Simultaneous inhibition of TXA2 and PGI2 synthesis increases NO release in mesenteric resistance arteries from cirrhotic rats

Xavier, Fabiano E.; Blanco-Rivero, Javier; Sastre, Esther; Badimón, Lina; Balfagón, Gloria

doi:10.1042/cs20090536

Cited by 13 publications

(37 citation statements)

References 29 publications

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“…We showed that, in according to the previous studies endothelial vasodilatory response of aortic ring (Clària et al 1994) and SMA (Bolognesi et al 2011;Xavier et al 2010) to acetylcholine is increased in cirrhosis. Also cirrhotic patients displayed an increased endothelium-mediated vasodilation by methacholine, which proposes an amplified synthesis of nitric oxide (Albillos et al 1995).…”

Section: Discussionsupporting

confidence: 79%

“…In vascular bed, involving those of the mesenteric arteries, the endothelium releases three important vasorelaxator agent; NO, prostacyclin, and endothelial-derived hyperpolarizing factor .However in mesenteric artery, each of these pathways have a role in the vasorelaxation response to acetylcholine (Furchgott et al 1987;Furchgott and Zawadzki 1980) but NO is the principal pathway in these vascular bed because acetylcholine vasorelaxation responses (Harrington et al 2007). It has been shown that endothelium-derived hyperpolarizing factor through activation of K channels (Barriere et al 2000) ,increased myoendothelial gap junctions (Bolognesi et al 2011) and cyclooxygenase/ prostaglandin I 2 system (Graupera et al 2003;Xavier et al 2010) also contributes to the mesenteric vasodilatation elicited by acetylcholine in cirrhotic rats.…”

Section: Discussionmentioning

confidence: 97%

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Mesenteric artery responsiveness to acetylcholine and phenylephrine in cirrhotic rats challenged with endotoxin: the role of TLR4

Ostadhadi

Rezayat

Ejtemaei-Mehr

et al. 2015

Can. J. Physiol. Pharmacol.

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Cirrhosis is associated with vascular dysfunction and endotoxemia. These experiments were designed to investigate the hypothesis that the administration of a low-dose of lipopolysaccharide (LPS) worsens vascular dysfunction in rats subjected to bile-duct ligation (BDL), and to determine whether LPS initiates changes in vascular Toll-like receptor 4 (TLR4) expression. Four weeks after BDL, the animals were given an intraperitoneal injection of either saline or LPS (1.0 mg/kg body mass). Three hours later, the superior mesenteric artery was isolated, perfused, and then subjected to the vasoconstriction and vasodilatation effects of phenylephrine and acetylcholine, respectively. Our results show that phenylephrine-induced vasoconstriction decreased in the cirrhotic vascular bed (BDL rats) compared with the vascular bed of the sham-operated animals, and that the LPS injections in the cirrhotic (BDL) rats worsened this response. LPS injection administered to the sham-operated animals had no such effect. On the other hand, both the BDL procedure and the LPS injection increased acetylcholine-induced vasorelaxation, but LPS administration to the BDL rats had no effect on this response. The mRNA levels of TLR4 did not change, but immunohistochemical studies showed that TLR4 localization switched from the endothelium to vascular smooth muscle cells following chronic BDL. In conclusion, acute endotoxemia in cirrhotic rats is associated with hyporesponsiveness to phenylephrine and tolerance to the effects of acetylcholine. Altered localization of TLR4 may be responsible for these effects.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 97%

Mesenteric artery responsiveness to acetylcholine and phenylephrine in cirrhotic rats challenged with endotoxin: the role of TLR4

Ostadhadi

Rezayat

Ejtemaei-Mehr

et al. 2015

Can. J. Physiol. Pharmacol.

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“…Thus, COX inhibition in the inflammatory setting of hypercholesterolemia and chronic ischemia may preferentially inhibit thromboxane production, allowing vasodilatory mechanisms to prevail. This theory is supported by a recent study of a rat model of cirrhosis, where cirrhotic rats demonstrated mesenteric vessel vasodilation in response to both nonselective and selective COX-2 inhibition while noncirrhotic rats did not (27).…”

Section: Discussionsupporting

confidence: 65%

Effects of cyclooxygenase inhibition on cardiovascular function in a hypercholesterolemic swine model of chronic ischemia

