Enhanced cyclooxygenase-1 expression within the superior mesenteric artery of portal hypertensive rats: Role in the hyperdynamic circulation

Hou, Ming‐Chih; Cahill, Paul A.; Zhang, Shuangmin; Wang, Yining; Hendrickson, Richard J.; Redmond, Eileen M.; Sitzmann, James V.

doi:10.1002/hep.510270105

Cited by 49 publications

(30 citation statements)

References 38 publications

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“…This could be explained by a decrease in platelet synthesis of TXA2 [13] . There was a decrease in 6-keto PGF1α in the portal hypertensive group with COX 1 inhibition, and this effect is probably due to the inhibition of the increased production of PGI2 [14,15] and COX 1 over-expression observed in this model of portal vein ligation [16][17][18] . It is interesting to note that COX 1 inhibition had almost not modified the prothrombotic effect of ULDA in portal hypertensive animals and observed as an increase in number of emboli (P < 0.05) and a decrease in IHT (P < 0.01).…”

Section: Discussionmentioning

confidence: 75%

Modifications produced by selective inhibitors of cyclooxygenase and ultra low dose aspirin on platelet activity in portal hypertension

Eizayaga

Aguejouf²,

Desplat³

et al. 2007

WJG

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INTRODUCTIONPortal hypertension is a major complication of chronic liver disease. In its pathophysiology, increased hepatic resistance is followed by a hyperdynamic circulatory state [1] . This hyperdynamic state, in which nitric oxide (NO) and prosatcyclin (PGI2) are important vasoactive substances, induces a decreased platelet activity, even in the absence of hepatic damage. Although NO plays an important role in modifying platelet adhesion in portal hypertension [2] , PGI2, a powerful vasodilator prostanoid with antithrombotic properties, was also found increased in mesenteric vascular bed [3] . Ultra low dose aspirin (ULDA) has shown prothrombotic activity when analysed in humans and in the interface platelet-endothelial cell [4,5] . Previous papers have shown the potentially beneficial effect of ULDA in portal hypertensive animals normalizing altered platelet activity and induced hemorrhagic time [6] . Further experiments were performed to clarify if this effect was mediated mostly by a cyclooxigenase (COX) pathway or by modifying NO synthesis, the two aspirin mechanisms of action [7] , although a previous study with a different model suggested that ULDA could decrease PGI2 synthesis [8] . The same in vivo Laser induced thrombus formation, was used in portal hypertensive rats to investigate the effects of Indomethacin, a non selective COX inhibitor, and L-Nitro Arginin Methyl Ester (NAME), a non selective inhibitor of NO production. The results suggested that the effects of ULDA were more influenced by COX pathway than by NO synthesis inhibition [9] . Addition of ULDA in portal hypertensive rats, when previously inhibiting COX with Indomethacin, increased number of emboli and duration Abstract AIM: To study the mechanism involved in the potentially beneficial effect of ultra low dose aspirin (ULDA) in prehepatic portal hypertension, rats were pretreated with selective COX 1 or 2 inhibitors (SC-560 or NS-398 respectively), and subsequently injected with ULDA or placebo. METHODS:Portal hypertension was induced by portal vein ligation. Platelet activity was investigated with an in-vivo model of laser induced thrombus production in mesenteric circulation and induced hemorrhagic time (IHT). Platelet aggregation induced by ADP and dosing of prostanoid products 6-keto-PGF1α, TXB2, PGE2 and LTB4 were also performed. RESULTS:The portal hypertensive group receiving a placebo showed a decreased in vivo platelet activity with prolonged IHT, an effect that was normalized by ULDA. SC-560 induced a mild antithrombotic effect in the normal rats, and an unmodified effect of ULDA. NS-398 had a mild prothrombotic action in portal hypertensive rats, similar to ULDA, but inhibited a further effect when ULDA was added. An increased 6-keto-PGF1α was observed in portal hypertensive group that was normalised after ULDA administration. TXA2 level after ULDA, remained unchanged. CONCLUSION:These results suggest that the effect of ULDA on platelet activity in portal hypertensive rats, could act through a COX 2

