Roles of endothelin-1 and nitric oxide in the mechanism for ethanol-induced vasoconstriction in rat liver.

Oshita, Masahide; Takei, Yoshiyuki; Kawano, Seiji; Yoshihara, Hiroyuki; Hijioka, Taizo; Fukui, Hirokazu; Goto, Minoru; Masuda, Eiji; Nishimura, Y; Fusamoto, Hideyuki

doi:10.1172/jci116334

Cited by 112 publications

(79 citation statements)

References 30 publications

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“…[6][7][8]27 Since 1990, the effect of ET-1 on hepatic circulation has been extensively studied using in vivo, ex vivo, or in situ models of rat liver. [27][28][29][30][31][32][33][34][35][36][37] Most studies have shown that ET-1 causes vasoconstriction of the portal vasculatures associated with increased portal pressure. Stellate cells (Ito cells, lipocytes) have gained the greatest attention as the target of ET-1.…”

Section: Discussionmentioning

confidence: 99%

production and release of endothelin-1 from the gut and spleen in portal hypertension due to cirrhosis

et al. 2000

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This study was aimed to evaluate the source of endothelin-1 (ET-1) in cirrhotic patients. ET-1 is implicated in the pathogenesis of portal hypertension. However, the mechanism and source for increased plasma ET-1 in cirrhotic patients are still obscure. Plasma ET-1 levels in systemic (SV), superior mesenteric (SMV), and splenic venous (SPV) blood were measured in 23 patients with cirrhosis and 8 controls with normal liver. Fourteen removed spleens were immunohistochemically studied for ET-1, CD34, CD68, and CD20. In situ hybridization was done to localize ET-1 messenger RNA (mRNA). In cirrhosis, ET-1 levels in both SMV and SPV were higher than in SV. ET-1 in SV and SPV were significantly higher in cirrhotic patients than in control patients. Three groups of cells in the spleen expressed both protein and mRNA of ET-1: endothelial cells in the sinus, which were also stained for CD34; cells in the germinal center; and cells in the marginal zone of lymphoid sheaths and follicles, which were also stained for CD20 but not for CD34 and CD68. Endothelins (ETs) are a group of three related peptides of 21 amino acids (ET-1, ET-2, and ET-3) first described as potent vasoconstrictors. 1,2 At present, it is known that ETs exert a variety of biological, physiological, and metabolic actions through two types of receptors (ET A and ET B ) in humans. [3][4][5] In recent years, much attention has been paid to the role of ET-1 in hepatic circulation, particularly in relation to portal hypertension. [6][7][8] Since 1992, more than 10 investigative groups have shown the increased level of plasma ET-1 in patients with cirrhosis. [9][10][11][12][13][14][15][16][17][18][19] The grade of the ET-1 elevation seems to be related to the severity of cirrhosis 13,16 and the presence or absence of ascites. 10,11,19 The highest levels were observed in hepatorenal syndrome. 9 However, the physiological significance of elevated ET-1 levels in cirrhosis is still controversial. The role of endotoxin or plasma volume remains to be elucidated. 10,11,15 Furthermore, the origin and elimination of plasma ET-1 in cirrhosis have not been clarified.Of late, Gerbes et al. 14 and Moller et al. 17 suggested the hepatosplanchnic origin of ET-1 because the highest ET-1 concentrations were found in hepatic venous blood. Martinet et al. 18 showed that high ET-1 levels in the portal blood were reduced after portal decompression by transjugular intrahepatic portosystemic shunt. These studies, however, did not show from which organ or organs of the splanchnic region ET-1 was released in cirrhosis and portal hypertension.The present study was prospectively aimed to clarify this problem. While measuring plasma ET-1 levels in the systemic (SV), superior mesenteric (SMV), and splenic venous (SPV) blood in patients with cirrhosis of different Child-Turcotte classes and control patients with normal liver, we came to know that ET-1 was highest in the SMV in controls but that SPV ET-1 levels were significantly higher in cirrhosis.Therefore, the cellular source of ET-1 in t...

