Systemic prostacyclin in cirrhotic patients

Guarner, Carlos; Soriano, Germán; Such, José; Teixidó, Mercè; Ramis, Isabel; Bulbena, O.; Roselló, J.; Guarner, Francisco; Gelpí, E.; Balanzó, J.; Vilardell, F

doi:10.1016/0016-5085(92)91814-k

Cited by 46 publications

(5 citation statements)

References 39 publications

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“…Moreover, in cirrhotic rats (but not in rats with portal vein stenosis) urine 6-keto-PGF1, levels were also increased. Similar results have been reported in other experimental models of portal hypertension (14)(15)(16)(17) and in patients with cirrhosis and portal hypertension (18)(19)(20). The reasons for increased plasma 6-keto-PGFIa concentrations are not clear.…”

Section: Discussionsupporting

confidence: 83%

Role of prostacyclin in hemodynamic alterations in conscious rats with extrahepatic or intrahepatic portal hypertension

et al. 1993

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Although prostaglandins are thought to be involved in the hyperdynamic circulation of portal hypertension, the role of this substance has not been elucidated. Dose-response curves, the hemodynamic effects of prostacyclin (20 micrograms/kg) and its inhibitor indomethacin and measurements of plasma and urinary levels of 6-keto-prostaglandin F1 alpha were compared in three groups of six rats each: normal, with portal vein stenosis and with secondary biliary cirrhosis. Plasma and urinary levels of 6-keto-prostaglandin F1 alpha were higher in rats with portal vein stenosis and cirrhotic rats than in normal rats. Dose-response curves showed similar maximal decreases in arterial pressure in the three groups, whereas the maximal increase in portal pressure was less marked in cirrhotic rats than in normal rats and rats with portal vein stenosis. In normal rats, prostacyclin increased cardiac output by 21% and portal pressure by 41%. Similar increases were observed in rats with portal vein stenosis. In contrast, prostacyclin did not affect cardiac output and portal pressure in cirrhotic rats. Indomethacin induced a more marked vasoconstrictive effect in normal rats than in cirrhotic rats. This study shows that prostacyclin plays a role in the hemodynamic alterations in portal hypertension. Moreover, the hyporeactivity observed in cirrhotic rats suggests that prostacyclin plays a major role in the circulatory changes of portal hypertension due to chronic liver disease.

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Section: Discussionsupporting

confidence: 83%

Role of prostacyclin in hemodynamic alterations in conscious rats with extrahepatic or intrahepatic portal hypertension

et al. 1993

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“…Under normal physiological conditions, normal vascular tone is maintained by the balance between the activity of vasodilators and vasoconstrictors. In cirrhosis with portal hypertension, peripheral vasodilatation is mainly the result of overproduction of nitric oxide and PGI 2 , which overcomes vasoconstrictive activity (17,30,43). In contrast, dynamic components of increased IHR in the cirrhotic liver are the result of increased production of TXA 2 and Cys-LTs, which masks vasodilatory activities (13,15,36,40), Anandamide has been reported to induce both vasodilatation and vasoconstriction in cirrhotic and noncirrhotic humans and animals (1,4,9,20,37).…”

Section: Discussionmentioning

confidence: 99%

Roles of anandamide in the hepatic microcirculation in cirrhotic rats

Yang

Lin²,

Huang³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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Cannabinoids have been reported to participate in the pathogenesis of peripheral vasodilatation in cirrhosis. However, their roles in increased intrahepatic resistance (IHR) in cirrhotic livers are unknown. We aimed to investigate the effects of cannabinoids in the hepatic microcirculation of cirrhotic rats produced by bile duct ligation. In isolated liver perfusion, portal perfusion pressure (PPP) and the production of eicosanoids in the perfusate were measured. In addition, various hepatic protein levels [cyclooxygenase (COX) isoform and 5-lipoxygenase (5-LOX)] were also determined. Finally, concentration-response curves for PPP and the corresponding production of eicosanoids in response to anandamide (1.44 x 10(-10)-1.44 x 10(-3) M) after indomethacin (COX inhibitor), piriprost (5-LOX inhibitor), or furegrelate (thromboxane A(2) synthase inhibitor) preincubation were obtained. The study showed that cirrhotic livers had significantly higher levels of PPP, COX-2 and 5-LOX protein expression, and production of thromboxane B(2) (TXB(2)) and cysteinyl leukotrienes (Cys-LTs) than normal livers. Anandamide induced a dose-dependent increase in PPP in both normal and cirrhotic livers. The anandamide-induced increase in PPP was found concomitantly with a significant increase in TXB(2) and Cys-LT production in the perfusate. In response to anandamide administration, cirrhotic livers exhibited a significantly greater increase in IHR and production of TXB(2) and Cys-LTs than normal livers. Indomethacin and furegrelate, but not piriprost, significantly ameliorated the anandamide-induced increase in IHR in cirrhotic livers. In conclusion, anandamide plays, in part, an important role in increased IHR of cirrhotic livers. The anandamide-induced increase in IHR in cirrhotic livers may be mediated by increased COX-derived eicosanoid (mainly thromboxane A(2)) production.

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“…It has been reported that prostacyclin is elevated in both the systemic and portal circulations in human cirrhosis and several animal models of portal hypertension (13,26,41,45). It is believed that an increased production of the vasodilator prostacyclin is partly responsible for the hemodynamic changes in portal hypertension.…”

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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Systemic prostacyclin in cirrhotic patients

Cited by 46 publications

References 39 publications

Role of prostacyclin in hemodynamic alterations in conscious rats with extrahepatic or intrahepatic portal hypertension

Role of prostacyclin in hemodynamic alterations in conscious rats with extrahepatic or intrahepatic portal hypertension

Roles of anandamide in the hepatic microcirculation in cirrhotic rats

Role of thromboxane A₂in early BDL-induced portal hypertension

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Systemic prostacyclin in cirrhotic patients

Cited by 46 publications

References 39 publications

Role of prostacyclin in hemodynamic alterations in conscious rats with extrahepatic or intrahepatic portal hypertension

Role of prostacyclin in hemodynamic alterations in conscious rats with extrahepatic or intrahepatic portal hypertension

Roles of anandamide in the hepatic microcirculation in cirrhotic rats

Role of thromboxane A2in early BDL-induced portal hypertension

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Role of thromboxane A₂in early BDL-induced portal hypertension