Ascorbic acid improves the intrahepatic endothelial dysfunction of patients with cirrhosis and portal hypertension

Abstract

Patients with cirrhosis show intrahepatic endothelial dysfunction, characterized by an impaired flow-dependent vasorelaxation. This alteration is responsible for the marked postprandial increase in portal pressure and is attributed to an insufficient release of nitric oxide (NO). Ascorbic acid reverts endothelial dysfunction in other vascular disorders, via the increase of NO bioavailability through the neutralization of superoxide anions, thus preventing the scavenging of NO by superoxide. This study examined whether acute ascorbic acid administration might improve endothelial dysfunction in cirrhosis. Thirty-seven portal hypertensive patients with cirrhosis had measurements of hepatic and systemic hemodynamics, ascorbic acid, and malondialdehyde (MDA). Patients were randomly allocated to receive ascorbic acid (3 g, intravenously, n ‫؍‬ 15) or placebo (n ‫؍‬ 12) followed by a liquid meal. A third group received ascorbic acid followed by a sham meal (n ‫؍‬ 10). Measurements were repeated after 30 minutes (hepatic venous pressure gradient at 15 and 30 minutes). Patients with cirrhosis had significantly lower ascorbic acid levels and higher MDA than healthy controls. Ascorbic acid significantly reduced MDA levels and markedly attenuated the postprandial increase in the hepatic venous pressure gradient (4% ؎ 7% vs. 18% ؎ 10% in placebo at 30 minutes, P < .001). Ascorbic acid followed by sham meal did not modify hepatic or systemic hemodynamics. In conclusion, patients with cirrhosis exhibited intrahepatic endothelial dysfunction, associated with decreased levels of ascorbic acid and increased levels of MDA. Ascorbic acid improved intrahepatic endothelial dysfunction, blunting the postprandial increase in portal pressure. These results encourage the performance of further studies testing antioxidants as adjunctive therapy in the treatment of portal hypertension. (HEPATOLOGY 2006;43:485-491.) P ortal hypertension is a serious consequence of cirrhosis and can result in life-threatening complications with increased mortality and morbidity. 1 Portal hypertension is determined by an increased resistance to portal-collateral blood flow and aggravated by an increased portal venous inflow, caused by splanchnic vasodilatation. 2 The primary factor in the pathophysiology of portal hypertension is increased resistance. 3 In cirrhosis, the increase in resistance occurs at the level of the hepatic microcirculation and is promoted by the morphological changes occurring in chronic liver diseases. In addition, the active contraction of different cell types that are able to constrict or relax in a reversible and graded manner in response to several stimuli promote a further increase or decrease in the intrahepatic resistance. 4 Insufficient nitric oxide (NO) production is considered a major pathogenic factor increasing intrahepatic vascular tone in cirrhosis. [5][6][7] The increased vascular tone is From the

Bacterial DNA translocation is associated with systemic circulatory abnormalities and intrahepatic endothelial dysfunction in patients with cirrhosis

“…The systemic and splanchnic response to the test meal was evaluated at 30 minutes, when maximal postprandial hyperemia and increase in HVPG has been demonstrated to occur. [17][18][19][20] HVPG was also measured at 15 minutes.…”

The effects of vitamin C and nitric oxide synthase inhibition on coronary flow and oxidative stress markers in isolated rat heart

“…It was demonstrated that ascorbic acid reverse endothelial dysfunction in patients with numerous diseases (Levine et al 1996;Ting et al 1996;Motoyama et al 1997;Hornig et al 1998;Taddei et al 1998;Teramoto et al 2004;de Sousa et al 2005;Grebe et al 2006;Hernández-Guerra et al 2006;Cangemi et al 2007). These remarkably consistent findings prompt studies to elucidate the mechanism of this beneficical effect of ascorbic acid on the bioactivity of endothelium-derived NO.…”

Pathophysiology of Portal Hypertension

“…LSECs receive oxidative stress in response to a wide variety of agents, such as bacterial endotoxins, viruses, drugs, and ethanol. [13][14][15] During cirrhosis, increased superoxide radicals spontaneously react with NO to form peroxynitrite (ONOO-), an endogenous toxicant 16 , thereby decreasing NOs bioavailability as a vasodilator. 13 Antioxidant molecules such as vitamin C 14 , vitamin E 17 , superoxide dismutase (SOD) 15,18 , and N-acetylcysteine 19 , have been shown to ameliorate intrahepatic vascular resistance and portal hypertension.…”