and SOD-1 was also measured in the aorta. Results: Compared with vehicle high Ang II increased BP, LV mass index, media-to-lumen ratio, and hydroperoxide radicals. The GTE blunted these increases, prevented the increase in HO-1, p22phox, and SOD-1 mRNA in aorta caused by Ang II, and reduced them below baseline levels. Low Ang II dose increased BP values and plasma hydroperoxides only during the first week. Both Ang II doses shifted rightward the curves to acetylcholine; this was prevented in vivo by GTE and abolished in vitro by tempol. Conclusions: The GTE prevented hypertension and target organ damage induced by a high Ang II dose, likely by prevention or scavenging of superoxide anion generation. [Copyright &y& Elsevier]

Metabolic disturbances of bone are frequent in patients with chronic liver disease. The prevalence of osteoporosis among patients with advanced chronic liver disease is reported between 12% and 55%; it is higher in primary biliary cirrhosis. All patients with advanced liver disease should be screened for osteoporosis with a densitometry, especially if the etiology is cholestatic and in the presence of other risk factors. Clinical relevance of hepatic osteodystrophy increases after liver transplantation. After liver transplant, a rapid loss of bone mineral density can be detected in the first 6 months, followed by stabilization and slight improvement of the values. At the time of transplantation, bone density values are very important prognostic factors. Therapy of hepatic osteodystrophy is based primarily on the control of risk factors: cessation of tobacco and alcohol assumption, reduction of caffeine ingestion, exercise, supplementation of calcium and vitamin D, limitation of drugs such as loop diuretics, corticosteroids, cholestyramine. Bisphosphonates have been proposed for the therapy of osteoporosis in patients with liver disease, particularly after liver transplantation. The possible side effects of oral administration of bisphosphonates, such as the occurrence of esophageal ulcerations, are of particular concern in patients with liver cirrhosis and portal hypertension, due to the risk of gastrointestinal hemorrhage from ruptured esophageal varices, although this risk is probably overestimated. [ABSTRACT FROM AUTHOR]

In liver cirrhosis, oxidative stress plays a major role in promoting liver inflammation and fibrosis. Mitochondria dysregulation is responsible for excessive reactive oxygen species production. Therefore, in an experimental model of cirrhosis, we investigated the effect of mitochondria-targeted antioxidant mitoquinone. Liver cirrhosis was induced in Spraque-Dawley rats by common bile duct ligation (CBDL). Mitoquinone (10 mg·kg -1 ·day -1 , oral gavage) or vehicle was administered from 3rd to 28th day after CBDL, when animals were euthanized; liver oxidative stress, inflammation, fibrosis, mitophagy were evaluated; and in vivo and ex vivo hemodynamic studies were performed. In cirrhotic rats, mitoquinone prevented liver inflammation, hepatocyte necrosis, and fibrosis at histological examination; decreased circulating TNF-α, gene expression of transforming growth factor-β1, collagen type 1a1, TNF-α, IL-6, IL-1β, tissue inhibitor of metalloproteinase-1, matrix metalloproteinase (MMP)-2, and MMP-13; and reduced hepatic oxidative stress, as shown by reduced oxidative carbonylation of the proteins, by modulating antioxidants catalase, Mn superoxide dismutase, and Cu/Zn superoxide dismutase. Furthermore, mitoquinone attenuated apoptosis by reducing hepatic protein expression of cleaved caspase-3. A selective removal of dysfunctional mitochondria was improved by mitoquinone, as shown by the increase in Parkin translocation to mitochondria. Treatment with mitoquinone normalized the weight of the spleen; however, it increased portal blood flow and reduced splenic artery intrahepatic resistance, suggesting an effect on resistance index. Mitochondria-targeted antioxidant mitoquinone improves liver inflammation and fibrosis in cirrhotic rats by reducing hepatic oxidative stress, preventing apoptosis, and promoting removal of dysfunctional mitochondria. Therefore, it may represent a promising strategy for the prevention and treatment of liver cirrhosis.

Alcohol-related cirrhosis is a consequence of heavy and prolonged drinking. Similarly to patients with cirrhosis of other etiologies, patients with alcoholic cirrhosis develop portal hypertension and the hepatic, splanchnic and systemic hemodynamic alterations that follow. However, in alcoholic cirrhosis, some specific features can be observed. Compared to viral cirrhosis, in alcohol-related cirrhosis sinusoidal pressure is generally higher, hepatic venous pressure gradient reflects portal pressure better, the portal flow perfusing the liver is reduced despite an increase in liver weight, the prevalence of reversal portal blood flow is higher, a patent paraumbilical vein is a more common finding and signs of hyperdynamic circulations, such as an increased cardiac output and decreased systemic vascular resistance, are more pronounced. Moreover, alcohol consumption can acutely increase portal pressure and portal-collateral blood flow. Alcoholic cardiomyopathy, another pathological consequence of prolonged alcohol misuse, may contribute to the hemodynamic changes occurring in alcohol-related cirrhosis. The aim of this review was to assess the portal-hepatic changes that occur in alcohol-related cirrhosis, focusing on the differences observed in comparison with patients with viral cirrhosis. The knowledge of the specific characteristics of this pathological condition can be helpful in the management of portal hypertension and its complications in patients with alcohol-related cirrhosis.

Portal hypertension is a clinical syndrome which leads to several clinical complications, such as the formation and rupture of esophageal and/or gastric varices, ascites, hepatic encephalopathy and hepato-renal syndrome. In cirrhosis, the primary cause of the increase in portal pressure is the enhanced resistance to portal outflow. However, also an increase in splanchnic blood flow worsens and maintains portal hypertension. The vasodilatation of arterial splanchnic vessels and the opening of collateral circulation are the determinants of the increased splanchnic blood flow. Several vasoactive systems/substances, such as nitric oxide, cyclooxygenase-derivatives, carbon monoxide and endogenous cannabinoids are activated in portal hypertension and are responsible for the marked splanchnic vasodilatation. Moreover, an impaired reactivity to vasoconstrictor systems, such as the sympathetic nervous system, vasopressin, angiotensin II and endothelin-1, plays a role in this process. The opening of collateral circulation occurs through the reperfusion and dilatation of preexisting vessels, but also through the generation of new vessels. Splanchnic vasodilatation leads to the onset of the hyperdynamic circulatory syndrome, a syndrome which occurs in patients with portal hypertension and is characterized by increased cardiac output and heart rate, and decreased systemic vascular resistance with low arterial blood pressure. Understanding the pathophysiology of splanchnic vasodilatation and hyperdynamic circulatory syndrome is mandatory for the prevention and treatment of portal hypertension and its severe complications.

Heme oxygenase (HO) has been shown to provide cytoprotection to the vascular system in diabetes. Isolated femoral arteries from diabetic rats treated with cobalt protoporphyrin (CoPP) exhibited increased relaxation to acetylcholine (ACh), which was markedly decreased in control diabetic rats. In control rats treated with either CoPP or with CO releasing molecules-3 (CORM-3), but not in rats treated with biliverdin, we observed an increased dilatory response to ACh. The inhibition of guanylyl-cyclase (GC) with 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) caused a contractile response to ACh in control rats and in biliverdin-treated rats, while in rats treated with CoPP and CORM-3, the ACh dilatory effect was only decreased. Moreover, the inhibition of HO with chromium mesoporphyrin did not change the response to ACh in rats treated with CoPP, suggesting that the improving effect of overproduction of CO on vascular reactivity is due to a decrease in iNOS and the beneficial effect on vascular function.