Lipoic Acid Prevents Development of the Hyperdynamic Circulation in Anesthetized Rats With Biliary Cirrhosis

Abstract

Chronic bile duct ligation is associated with the development of oxidant injury, biliary cirrhosis, portal hypertension, and a hyperdynamic circulation. We have previously demonstrated that the hyperdynamic circulation in the partial portal vein-ligated rat can be prevented by the administration of N-acetylcysteine. To extend these findings, we have examined the effect of lipoic acid, a thiolcontaining antioxidant, on hemodynamics, oxidative stress, and nitric oxide (NO) production in bile duct-ligated (BDL) cirrhotic rats. Lipoic acid was given continuously in drinking water to normal and BDL rats; control rats received ordinary drinking water, and animals were studied at 24 days following surgery. Lipoic acid prevented the development of the hyperdynamic circulation (cardiac index [CI]: 15.7 ؎ 2.0 vs. 29.5 ؎ 2.1 mL и min ؊1 и 100 g ؊1 ; P F .05) and significantly attenuated the rise in portal pressure (PP) (12.7 ؎ 0.8 vs. 15.2 ؎ 0.5 mm Hg; P F .05). Hepatic nitric oxide synthase (NOS) activity and plasma nitrite/nitrate concentration increased significantly following bile duct ligation, and both of these were prevented by lipoic acid. Lipoic acid had no effect on the biochemical or histological parameters of liver function in the cirrhotic group. We conclude that lipoic acid prevents the development of the hyperdynamic circulation in the rat model of biliary cirrhosis, and that this is associated with decreased synthesis of NO. (HEPATOLOGY 1999;29:1358-1363.)Chronic bile duct ligation leads to biliary cirrhosis within 3 to 4 weeks in the rat. Following bile duct ligation, there is cholestatic liver injury, with depletion of endogenous antioxidants 1,2 and increased levels of markers of oxidant injury. 1,3 This is followed by the development of ductular proliferation and fibrosis, and is associated with the development of portal hypertension and a hyperdynamic circulation, characterized by a high cardiac output and low systemic vascular resistance. Previous studies have shown protective effects of antioxidants on liver damage in this model as assessed by biochemical and histological parameters, 1,4,5 and also a moderate reduction in portal pressure (PP). 6 The hyperdynamic circulation that occurs in this model following the development of biliary cirrhosis is central to the development of many of the complications that occur in advanced liver disease, including ascites and renal dysfunction, portal hypertension, and the hepatopulmonary syndrome. We previously demonstrated that chronic administration of N-acetylcysteine prevents development of the hyperdynamic circulation following partial portal vein ligation 7 and is accompanied by decreased plasma concentrations of the metabolic products of nitric oxide (NO), nitrite and nitrate. However, in the above study, N-acetylcysteine was given twice daily by intraperitoneal injection, because it has a limited oral bioavailability. Therefore, to extend these studies to a cirrhotic model, we have used the sodium salt of lipoic acid, a thiol-containing antioxidant with g...

Protective Effect Of Curcumin On Liver Damage Induced By Biliary Obstruction In Rats

“…BDL is associated with the development of oxidant injury, hepatic fibrosis, biliary cirrhosis, portal hypertension, and a hyperdynamic circulation that is a dynamic process implying different rates of progres- sion or regression (18). It has been reported that BDL reduces antioxidant defences and increases free radical formation (19).…”

Nitration of cardiac proteins is associated with abnormal cardiac chronotropic responses in rats with biliary cirrhosis†

“…31 There is now good evidence that liver disease is associated with oxidative stress and increased formation of reactive oxygen species. 32,33 Ljubuncic et al reported an increased formation of lipid peroxidation products in the cardiac tissue of rats with biliary cirrhosis compared with controls. 33 This finding may be partly owing to enhanced generation of superoxide by NADPH oxidase in response to angiotensin II, 34 endothelin, 35 bile acids, 36 or can occur secondary to the formation of peroxynitrite.…”

“…37 We have previously observed that administration of N-acetylcysteine normalizes the systemic hemodynamic abnormalities in rats with portal hypertension, 16 and lipoic acid (another low molecular weight thiol antioxidant) had a similar effect in rats with chronic bile duct ligation. 32 Therefore, we investigated whether N-acetylcysteine could improve cardiac function in rats with biliary cirrhosis, and made the critical observation that administration of N-acetylcysteine led to normalization of bradycardia in vivo, as well as improved cardiac responses to adrenergic stimulation in vitro (Figs. 1 and 2).…”

Effect of sirolimus on renal injury induced by bile duct ligation in rats

“…The oxidative stress known to occur as a systemic response to cholestasis could give rise to the involvement of organs other than liver, such as the kidney, which could explain the renal morphological and functional alterations here reported 19 . This contention is based on previous studies 21 , which found that the antioxidants -lipoic acid and N-acetylcysteine prevented the hyperdynamic circulation induced by either experimental cholestasis or portal hypertension. Another study further supported this notion, as vitamin E prevented the fall in blood pressure and restored PRA to normal (likely because of the improved hemodynamic state) 22 .…”