Endothelin-Induced Contraction of the Portal Vein in Cirrhosis

Petrowsky, Henrik; Schmandra, T. C.; Lorey, Th.; Hanisch, E.; Herrmann, G.

doi:10.1159/000008705

Cited by 14 publications

(6 citation statements)

References 45 publications

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“…The mechanism by which portal hypertension develops in cirrhosis has been associated with overproduction of endothelins and underproduction of NO as a result of dysfunctional NO synthase in the cirrhotic liver (12,16,18,27,30,34,37). However, the role of TXA 2 in the cirrhosis-induced portal hypertension has not been explicitly explored.…”

Section: Discussionmentioning

confidence: 99%

Role of thromboxane A₂in early BDL-induced portal hypertension

Yokoyama

Kresge

et al. 2003

American Journal of Physiology-Gastrointestinal and Liver Physi

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Although the mechanisms of cirrhosis-induced portal hypertension have been studied extensively, the role of thromboxane A2 (TXA2) in the development of portal hypertension has never been explicitly explored. In the present study, we sought to determine the role of TXA2 in bile duct ligation (BDL)-induced portal hypertension in Sprague-Dawley rats. After 1 wk of BDL or sham operation, the liver was isolated and perfused with Krebs-Henseleit bicarbonate buffer at a constant flow rate. After 30 min of nonrecirculating perfusion, the buffer was recirculated in a total volume of 100 ml. The perfusate was sampled for the enzyme immunoassay of thromboxane B2(TXB2), the stable metabolite of TXA2. Although recirculation of the buffer caused no significant change in sham-operated rats, it resulted in a marked increase in portal pressure in BDL rats. The increase in portal pressure was found concomitantly with a significant increase of TXB2 in the perfusate (sham vs. BDL after 30 min of recirculating perfusion: 1,420 ± 803 vs. 10,210 ± 2,950 pg/ml; P < 0.05). Perfusion with a buffer containing indomethacin or gadolinium chloride for inhibition of cyclooxygenase (COX) or Kupffer cells, respectively, substantially blocked the recirculation-induced increases in both portal pressure and TXB2 release in BDL group. Hepatic detection of COX gene expression by RT-PCR revealed that COX-2 but not COX-1 was upregulated following BDL, and this upregulation was confirmed at the protein level by Western blot analysis. In conclusion, these results clearly demonstrate that increased hepatic TXA2 release into the portal circulation contributes to the increased portal resistance in BDL-induced liver injury, suggesting a role of TXA2 in liver fibrosis-induced portal hypertension. Furthermore, the Kupffer cell is likely the source of increased TXA2, which is associated with upregulation of the COX-2 enzyme.

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Section: Discussionmentioning

confidence: 99%

Role of thromboxane A₂in early BDL-induced portal hypertension

Yokoyama

Kresge

et al. 2003

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…The latter possesses marked vasoconstrictive action and it has been postulated that it is involved not only in the development and maintenance of portal hypertension, but also in functional renal insufficiency in advanced cirrhosis [15-18, 27, 28] Experimental studies on cirrhotic rats have revealed elevated circulating ET-1 levels and intraportal ET-1 administration to increase portal vein pressure [29]. Furthermore, administration of ET-1 receptor antagonists was capable of reducing portal pressure without modifying systemic blood pressure [30].…”

Section: Discussionmentioning

confidence: 99%

Plasma endothelin-1 levels in liver cirrhosis

et al. 2000

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The role of circulating endothelin- , a potent vasoconstricting peptide, in liver cirrhosis is still controversial. It has been postulated that endothelin-1 may play a role in the circulatory derangement occurring in cirrhotic subjects, and increased plasma endothelin-1 levels have been reported in these patients. In this study we looked for a relationship between the severity of the liver disease according to Child's classification and plasma endothelin-1 concentrations in a group of cirrhotic patients compared with a healthy control group. Twenty-two cirrhotic patients and 10 healthy controls, matched for sex and age, were selected for study after informed consent. The etiology of cirrhosis was posthepatitis B in 8 of 22 cases, posthepatitis C in 13 of 22 cases, and alcoholism in 1 patient. According to Child's classification, 6 patients were in class A, 6 in class B, and 10 in class C. Plasma endothelin-1 was measured by a commercial RIA kit (Amersham UK). Mean +/- SD plasma endothelin-1 levels were 8.8 +/- 0.9 pg/ml in controls and 9.2 +/- 1.1 pg/ml in all cirrhotic patients (P > 0.05). In each sub-group of cirrhotics, plasma endothelin- was 8.6 +/- 1.2 pg/ml in Child A, 8.9 +/- 1.9 pg/ml in Child B, and 10.6 +/- 1.5 pg/ml in Child C groups, respectively. There were no statistical differences between control subjects and Child A and B cirrhotic patients (P > 0.05). A significant increase in endothelinl was observed only in the Child C group versus either group A or B (P = 0.004). Our results show that alterations of circulating endothelin-1 do not occur in all cirrhotic patients; higher plasma levels than controls are only detectable in patients with more-severe hepatic failure. We do not know whether increased endothelin-1 levels are a consequence of hemodynamic disorders occurring in the advanced phase of liver cirrhosis or play a pathogenic role.

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“…Increased resistance in the portal venous system is induced by the destruction of normal hepatic structure as a result of fibrin deposition 65 or by the impaired balance between the action of vasodilators 66 and vasoconstrictors. 67,68 Studies have shown that cirrhotic livers exhibit hyperresponse to vasoconstrictors such as catecholamine, 68 endothelin, 69 and leukotriene D 4 . 70 In addition to these vasoconstrictors, the production of TXA 2 is enhanced in the cirrhotic liver and has been shown to be responsible for an increased resistance in the portal venous system.…”

Section: Hepatic Cirrhosismentioning

confidence: 99%