Chu

Robich

Bianchi

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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T, Sellke FW. Effects of cyclooxygenase inhibition on cardiovascular function in a hypercholesterolemic swine model of chronic ischemia. Am J Physiol Heart Circ Physiol 302: H479 -H488, 2012. First published October 28, 2011 doi:10.1152/ajpheart.00146.2011The cardiovascular effects of cyclooxygenase (COX) inhibition remain controversial, especially in the setting of cardiovascular comorbidities. We examined the effects of nonselective and selective COX inhibition on cardiovascular function in a hypercholesterolemic swine model of chronic ischemia. Twenty-four intact male Yorkshire swine underwent left circumflex ameroid constrictor placement and were subsequently given either no drug (HCC; n ϭ 8), a nonselective COX inhibitor (440 mg/day naproxen; HCNS; n ϭ 8), or a selective COX-2 inhibitor (200 mg/day celecoxib; HCCX; n ϭ 8). After 7 wk, myocardial functional was measured and myocardium from the nonischemic ventricle and ischemic area-at-risk (AAR) were analyzed. Regional function as measured by segmental shortening was improved in the AAR of HCCX compared with HCC. There was no significant difference in perfusion to the nonischemic ventricle between groups, but myocardial perfusion in the AAR was significantly improved in the HCCX group compared with controls at rest and during pacing. Endothelium-dependent microvessel relaxation was diminished by ischemia in HCC animals, but both naproxen and celecoxib improved vessel relaxation in the AAR compared with controls, and also decreased the vasoconstrictive response to serotonin. Thromboxane levels in the AAR were decreased in both HCNS and HCCX compared with HCC, whereas prostacyclin levels were decreased only in HCNS, corresponding to a decrease in prostacyclin synthase expression. Chronic ischemia increased apoptosis in Troponin T negative cells and intramyocardial fibrosis, both of which were reduced by celecoxib administration in the AAR. Capillary density was decreased in both the HCNS and HCCX groups. Protein oxidative stress was decreased in both HCNS and HCCX, whereas lipid oxidative stress was decreased only in the HCCX group. Thus nonselective and especially selective COX inhibition may have beneficial myocardial effects in the setting of hypercholesterolemia and chronic ischemia. Whether these effects modulate cardiovascular risk in patients taking these drugs remains to be seen, but evidence to date suggests that they do not. cholesterol; myocardial ischemia; perfusion; prostaglandins NONSTEROIDAL ANTI-INFLAMMATORY drugs (NSAIDs) function by inhibiting the conversion of arachadonic acid into prostaglandin H 2 by cyclooxygenase (COX), inhibiting the production of a family of prostanoids that includes prostacyclin and thromboxane. Unfortunately, the gastrointestinal side effects of

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“…Xavier et al (2010) reported that inhibition of TXA 2 and PGI 2 synthesis increased P-eNOS protein, but not eNOS release in mesenteric artery. The detailed mechanism is still unclear; however, ozagrel may activate phosphorylation of eNOS by inhibiting TXA 2 synthase.…”

Section: P-enosmentioning

confidence: 99%

Fasudil and Ozagrel in Combination Show Neuroprotective Effects on Cerebral Infarction after Murine Middle Cerebral Artery Occlusion

Koumura¹,

Hamanaka²,

Kawasaki³

et al. 2011

J Pharmacol Exp Ther

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Rho kinase (ROCK), one of the serine/threonine kinases, is involved in pathologic conditions, and its activation causes neuronal cell death. Fasudil, a selective ROCK inhibitor, has been reported to cause increased cerebral blood flow (CBF) in the ischemic brain and protect against neuronal cell death by inhibiting ROCK. Ozagrel, a thromboxane A 2 synthase inhibitor, inhibits platelet aggregation and causes vasodilatation, thereby increasing CBF in cerebral thrombosis. The present study evaluates the combination therapy of fasudil and ozagrel on focal brain ischemia induced by middle cerebral artery occlusion (MCAO) in mice. Each monotherapy of fasudil at 10 mg/kg i.p. and ozagrel at 30 mg/kg i.p. significantly reduced cerebral infarction. The combination therapy of fasudil (3 mg/kg i.p.) and ozagrel (10 mg/kg i.p.), which are noneffective doses, resulted in reduction of cerebral infarction, and the protective effect was observed up to 5 min, but not 3 h, after reperfusion. Regional CBF after MCAO and phosphorylation of endothelial nitricoxide synthase (NOS) significantly increased in response to the combination therapy, whereas these effects were not observed with monotherapy of either drug. The protective effect of combination treatment was antagonized by the treatment of a NOS inhibitor, nitro-L-arginine methyl ester hydrochloride. These findings indicate that the combination treatment of fasudil and ozagrel exhibits additive effects for neuroprotection after MCAO. These findings indicate that the combination treatment of fasudil and ozagrel may be useful as a potential therapeutic strategy for the treatment of stroke.

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Simultaneous inhibition of TXA2 and PGI2 synthesis increases NO release in mesenteric resistance arteries from cirrhotic rats

Cited by 13 publications

References 29 publications

Mesenteric artery responsiveness to acetylcholine and phenylephrine in cirrhotic rats challenged with endotoxin: the role of TLR4

Mesenteric artery responsiveness to acetylcholine and phenylephrine in cirrhotic rats challenged with endotoxin: the role of TLR4

Effects of cyclooxygenase inhibition on cardiovascular function in a hypercholesterolemic swine model of chronic ischemia

Fasudil and Ozagrel in Combination Show Neuroprotective Effects on Cerebral Infarction after Murine Middle Cerebral Artery Occlusion

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