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Section: Discussionmentioning

confidence: 75%

Modifications produced by selective inhibitors of cyclooxygenase and ultra low dose aspirin on platelet activity in portal hypertension

Eizayaga

Aguejouf²,

Desplat³

et al. 2007

WJG

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“…37 Recently, increased prostacyclin (PGI 2 ) activities have been observed in systemic circulation and portal vein segments of the portal hypertensive rats. 38,39 It was also shown that Iloprost, a PGI 2 analogue, counteracted the elevation of portal pressure caused by ET-1 in isolated liver perfusion of normal rats. 37 Recently, prostaglandin was found to be involved in the modulation of collateral vascular tone in portal hypertensive rats and could modify the vasoconstrictive effect of vasopressin.…”

Section: Discussionmentioning

confidence: 96%

Endothelin-1 induces vasoconstriction on portal-systemic collaterals of portal hypertensive rats

et al. 2001

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Cirrhosis of liver leads to portal hypertension and the development of portal-systemic collaterals. 10 The increased hepatic and collateral resistances to an increased portal blood flow maintain portal hypertension. 11 Recently, a possible role of endothelins in the pathophysiology of portal hypertension has been suggested. ET-1 was found to induce hepatic vasoconstriction and subsequently increase portal venous resistance. 4,12 In addition, ET-1 could stimulate contraction of hepatic stellate cells to increase intrahepatic resistance. 13 In vitro experiments also showed that ET-1 produced contraction of rat portal vein. 14 Furthermore, the mesenteric expressions of ET A and ET B receptors and ET-1-induced vasoconstriction were significantly enhanced in partially portal veinligated (PVL) rats. 5 Recently, it has been shown that bosentan, a nonselective endothelin receptor antagonist, significantly reduced the portal pressure of portal hypertensive rats. 15 However, it is not clear if ET-1 could modulate portal pressure by a direct constrictive effect on the collateral vessels of portal hypertensive rats.The aims of this study were to investigate the vascular activity and the receptor-mediated effects of ET-1 on the portalsystemic collaterals of portal hypertensive rats. The regulation of nitric oxide (NO) and prostaglandin on the effects of ET-1 was also evaluated. MATERIALS AND METHODSMale Sprague-Dawley rats weighing 280 to 300 g at the time of surgery were used for experiments. The rats were housed in a plastic cage and allowed free access to food and water. All rats were fasted for 12 hours before operation. In all experiments, the investigators adhered to the American Physiological Society Guiding Principles for the Care and Use of Laboratory Animals.A prehepatic portal hypertensive animal model was created as previously reported. 16 Anesthesia was performed with ketamine HCl (100 mg/kg body weight, intramuscularly). In brief, the portal vein was isolated and a 3-0 silk ligature was tied around both the portal vein and an adjacent 20-gauge blunt-tipped needle. The needle was then removed and the vein allowed to reexpand. A second loose ligature was left around the portal vein with 2 endings of the ligature placed on each side in the abdominal cavity. The abdomen was then closed and the animal was allowed to recover. Perfusion studies were performed in overnight-fasted rats 10 to 13 days after the operation, at which time an extensive collateralization of the portal system was fully established. 17 The body weights of rats were measured on the day of perfusion studies.Abbreviations: ET-1, endothelin-1; PVL, portal vein-ligated; NO, nitric oxide; NNA, n -nitro-L-arginine; INDO, indomethacin.From the Divisions of

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“…10 In addition, increased PGI 2 activities have been observed in systemic circulation 10 and portal vein segments 13 in portal hypertensive rats. Furthermore, inhibition of prostaglandin production with INDO ameliorates splanchnic hyperdynamic circulation.…”

