Effects of Nimesulide, a Selective Cyclooxygenase-2 Inhibitor, on Cardiovascular Alterations in Endotoxemia

Azab, Abed N.; Kobal, Sergio; Rubin, Mazal; Kaplanski, Jacob

doi:10.1159/000082470

Cited by 11 publications

(3 citation statements)

References 75 publications

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“…The "mild" LPS dosing regimen (2 mg/kg iv) is different from a study designed to examine survival, where COX-2 Ϫ/Ϫ mice were significantly protected from death compared with COX-2 ϩ/ϩ in response to LPS (3 daily injections of 40 mg/kg ip or 100 mg/kg ip once) (19). The present observations suggest that the better survival in COX-2 Ϫ/Ϫ mice and in mice given COX-2-selective blockers (4,34) is less likely to be caused by an improved cardiovascular function. Of note, two selective COX-2 inhibitors and the glucocorticoid-receptor agonist dexamethasone showed equal ability to suppress the excretion of prostacyclin metabolite 6-keto-PGF 1␣ in rats after LPS, but only dexamethasone improved arterial pressure and attenuated the rise in plasma levels of nitrite and nitrate caused by LPS (30).…”

Section: Discussioncontrasting

confidence: 68%

Disruption of COX-2 and eNOS does not confer protection from cardiovascular failure in lipopolysaccharide-treated conscious mice and isolated vascular rings

Stæhr

Madsen

Vanhoutte

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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It was hypothesized that a serial stimulation of vascular cyclooxygenase-2 (COX-2) with subsequent activation of endothelial nitric oxide synthase (eNOS) is responsible for decrease in blood pressure, cardiac performance, and vascular reactivity in endotoxemia caused by LPS. The hypothesis was tested in catheterized, conscious, freely moving, wild-type mice and mice (C57BL/6J background) with targeted deletion of COX-2 and eNOS that were given an intravenous LPS bolus (2 mg/kg, 055:B5). In vitro studies were performed on murine aorta rings. LPS caused a concomitant decrease in mean arterial blood pressure (MAP) and heart rate (HR) that was significant after 3 h and was sustained throughout the experiment (8 h). The LPS-induced changes in MAP and HR were not different from control in COX-2(-/-) and eNOS(-/-) mice. A prostacyclin receptor antagonist (BR5064) blocked the hypotensive effect of a prostacyclin agonist (beraprost), but did not attenuate the LPS-induced decrease in MAP and HR. LPS decreased eNOS and neuronal NOS mRNA abundances in several organs, while inducible NOS mRNA was enhanced. In aortic rings, LPS suppressed α(1)-adrenoceptor-mediated vascular tone. Inhibition of COX-2 activity (NS 398), disruption of COX-2, endothelium removal, or eNOS deletion (eNOS(-/-)) did not improve vascular reactivity after LPS, while the NO synthase blockers 1400W and N(G)-nitro-l-arginine methyl ester prevented loss of tone. COX-2 and eNOS activities are not necessary for LPS-induced decreases in blood pressure, heart rate, and vascular reactivity. Inducible NOS activity appears crucial. COX-2 and eNOS are not obvious therapeutic targets for cardiovascular rescue during gram-negative endotoxemic shock.

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Section: Discussioncontrasting

confidence: 68%

Disruption of COX-2 and eNOS does not confer protection from cardiovascular failure in lipopolysaccharide-treated conscious mice and isolated vascular rings

Stæhr

Madsen

Vanhoutte

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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“…The anti-mutagenic effect of nimesulide has been observed on pancreatic cancer cells [43]. Nimesulide is effective against increased TNF-, PGE 2 and IL-1 levels in endotoxemic rats [44]. The other effects of nimesulide can be summarized as; blockage of superoxide anion releasing from leucocytes, inhibition of phosphodiesterase type IV, prevention of TNF-releasing, increasing glutathione (tGSH) levels in the stomach tissue, blockage of histamine, attenuation of hypochloric acid, and the inhibition of metalloprotease and platelet activating factor (PAF) [45][46][47][48][49][50][51][52].…”

