Altered prostacyclin synthesis by aortae from hepatic portal vein-constricted rats: evidence for effects on protein kinase C and calcium

Jeremy, Jamie Y.; Mikhailidis, Dimitri P.; Karatapanis, Stelios; Harry, David; Burroughs, Andrew K.; McIntyre, Neil; Stansby, Gerard; Jacobs, Michael; McCormick, Aiden

doi:10.1016/s0168-8278(05)80611-7

Cited by 19 publications

(9 citation statements)

References 32 publications

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“…This result reinforces the lack of participation by the COX-1 derivatives in the vasodilator response to ACh in aged and aged plus long-term PH and, consequently, supports the hypothesis that the effect is mediated by COX-2 derivatives. PGI 2 is the most important vasodilator COX-2 derivative, but its participation in short-term PH is controversial, as both participation and no participation have been reported [31][32][33][34][35]. On the other hand, the role of PGI 2 in PH has been reported to be different depending on the evolution of PH [8].…”

Section: Discussionmentioning

confidence: 99%

Long-term portal hypertension increases the vasodilator response to acetylcholine in rat aorta: role of prostaglandin I2

et al. 2009

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In the present study, we have analysed both the effect of long-term portal hypertension on the vasomotor response to acetylcholine in rat aorta and the mechanism involved in this response. For this purpose, sham-operated rats and rats with pre-hepatic PH (portal hypertension; triple partial portal vein ligation) were used at 21 months after surgery. The participation of NO and COX (cyclo-oxygenase) derivatives in the vasodilator response elicited by acetylcholine after incubation with L-NAME (NG-nitro-L-arginine methyl ester), indomethacin, SC-560, NS-398, tranylcypromine and furegrelate, was analysed. NO, TXB2 (thromboxane B2) and 6-keto PGF1alpha (prostaglandin F1alpha) release were measured. In addition, SNP (sodium nitroprusside), U-46619, PGI2 and forskolin vasomotor responses were analysed. COX-1 and COX-2 expression was also determined. The acetylcholine-induced vasodilating response was higher in rats with PH. TXA2 and NO release, and SNP and U-46619 sensitivity were similar in both groups. PGI2 release was not modified by portal hypertension, but vasodilator responses to this prostanoid and to forskolin were higher in rats with PH. COX-1 and COX-2 expression remained unmodified by surgery. In conclusion, increased vasodilation to acetylcholine is maintained in long-term PH. Although the participation of endothelial NO remained unmodified, the COX-2 derivative PGI2 does participate through an increased vasodilator response.

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Section: Discussionmentioning

confidence: 99%

Long-term portal hypertension increases the vasodilator response to acetylcholine in rat aorta: role of prostaglandin I2

et al. 2009

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“…In addition, certain studies have suggested that PKC may be altered in vascular cells from portal hypertensive rats. [12][13][14][15] Therefore, PKC may play a role in any cirrhosiselicited alterations of Na ϩ /K ϩ ATPase. The present study measured Na ϩ /K ϩ ATPase activity under baseline conditions and in response to PKC modulators in aortae from normal and cirrhotic rats.…”

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confidence: 99%

Effects of protein kinase C modulators on Na+/K+ adenosine triphosphatase activity and phosphorylation in aortae from rats with cirrhosis

Lahaye

Tazi

Rona³

et al. 1998

Hepatology

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Protein kinase C (PKC) modulates the activity and phosphorylation of the catalytic ␣-subunit of sodiumpotassium-adenosine triphosphatase (Na ؉ /K ؉ ATPase) in normal arteries. Because PKC is altered in cirrhotic aortae, Na ؉ /K ؉ ATPase may also be altered in these arteries. The aim of the present study was to investigate ␣-subunit activity and phosphorylation in aortae from normal and cirrhotic rats, under baseline conditions and during exposure to PKC modulators. ␣-Subunit activity was assessed by measuring the amount of 32 P released by hydrolysis of [␥-32 P]ATP in freshly isolated cell membranes (in the absence of PKC modulators only) and membrane depolarization caused by ouabain-induced ␣-subunit inhibition in isolated aortae (in the absence and presence of PKC modulators). ␣-Subunit phosphorylation was assessed by incorporation of 32 P into ␣-subunits. Staurosporine, a PKC inhibitor, and phorbol 12,13-dibutyrate (PDBU), a PKC activator, were used. In addition, ␣-subunit expression was studied by Western blot analysis. In the absence of PKC modulators, the amount of 32 P released by hydrolysis of [␥-32 P]ATP and ouabain-induced membrane depolarization were significantly lower in cirrhotic than in normal aortae. Staurosporine suppressed ouabain-induced membrane depolarization in cirrhotic and normal arteries. Ouabaininduced membrane depolarization was similar in cirrhotic aortae exposed to PDBU and in normal arteries studied under baseline conditions. ␣-Subunit phosphorylation was significantly lower in cirrhotic than in normal aortae, in aortae under baseline conditions, and in arteries exposed to staurosporine. Phosphorylation of the ␣-subunit was similar in cirrhotic aortae exposed to PDBU and in normal arteries under baseline conditions. Western blot analysis showed that the amount of ␣-subunit did not significantly differ between cirrhotic and normal aortae. In conclusion, a decrease in baseline Na ؉ /K ؉ ATPase ␣-subunit activity occurs in aortae from cirrhotic rats as a result of reduced basal PKC activity. This PKC-dependent decreased ␣-subunit activity may be caused by a reduction in PKC-induced ␣-subunit phosphorylation. (HEPATOLOGY 1998;28:663-669.)

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“…A previous study using rat thoracic aorta from PHT animals did not show any changes in Cox expression, despite increased agonist stimulated PGI 2 synthesis in these vessels. 34 Hence, the exaggerated PGI 2 levels in these animals may also partially reflect enhanced PGI 2 synthesis without any change in Cox expression within specific vascular beds. Indeed, Cox-I mRNA levels remained unchanged in the thoracic aorta following the development of PHT.…”

Section: Discussionmentioning

confidence: 95%

“…Of note Cox-I mRNA expression was significantly enhanced in thoracic aorta from PHT animals 2 and 4 days post-ligation but unchanged after 15 days. Moreover, following ligation of the portal vein, there was a marked increase in portal venous pressure and a subsequent distension leading to smooth muscle hypertrophy, 33,34 which has previously been shown to increase PGI 2 synthesis. 17,22,[35][36][37] Alternatively, it is possible that the initial increase in PGI 2 levels are a direct result of PGI 2 escaping hepatic degradation caused by the portosystemic collaterals which shunts up to 90% of portal flow away from the liver.…”

Section: Discussionmentioning

confidence: 97%

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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Altered prostacyclin synthesis by aortae from hepatic portal vein-constricted rats: evidence for effects on protein kinase C and calcium

Cited by 19 publications

References 32 publications

Long-term portal hypertension increases the vasodilator response to acetylcholine in rat aorta: role of prostaglandin I2

Long-term portal hypertension increases the vasodilator response to acetylcholine in rat aorta: role of prostaglandin I2

Effects of protein kinase C modulators on Na+/K+ adenosine triphosphatase activity and phosphorylation in aortae from rats with cirrhosis

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

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