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Section: Discussionmentioning

confidence: 99%

production and release of endothelin-1 from the gut and spleen in portal hypertension due to cirrhosis

et al. 2000

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“…24 Thus, an imbalance between the vasoconstrictor effects of endothelins and the vasodilator effects of NO may contribute to increased vascular resistance. 25 Both ET-1 and NO are known to regulate vascular tone in the liver 11 and splanchnic circulation; further, nitric oxide regulates endothelin receptors. 26 It is presumed that structural factors are less reversible and result in a more fixed resistance.…”

Section: Discussionmentioning

confidence: 99%

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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“…1,2 It has recently been proposed that hepatic stellate cells play an important role in regulating hepatic sinusoidal tonus and the blood flow under physiological and pathological conditions. [3][4][5][6][7] The contractility of hepatic stellate cells depends on the dynamic control of the balance of two endothelium-derived vasoactive substances, endothelin 1 and nitric oxide (NO). [3][4][5][6][7] Endothelin produces sustained vasoconstriction in the liver, which appears to be related to the contraction of hepatic stellate cells.…”

mentioning

confidence: 99%

“…[3][4][5][6][7] The contractility of hepatic stellate cells depends on the dynamic control of the balance of two endothelium-derived vasoactive substances, endothelin 1 and nitric oxide (NO). [3][4][5][6][7] Endothelin produces sustained vasoconstriction in the liver, which appears to be related to the contraction of hepatic stellate cells. 3,4 In addition, NO is also a potent modulator of stellate cell contractility 5,6 and inhibits the vasoconstriction induced by endothelin in the perfused rat liver.…”

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Effects of l-arginine on the systemic, mesenteric, and Hepatic circulation in patients with cirrhosis

et al. 1998

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Nitric oxide (NO) is known to play an important role in modulating both the hepatic and mesenteric circulation under physiological and pathological conditions. We investigated how L-arginine, a precursor of NO, modifies the hepatic and mesenteric circulation in patients with cirrhosis. The study design was a single-blind controlled study. We measured the systemic and portal hemodynamics before and following intravenous L-arginine and saline infusion using pulsed Doppler ultrasonography in 20 patients with cirrhosis, and then the effects were compared with those found in 20 healthy subjects. In these patients, the effects of L-arginine on hepatic circulation were investigated using hepatic catheterization. L-Arginine infusion induced systemic vasodilation in both the healthy controls and the cirrhotic patients in a similar hemodynamic manner. In these patients, the L-arginine-induced increase in the portal flow was significantly higher than that of cardiac output (CO); however, the relation was the inverse in healthy subjects. Moreover, the L-arginine-induced increase in the portal flow was greater in the cirrhotic patients than that seen in healthy subjects. As a result, L-arginine infusion was thus found to selectively augment the hepatopetal portal blood flow in the cirrhotic liver. In patients, L-arginine infusion induced marked hepatic vasodilation as demonstrated by the reduced hepatic sinusoidal resistance (HSR) and increased estimated hepatic blood flow (EHBF) associated with the ameliorated intrinsic clearance of indocyanine green. Despite the fall in HSR, the hepatic venous pressure gradient (HVPG) increased following L-arginine infusion. The mesenteric and hepatic vascular areas of cirrhosis exhibited an increased susceptibility to the dilator action of L-arginine. These findings suggest that the enhanced NO production in the splanchnic vascular area has an important role in the hepatic circulation in patients with cirrhosis. (HEPA-TOLOGY 1998;27:377-382.)Patients with cirrhosis exhibit circulatory abnormalities such as perturbation of the hepatic microcirculation, as well as systemic and mesenteric hyperemia. 1,2 It has recently been proposed that hepatic stellate cells play an important role in regulating hepatic sinusoidal tonus and the blood flow under physiological and pathological conditions. 3-7 The contractility of hepatic stellate cells depends on the dynamic control of the balance of two endothelium-derived vasoactive substances, endothelin 1 and nitric oxide (NO). [3][4][5][6][7] Endothelin produces sustained vasoconstriction in the liver, which appears to be related to the contraction of hepatic stellate cells. 3,4 In addition, NO is also a potent modulator of stellate cell contractility 5,6 and inhibits the vasoconstriction induced by endothelin in the perfused rat liver. 7 Therefore, both endothelin and NO play a critical role in modulating hepatic microcirculation.L-Arginine, a precursor of NO, induces systemic vasodilation and natriuresis when infused intravenously in humans. [8][9][10]...

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Roles of endothelin-1 and nitric oxide in the mechanism for ethanol-induced vasoconstriction in rat liver.

Cited by 112 publications

References 30 publications

production and release of endothelin-1 from the gut and spleen in portal hypertension due to cirrhosis

production and release of endothelin-1 from the gut and spleen in portal hypertension due to cirrhosis

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

Effects of l-arginine on the systemic, mesenteric, and Hepatic circulation in patients with cirrhosis

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