Inhibition of epoxyeicosatrienoic acid production in rats with cirrhosis has beneficial effects on portal hypertension by reducing splanchnic vasodilation.

UNLABELLED: In cirrhosis, 11,12-epoxyeicosatrienoic acid (EET) induces mesenteric arterial vasodilation, which contributes to the onset of portal hypertension. We evaluated the hemodynamic effects of in vivo inhibition of EET production in experimental cirrhosis. Sixteen control rats and 16 rats with carbon tetrachloride-induced cirrhosis were studied. Eight controls and eight rats with cirrhosis were treated with the specific epoxygenase inhibitor N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MS-PPOH; 20 mg/kg/day) for 3 consecutive days. Portal blood flow and renal and splenic resistive indexes were calculated through echographic measurements, while portal and systemic pressures were measured through polyethylene-50 catheters. Small resistance mesenteric arteries were connected to a pressure servo controller in a video-monitored perfusion system, and concentration-response curves to phenylephrine and acetylcholine were evaluated. EET levels were measured in tissue homogenates of rat liver, kidney, and aorta, using an enzyme-linked immunosorbent assay. Urinary Na(+) excretion function was also evaluated. In rats with cirrhosis, treatment with MS-PPOH significantly reduced portal blood flow and portal pressure compared to vehicle (13.6 ± 5.7 versus 25.3 ± 7.1 mL/min/100 g body weight, P < 0.05; 9.6 ± 1.1 versus 12.2 ± 2.3 mm Hg, P < 0.05; respectively) without effects on systemic pressure. An increased response to acetylcholine of mesenteric arteries from rats with cirrhosis (50% effect concentration -7.083 ± 0.197 versus -6.517 ± 0.73 in control rats, P < 0.05) was reversed after inhibition of EET production (-6.388 ± 0.263, P < 0.05). In liver, kidney, and aorta from animals with cirrhosis, treatment with MS-PPOH reversed the increase in EET levels. In both controls and rats with cirrhosis, MS-PPOH increased urinary Na(+) excretion. CONCLUSION: In rats with cirrhosis, in vivo inhibition of EET production normalizes the response of mesenteric arteries to vasodilators, with beneficial effects on portal hypertension. (Hepatology 2016;64:923-930).

Hepatic osteodystrophy.

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.

Prevention of hypertension, cardiovascular damage and endothelial dysfunction with green tea extracts.

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 microg/kg/d) or a low (350 microg/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 p22(phox) 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, p22(phox), 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.