Acute and chronic cyclooxygenase blockage in portal-hypertensive rats: Influence in nitric oxide biosynthesis

Fernández, Mercedes; García-Pagán, Juan Carlos; Casadevall, María; Mourelle, MI; Piqué, JM; Bosch, Jaime; Rodés, Juan

doi:10.1053/gast.1996.v110.pm8613060

Cited by 94 publications

(66 citation statements)

References 2 publications

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“…[11][12][29][30] However, to date few studies have examined the effect of chronic treatment of PHT rats with L-NAME or indomethacin. 18 Consistent with previous acute studies, chronic treatment of PHT animals with L-NAME inhibited endothelial NOS activity within the hyperemic vasculature 4,10 ; subsequently, it also significantly decreased superior mesenteric artery blood flow in both sham and PHT animals supporting a role for NO in the control of splanchnic vascular tone under normal conditions and, preferentially, in the development of the hyperdynamic circulation of PHT. In contrast, indomethacin treatment did not significantly alter splanchnic blood flow in sham animals, suggesting that Cox products and in particular PGI 2 may not play a major role in regulating superior mesenteric artery blood flow under normal conditions.…”

Section: Discussionsupporting

confidence: 88%

“…In contrast, indomethacin treatment did not significantly alter splanchnic blood flow in sham animals, suggesting that Cox products and in particular PGI 2 may not play a major role in regulating superior mesenteric artery blood flow under normal conditions. 18,30 However, in the current study, Cox inhibition significantly decreased circulating PGI 2 levels while preferentially decreasing superior mesenteric artery blood flow in PHT animals following the development of PHT (i.e., after 15 days).…”

Section: Discussioncontrasting

confidence: 59%

“…In comparison with the pressor response of L-NAME, the pressor response following Cox blockade was as significant, suggesting that NO and PGI 2 may be the predominant regulators of superior mesenteric artery blood flow in portal hypertension. Despite the preferential pressor response to endothelial NOS and Cox blockade, or a combination of both, 13,18 superior mesenteric artery blood flow still remained significantly elevated in PHT; this result indicates that, in addition to PGI 2 and NO, other vasoactive substances may be involved.…”

Section: Discussionmentioning

confidence: 94%

“…[15][16][17] Moreover, indomethacin administration attenuates the hyperdynamic circulation and vascular hyporesponsiveness to vasoconstrictors typical of PHT. 12,18 However the mechanism(s) controlling the vascular synthesis of PGI 2 , particularly in the splanchnic vascular bed, and its relationship to the reduced vascular resistance in PHT are not clearly defined.The following two major steps control the production of PGI 2 : 1) The release of arachidonic acid from phospholipids, through the action of phospholipase A, C and/or D 19 ; 2) the formation of prostaglandin H 2 (PGH 2 ) from arachidonic acid following activation of cyclooxygenase (Cox) enzyme activity. 20 Similar to NO production, prostacylin synthesis is stimulated by shear stress caused by increased blood flow and proinflammatory agents.…”

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confidence: 99%

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confidence: 99%

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

et al. 1998

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Portal hypertension (PHT) is characterized by splanchnic hyperemia due to enhanced production of vasodilator substances. Enhanced vasodilation and increased splanchnic blood flow contribute to the elevated portal pressure characteristic of PHT. The aim of this study was to determine whether cyclooxygenase (Cox) expression is altered in PHT vessels and whether chronic inhibition of this enzyme impacts on splanchnic blood flow in PHT. PHT was created in Sprague-Dawley rats by a partial portal vein ligation. Control animals were sham operated. Plasma 6-keto-PGF 1 ␣ (prostaglandin F 1 ␣) levels were significantly elevated in PHT after 2 days as compared with sham and remained elevated up to day 15. Treatment with indomethacin (2 mg/kg ip daily for 15 days) resulted in a significant decrease in 6-keto-PGF 1 ␣ levels, which was concomitant with a significant decrease in superior mesenteric artery blood flow (Qsma) after 15 days in PHT rats. Cox-I expression was differentially enhanced in the PHT superior mesenteric artery and thoracic aorta during the development and progression of PHT. In contrast, Cox-II messenger RNA (mRNA) and protein expression was not detected in either of these vessels throughout the development of PHT. These data suggest that PHT is associated with enhanced Cox-I expression within the splanchnic vasculature concomitant with elevated plasma prostacyclin levels and a significant pressor response to indomethacin in PHT animals. We conclude that enhanced Cox-I expression results in increased prostacyclin levels that partially contribute to the maintenance of the hyperemia typical of PHT. (HEPATOLOGY 1998;27:20-27.)Portal hypertension (PHT) is characterized by a hyperdynamic circulatory state which is commonly observed in patients with chronic liver disease and in experimental models of PHT with extensive collateral circulation. 1,2 The main pathophysiological change of the hyperdynamic circulation is a generalized reduced vascular resistance. 1,2 The reasons for the decreased vascular resistance include exaggerated endothelial function with enhanced synthesis and/or release of vasoactive substance, such as prostacyclin and nitric oxide (NO), and altered vascular responsiveness to vasoconstrictor substances, such as vasopressin, angiotensin, norepinephrine, and methoxamine. 3-6 NO, a potent endothelium-derived relaxing factor, is one of the major vasoactive substances implicated in the pathogenesis of the reduced vascular resistance in PHT. 7,8 PHT is associated with enhanced nitric oxide synthase (NOS) activity within the hyperemic vasculature. 4,9,10 Moreover, the altered vascular responsiveness and circulatory abnormalities of PHT are in part corrected following inhibition of NOS with specific NOS inhibitors. 11,12 While the enhanced NO production may be a major modulator of the altered vascular response in PHT, other vasodilator substances may also be involved inasmuch as acute blockade of NOS activity fails to completely reverse the hyperdynamic circulation. 13,14 The production of prostacycli...

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