Nitric oxide modulates hepatic vascular tone in normal rat liver

Mittal, Manish; Gupta, Tarun; Lee, Fa-Yauh; Sieber, Cornel C.; Groszmann, R. J.

doi:10.1152/ajpgi.1994.267.3.g416

Cited by 134 publications

(140 citation statements)

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“…34 Previous studies have shown that NO decreases portal resistance. 35 Our studies confirm that there is some decrease but not normalization of portal pressures with administration of L-arginine the precursor to NO. In the present study, the livers were perfused with blood from donor rats, unlike in the previous study where crystalloids with albumin were used.…”

Section: Discussionsupporting

confidence: 68%

Endothelin-1 modulates intrahepatic resistance in a rat model of noncirrhotic portal hypertension

et al. 1999

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Factors that increase resistance to blood flow through the hepatic sinusoids when portal hypertension occurs in the absence of significant hepatic fibrosis are not completely understood. Experiments were designed to test the hypothesis that endothelin-1 (ET-1) is one of the humoral factors that increases sinusoidal vascular resistance in a bile ductligated noncirrhotic portal hypertensive (BDL) rat. The effect of ET-1 and nitric oxide (NO) on contractility of rings of portal vein taken from BDL rats was tested. The effect of ET-1 and NO on intrahepatic resistance in an isolated perfused liver was studied, and localization of ET-1 in the liver was identified by immunohistochemistry. Portal vein rings in BDL rats showed increased maximal tension in response to ET-1, as well as a shift of the dose-response curve to the left as compared with sham-operated animals. Removal of the endothelium further increased contractility. In isolated perfused liver studies, ET-1 increased portal resistance in both sham operated and BDL rats. Portal hypertension is a circulatory consequence of increased portal blood flow and increased resistance to hepatic sinusoidal blood flow 1 . Nitric oxide (NO) is believed to be a significant factor contributing to increased portal blood flow, 2 but the factors responsible for increasing vascular resistance within the liver are not clearly established, especially in noncirrhotic portal hypertension. A major factor that may increase sinusoidal resistance in cirrhosis is fibrosis with nodule formation, which distorts hepatic sinusoidal architecture, thus increasing resistance to blood flow. Fibrosis, however, is a late feature of liver disease. Thus, early in the onset of portal hypertension, before fibrosis becomes sufficiently established to distort sinusoidal structure, there may be humoral factors that initiate an increase in portal resistance. The role of humoral factors is suggested by recent studies that indicate that portal resistance is decreased by vasodilators such as papavarine and sodium nitroprusside. 3 Endothelin-1 (ET-1) is a member of a family of 21 amino acid peptides, which are potent constrictors of vascular smooth muscle. ET-1 is elevated in the peripheral blood of patients with chronic liver disease with or without ascites [4][5][6] and in the hepatorenal syndrome. 7 ET-1 has been identified in endothelial cells of the hepatic sinusoids, portal vein, and hepatic central vein 8 and has been shown to cause contraction of hepatic sinusoids as well as preterminal portal venules. 9-11 Studies of cirrhotic liver tissue in humans have shown enhanced ET-1 expression, activated hepatic stellate cells (HSC) being the major site of synthesis. 12-13 Endothelin receptors expression is increased in portal hypertensive rats 14 and bosentan, a mixed ET A and ET B receptor antagonist, lowers portal pressure in cirrhotic rats, as well as portal vein stenosed animals. 15 Thus, indirect evidence suggests that ET-1 can act as a paracrine or autocrine factor contributing to increased resistance t...

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Section: Discussionsupporting

confidence: 68%

Endothelin-1 modulates intrahepatic resistance in a rat model of noncirrhotic portal hypertension

et al. 1999

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2006

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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

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“…17 Although it is clear that NO controls basal resistance in the hepatic artery, [18][19][20] a functional role for eNOS in the portal circulation has been more controversial. [21][22][23] By contrast, iNOS is virtually absent in the normal liver but markedly increased in response to inflammation and a variety of oxidative stresses. This led to the postulate that iNOS, but not eNOS, contributed to maintaining sinusoidal perfusion following stress conditions.…”

Section: Blood Flow Regulationmentioning

confidence: 99%