Abstract:In cirrhotic livers, increased resistance to portal flow, in part due to an exaggerated response to vasoconstrictors, is the primary factor in the pathophysiology of portal hypertension. Our aim was to evaluate the response of the intrahepatic circulation of cirrhotic rat livers to the I n cirrhotic livers, increased resistance to portal blood flow is the primary factor in the pathophysiology of portal hypertension. 1 This increased resistance is determined in part by the architectural distortion of the hepati… Show more
“…2,4 This latter component, which results from an insufficient hepatic bioavailability of NO 5,30 and an increased production of circulating and local vasoconstrictors (angiotensin, endothelin, cysteinyl-leukotrienes, thromboxane, and prostaglandins, among others), [31][32][33][34][35] is theoretically amenable to treatment with vasodilators. 36 Attempts to correct the intrahepatic NO deficiency in experimental cirrhosis have involved NOS overexpression by transfecting the liver with adenovirus encoding eNOS, nNOS, or constitutively active AKT 10,37,38 or by selective NO donors.…”
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
“…2,4 This latter component, which results from an insufficient hepatic bioavailability of NO 5,30 and an increased production of circulating and local vasoconstrictors (angiotensin, endothelin, cysteinyl-leukotrienes, thromboxane, and prostaglandins, among others), [31][32][33][34][35] is theoretically amenable to treatment with vasodilators. 36 Attempts to correct the intrahepatic NO deficiency in experimental cirrhosis have involved NOS overexpression by transfecting the liver with adenovirus encoding eNOS, nNOS, or constitutively active AKT 10,37,38 or by selective NO donors.…”
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
“…21,22 Increase in TXA2 production and cyclooxygenase overexpression have been demonstrated in perfusion models in rats. 37,38 The increase in TXAS points towards an increase in TXA2 production in rats with severe steatosis. ET-1, which mainly acts as a vasoconstrictor via the ET A receptor on smooth muscle cells, is also overexpressed in rats with severe steatosis, and its serum concentration is elevated.…”
Section: Intrahepatic Resistance In Steatosis S Francque Et Almentioning
Non-alcoholic fatty liver disease can progress to steatohepatitis and fibrosis, and is also associated with impaired liver regeneration. The pathophysiology remains elusive. We recently showed that severe steatosis is associated with an increase in portal pressure, suggesting liver flow impairment. The objective of this study is to directly assess total intrahepatic resistance and its potential functional and structural determinants in an in situ perfusion model. Male Wistar rats fed a control (n ¼ 30) or a methionine-choline-deficient (MCD) diet (n ¼ 30) for 4 weeks were compared. Liver tissue and serum analysis, in vivo haemodynamic measurements, in situ perfusion experiments and vascular corrosion casts were performed. The MCD group showed severe steatosis without inflammation or fibrosis on histology. Serum levels and liver tissue gene expression of interleukin (IL)-6, tumour necrosis factor-a, IL-1b and interferon-g, liver tissue myeloperoxidase activity and liver immunohistochemistry with anti-CD68 and anti-a smooth muscle actin were comparable between groups, excluding significant inflammation. Flow-pressure curves were significantly different between groups for all flows (slope values: 0.1636±0.0605 mm Hg/ml/min in controls vs 0.7270±0.0408 mm Hg/ml/min in MCD-fed rats, Po0.001), indicating an increased intrahepatic resistance, which was haemodynamically significant (portocaval pressure gradient 2.2 ± 1.1 vs 8.2 ± 1.3 mm Hg in controls vs MCD, Po0.001). Dose-response curves to acetylcholine were significantly reduced in MCD-fed rats (Po0.001) as was the responsiveness to methoxamine (Po0.001). Vascular corrosion casts showed a replacement of the regular sinusoidal anatomy by a disorganized pattern with multiple interconnections and vascular extensions. Liver phosphorylated endothelial NO synthase (eNOS)/eNOS and serum nitrite/nitrate were not increased in severe steatosis, whereas liver thromboxane synthase expression, liver endothelin-1 (ET-1) expression and serum andothelin-1 concentration were significantly increased. Severe steatosis induces a haemodynamically significant increase in intrahepatic resistance, which precedes inflammation and fibrogenesis. Both functional (endothelial dysfunction and increased thromboxane and ET-1 synthesis) and structural factors are involved. This phenomenon might significantly contribute to steatosis-related disease.
“…Endothelial nitric oxide synthase (eNOS) uncoupling due to deficiency of tetrahydrobiopterin (BH 4 ) results in decreased production of NO and plays a major role in endothelial dysfunction in other conditions. We examined whether eNOS uncoupling is involved in the pathogenesis of endothelial dysfunction of livers with cirrhosis.…”
mentioning
confidence: 99%
“…Endothelial dysfunction, characterized by an impairment in the endothelium-dependent response to vasodilators, is considered one of the mechanisms leading to the increased vascular tone of livers with cirrhosis 2 and has been attributed to reduced NO bioavailability 3 and to increased release of COX-1-derived vasoconstrictive prostanoids. 4 The unconjugated pterin cofactor (6R)-L-erythro-5, 6, 7, 8-tetrahydrobiopterin (BH 4 ) plays a crucial role in the regulation of eNOS activity. In the absence of BH 4, NOS cannot catalyze L-arginine oxidation 5,6 ; rather, it receives electrons from NADPH and donates them to O 2 , resulting in the formation of superoxide anion (O 2 Ϫ ) instead of NO, leading to reduced NO bioavailability.…”
mentioning
confidence: 99%
“…4 The unconjugated pterin cofactor (6R)-L-erythro-5, 6, 7, 8-tetrahydrobiopterin (BH 4 ) plays a crucial role in the regulation of eNOS activity. In the absence of BH 4, NOS cannot catalyze L-arginine oxidation 5,6 ; rather, it receives electrons from NADPH and donates them to O 2 , resulting in the formation of superoxide anion (O 2 Ϫ ) instead of NO, leading to reduced NO bioavailability. This situation is known as NOS "uncoupling."…”
In cirrhosis, intrahepatic endothelial dysfunction is one of the mechanisms involved in the increased resistance to portal blood flow and therefore in the development of portal hypertension. Endothelial nitric oxide synthase (eNOS) uncoupling due to deficiency of tetrahydrobiopterin (BH 4 ) results in decreased production of NO and plays a major role in endothelial dysfunction in other conditions. We examined whether eNOS uncoupling is involved in the pathogenesis of endothelial dysfunction of livers with cirrhosis. Basal levels of tetrahydrobiopterin and guanosine triphosphate (GTP)-cyclohydrolase (BH 4 rate-limiting enzyme) expression and activity were determined in liver homogenates of control and rats with CCl 4 cirrhosis. Thereafter, rats were treated with tetrahydrobiopterin, and eNOS activity, NO bioavailability, assessed with a functional assay, and the vasodilator response to acetylcholine (endothelial function) were evaluated. Livers with cirrhosis showed reduced BH 4 levels and decreased GTPcyclohydrolase activity and expression, which were associated with impaired vasorelaxation to acetylcholine. Tetrahydrobiopterin supplementation increased BH 4 hepatic levels and eNOS activity and significantly improved the vasodilator response to acetylcholine in rats with cirrhosis. In conclusion, the impaired response to acetylcholine of livers with cirrhosis is modulated by a reduced availability of the eNOS cofactor, tetrahydrobiopterin. Tetrahydrobiopterin supplementation improved the endothelial dysfunction of cirrhotic livers. (HEPATOLOGY 2006;44:44-52.)
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