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

Abstract

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.

Mechanisms of extrahepatic vasodilation in portal hypertension

“…This possibly explains the increased production of prostanoids, which contributes to endothelium-dependent vasodilation in BDL rats 94. However, such changed activities of PGI 2 -synthesising enzymes were not found in aortas from PVL rats,95 despite enhanced PGI 2 synthesis,94 at least in response to adrenaline 95. Nevertheless, the arterial cAMP content is elevated in PVL rats,34 despite the fact that the mechanisms causing this elevation apparently differ from those in other animal models.…”

“…Both COX isoforms, the constitutively expressed COX-1 and the inducible COX-2, are upregulated in hypocontractile vessels of PVL rats 92 93. This possibly explains the increased production of prostanoids, which contributes to endothelium-dependent vasodilation in BDL rats 94. However, such changed activities of PGI 2 -synthesising enzymes were not found in aortas from PVL rats,95 despite enhanced PGI 2 synthesis,94 at least in response to adrenaline 95.…”

Selective cyclooxygenase inhibition by SC-560 improves hepatopulmonary syndrome in cirrhotic rats

“…In addition, acute and chronic COX blockades by indomethacin significantly decreased mesenteric arterial blood flow in portal hypertensive rats and reduced PP in portal hypertensive rabbits [21,22]. However, a contradictory report by Oberti et al shows that acute administration of indomethacin did not affect cardiac output and PP in portal hypertensive and cirrhotic rats [6]. In our previous work, we found that 1-week indomethacin administration did not alter systemic hemodynamics, liver and renal biochemistry data and mortality rate in cirrhotic rats [23], S1 Table.…”

“…The attenuations of intrapulmonary shunts might be related to direct constriction of intrapulmonary vessels or inhibition of angiogenesis. Prostacyclin is a potent vasodilator affecting vascular tone in cirrhosis [6]. Regard the vascular reactivity, we found previously that selective COX-1 inhibition by SC-560 significantly reduced plasma prostacyclin levels; on the contrary, COX-2 inhibition by NS-398 only exerted modest effects [34].…”

“…As the portal pressure (PP) elevates, portal-systemic collaterals develop gradually to diverse excessive blood flow from the portal system [5]. Prostacyclin is a vasodilatory prostanoid which is capable of increasing portal tributary blood flow and portal pressure [6]. It is synthesized through cyclooxygenases (COX) including COX-1 and COX-2.…”