Section: Discussionmentioning

confidence: 99%

“…5,6 Both of them modulate mesenteric vascular tone and are important contributors to splanchnic hyperemia in portal hypertensive rats. [7][8][9][10][11] In addition, NO plays a role in modulating collateral vascular resistance, 12 and increased PGI 2 activities have been observed in systemic circulation 10 and portal vein segments. 13 Furthermore, the modulator role of NO and prostaglandins in the vascular actions of arginine vasopressin has been suggested.…”

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confidence: 99%

Effects of vasopressin on portal-systemic collaterals in portal hypertensive rats: Role of nitric oxide and prostaglandin

et al. 1999

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This study investigated the effect of vasopressin on portal-systemic collaterals in portal hypertensive rats and the influence of nitric oxide (NO) and prostaglandin on the responsiveness of collateral vessels to vasopressin. The vascular responsiveness to graded concentrations of vasopressin was tested with or without the incubation of n -nitro-L-arginine (NNA) (100 mol/L) and/or indomethacin (10 mol/L) in perfused collateral vascular beds of rats with portal hypertension induced by partial portal vein ligation. In addition, concentration-response curves to vasopressin with incubation of a vasopressin V 1 receptor antagonist d(CH 2 ) 5 Tyr(Me) arginine vasopressin and concentrationresponse curves to a V 2 receptor agonist 1-desamino-8-Darginine vasopressin were performed. Vasopressin significantly increased the perfusion pressure of collaterals, and this effect was suppressed by the addition of the V 1 receptor antagonist. Perfusion with the V 2 receptor agonist had no effect on the collaterals. Incubation with NNA, indomethacin, or both significantly potentiated the response of collaterals to vasopressin. In addition, the pressor response to vasopressin in the combination group was significantly higher than that in the NNA-alone group. The results show that vasopressin produces a direct vasoconstrictive effect on the portal-systemic collaterals of portal hypertensive rats. This effect is mediated by the vasopressin V 1, but not V 2 , receptors. The attenuation of the response to vasopressin by NO and prostaglandin suggest a function role of both mediators in the regulation of the portal-systemic collateral circulation in portal hypertensive rats. (HEPATOLOGY 1999;30:630-635.)Vasopressin, an agent that decreases portal and collateral blood flow and portal pressure, 1 has been used in cirrhotic patients for the management of esophageal variceal bleeding. 2 It is a powerful vasoconstrictor and exerts varying degree of contractile effect over arteries and veins. 3 Perfusion studies of splanchnic vascular beds have shown that vasopressin markedly increases the vascular resistance of mesenteric arteries but does not alter the venous resistance. 4 Therefore, the constriction of splanchnic arteries accompanied by the reduction of splanchnic and portal-systemic collateral blood flow have been postulated to be the major mechanisms by which vasopressin alleviates portal hypertension and controls variceal hemorrhage in patients with cirrhosis. However, it is uncertain if the effect of vasopressin on reducing collateral blood flow is also mediated by a direct vasoconstrictive effect on the collateral vascular beds.Nitric oxide (NO) and prostacyclin (PGI 2 ) are endogenous vasodilators synthesized by the vascular endothelium. 5,6 Both of them modulate mesenteric vascular tone and are important contributors to splanchnic hyperemia in portal hypertensive rats. [7][8][9][10][11] In addition, NO plays a role in modulating collateral vascular resistance, 12 and increased PGI 2 activities have been observed in systemic circulatio...

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Enhanced cyclooxygenase-1 expression within the superior mesenteric artery of portal hypertensive rats: Role in the hyperdynamic circulation

Cited by 49 publications

References 38 publications

Modifications produced by selective inhibitors of cyclooxygenase and ultra low dose aspirin on platelet activity in portal hypertension

Modifications produced by selective inhibitors of cyclooxygenase and ultra low dose aspirin on platelet activity in portal hypertension

Endothelin-1 induces vasoconstriction on portal-systemic collaterals of portal hypertensive rats

Effects of vasopressin on portal-systemic collaterals in portal hypertensive rats: Role of nitric oxide and prostaglandin

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