Section: Pharmacologic Effectsmentioning

confidence: 99%

Nimesulide is a Selective COX-2 Inhibitory, Atypical Non-Steroidal Anti-Inflammatory Drug

Süleyman

Çadırcı²,

Albayrak³

et al. 2008

CMC

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In this review it is shown that nimesulide, a selective cyclooxigenase-2 (COX-2) inhibitor, is different from other selective COX-2 inhibitors and classical non-steroidal anti-inflammatory drugs (NSAIDs). The anti-inflammatory effect mechanism of nimesulide (inhibition of inflammatory mediators) is similar to other classic NSAIDs, but the protective effect of nimesulide on classic NSAID-induced ulcers elucidates the difference between nimesulide and these other drugs. It is known that the selective COX-2 inhibitor nimesulide prevents NSAID-induced ulcers, while celecoxib and rofecoxib, which are more selective to COX-2, failed to prevent these ulcers. Nimesulide produces gastro-protective effects via a completely different mechanism. In addition, while selective COX-2 inhibitors increase the risk for cardiovascular diseases, nimesulide does not exert significant cardiotoxicity. This data suggests that gastrointestinal side effects of classic NSAIDs cannot be related to the COX-1 inhibition alone and also suggest that nimesulide is an atypical NSAID, which is different from both non-selective and selective COX-2 inhibitors.

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“…It should also be pointed out that hypophagia induced by LPS was not completely reversed by indomethacin pretreatment. Azab et al (2005) showed that plasma cytokines induced by LPS treatment are unchanged or partly reduced by COX‐2 inhibition. Therefore, circulating cytokines not suppressed by indomethacin pretreatment might signal to the central nervous system, thereby reducing food intake.…”

Section: Discussionmentioning

confidence: 99%

Prostaglandin mediates endotoxaemia‐induced hypophagia by activation of pro‐opiomelanocortin and corticotrophin‐releasing factor neurons in rats

Rorato¹,

Menezes²,

Giusti‐Paiva³

et al. 2009

Experimental Physiology

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Corticotrophin-releasing factor (CRF) and α-melanocyte-stimulating hormone (α-MSH), both of which are synthesized by hypothalamic neurons, play an essential role in the control of energy homeostasis. Neuroendocrine and behavioural responses induced by lipopolyssacharide (LPS) have been shown to involve prostaglandin-mediated pathways. This study investigated the effects of prostaglandin on CRF and α-MSH neuronal activities in LPS-induced anorexia. Male Wistar rats were pretreated with indomethacin (10 mg kg −1 ; i.p.) or vehicle; 15 min later they received LPS (500 μg kg −1 ; i.p.) or saline injection. Food intake, hormone responses and Fos-CRF and Fos-α-MSH immunoreactivity in the paraventricular and arcuate nuclei, respectively, were evaluated. In comparison with saline treatment, LPS administration induced lower food intake and increased plasma ACTH and corticosterone levels, as well as an increase in Fos-CRF and Fos-α-MSH double-labelled neurons in vehicle-pretreated rats. In contrast, indomethacin treatment partly reversed the hypophagic effect, blunted the hormonal increase and blocked the Fos-CRF and Fos-α-MSH hypothalamic double labelling increase in response to the LPS stimulus. These data demonstrate that the activation of pro-opiomelanocortin and CRF hypothalamic neurons following LPS administration is at least partly mediated by the prostaglandin pathway and is likely to be involved in the modulation of feeding behaviour during endotoxaemia.

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Effects of Nimesulide, a Selective Cyclooxygenase-2 Inhibitor, on Cardiovascular Alterations in Endotoxemia

Cited by 11 publications

References 75 publications

Disruption of COX-2 and eNOS does not confer protection from cardiovascular failure in lipopolysaccharide-treated conscious mice and isolated vascular rings

Disruption of COX-2 and eNOS does not confer protection from cardiovascular failure in lipopolysaccharide-treated conscious mice and isolated vascular rings

Nimesulide is a Selective COX-2 Inhibitory, Atypical Non-Steroidal Anti-Inflammatory Drug

Prostaglandin mediates endotoxaemia‐induced hypophagia by activation of pro‐opiomelanocortin and corticotrophin‐releasing factor neurons in rats

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