Nitric oxide reverses endotoxin-induced inflammatory hyperalgesia via inhibition of prostacyclin production in mice

Tunçtan, Bahar; Özveren, Elif; Korkmaz, Belma; Buharalioğlu, C. Kemal; Tamer, Lülüfer; Değirmenci, Ulaş; Atik, Uğur

doi:10.1016/j.phrs.2005.10.009

Cited by 25 publications

(26 citation statements)

References 83 publications

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“…DFU is a highly selective PGHS-2 inhibitor in vitro (12). The selectivity of the dosage regimen that we used has been reported previously (43)(44)(45) and was confirmed in this study (Supplemental Figure 1).…”

Section: Pghs-2 Inhibitorssupporting

confidence: 85%

Cyclooxygenases, microsomal prostaglandin E synthase-1, and cardiovascular function

Cheng

Wang²,

Yu³

et al. 2006

Journal of Clinical Investigation

319

282

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We investigated the mechanisms by which inhibitors of prostaglandin G/H synthase-2 (PGHS-2; known colloquially as COX-2) increase the incidence of myocardial infarction and stroke. These inhibitors are believed to exert both their beneficial and their adverse effects by suppression of PGHS-2-derived prostacyclin (PGI 2 ) and PGE 2 . Therefore, the challenge remains to identify a mechanism whereby PGI 2 and PGE 2 expression can be suppressed while avoiding adverse cardiovascular events. Here, selective inhibition, knockout, or mutation of PGHS-2, or deletion of the receptor for PGHS-2-derived PGI 2 , was shown to accelerate thrombogenesis and elevate blood pressure in mice. These responses were attenuated by COX-1 knock down, which mimics the beneficial effects of low-dose aspirin. PGE 2 biosynthesis is catalyzed by the coordinate actions of COX enzymes and microsomal PGE synthase-1 (mPGES-1). We show that deletion of mPGES-1 depressed PGE 2 expression, augmented PGI 2 expression, and had no effect on thromboxane biosynthesis in vivo. Most importantly, mPGES-1 deletion affected neither thrombogenesis nor blood pressure. These results suggest that inhibitors of mPGES-1 may retain their antiinflammatory efficacy by depressing PGE 2 , while avoiding the adverse cardiovascular consequences associated with PGHS-2-mediated PGI 2 suppression.

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Section: Pghs-2 Inhibitorssupporting

confidence: 85%

Cyclooxygenases, microsomal prostaglandin E synthase-1, and cardiovascular function

Cheng

Wang²,

Yu³

et al. 2006

Journal of Clinical Investigation

319

282

View full text Add to dashboard Cite

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“…It is now attractive to verify whether the observed NO imbalance can also be effective in mice in which BSO and L-NAME have been successfully used to inhibit GSH and NO synthesis in several tissues and organs (Cattan et al, 2008;Orucevic and Lala, 1996;Stevanovic et al, 2009;Tunctan et al, 2006;Watanabe et al, 2003). Work is in progress in our laboratory to dissect this issue.…”

Section: Discussionmentioning

confidence: 99%

Nitric oxide is the primary mediator of cytotoxicity induced by GSH depletion in neuronal cells

Aquilano

Baldelli

Cardaci

et al. 2011

Journal of Cell Science

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Glutathione (GSH) levels progressively decline during aging and in neurodegenerative disorders. However, the contribution of such event in mediating neuronal cell death is still uncertain. In this report, we show that, in neuroblastoma cells as well as in primary mouse cortical neurons, GSH decrease, induced by buthionine sulfoximine (BSO), causes protein nitration, S-nitrosylation and DNA strand breaks. Such alterations are also associated with inhibition of cytochrome c oxidase activity and microtubule network disassembly, which are considered hallmarks of nitric oxide (NO) toxicity. In neuroblastoma cells, BSO treatment also induces cell proliferation arrest through the ERK1/2-p53 pathway that finally results in caspase-independent apoptosis, as evident from the translocation of apoptosis-inducing factor from mitochondria towards nuclei. A deeper analysis of the signaling processes indicates that the NO-cGMP pathway is involved in cell proliferation arrest and death. In fact, these events are completely reversed by L-NAME, a specific NO synthase inhibitor, indicating that NO, rather than the depletion of GSH per se, is the primary mediator of cell damage. In addition, the guanylate cyclase (GC) inhibitor LY83583 is able to completely block activation of ERK1/2 and counteract BSO toxicity. In cortical neurons, NMDA (N-methyl-D-aspartic acid) treatment results in GSH decrease and BSO-mediated NO cytotoxicity is enhanced by either epidermal growth factor (EGF) or NMDA. These findings support the idea that GSH might represent the most important buffer of NO toxicity in neuronal cells, and indicate that the disruption of cellular redox buffering controlled by GSH makes neuronal cells susceptible to endogenous physiological flux of NO.

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“…These results are not surprising, because there are several reports suggesting a direct link between NO and arachidonic acid metabolites (Fleming, 2001; Goodwin et al , 1999; Mollace et al , 2005; Roman, 2002). NOS inhibitors act to increase COX expression and prostaglandin synthesis in response to cytokine stimulation and the addition of NO donors reverses their effects suggesting that NO inhibits COX activity (Amin et al , 1997; Habib et al , 1997; Swierkosz et al , 1995; Tunctan et al , 2006a). NO has also shown to activate COX-1, but inhibit COX-2-derived prostaglandin production in vitro (Clancy et al , 2000).…”

Section: Discussionmentioning

confidence: 99%

Prostaglandins inhibit cytochrome P450 4A activity and contribute to endotoxin-induced hypotension in rats via nitric oxide production

et al. 2008

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Increased production of nitric oxide (NO) and prostaglandins contribute to development of hypotension during endotoxemia. We have previously demonstrated that endotoxemia-induced increase in NO production suppresses renal cytochrome P450 (CYP) 4A expression and activity, and that selective inhibition of inducible NO synthase (iNOS) with 1,3-PBIT restores renal CYP 4A protein and activity and mean arterial pressure (MAP). By using cyclooxygenase (COX) inhibitor indomethacin, we investigated herein whether prostaglandins, via NO production, inhibit renal CYP 4A1 protein expression and CYP 4A activity and contribute to the endotoxin-induced hypotension. In conscious male Sprague-Dawley rats, endotoxin (10 mg/kg, intraperitoneal (i.p.)) reduced MAP, increased serum nitrite and bicyclo PGE 2 levels, renal nitrite production and iNOS protein expression, and decreased renal CYP 4A1 protein expression and CYP 4A activity after 4 h injection. All of the endotoxin-induced changes, except for increase in renal nitrite production, were prevented by indomethacin (5 mg/kg, i.p. 1 h after endotoxin). The effects of indomethacin on the endotoxininduced decrease in MAP, CYP 4A1 protein expression and CYP 4A activity were minimized by the CYP 4A inhibitor, aminobenzotriazole (50 mg/kg, i.p. 1 h after endotoxin). These data suggest that prostaglandins produced during endotoxemia increase iNOS protein expression and NO synthesis, and decrease CYP 4A protein expression and CYP 4A activity and that inhibition of iNOS or COX restores renal CYP 4A protein level and CYP 4A activity and MAP presumably due to increased production of arachidonic acid metabolites derived from CYP 4A.

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Nitric oxide reverses endotoxin-induced inflammatory hyperalgesia via inhibition of prostacyclin production in mice

Cited by 25 publications

References 83 publications

Cyclooxygenases, microsomal prostaglandin E synthase-1, and cardiovascular function

Cyclooxygenases, microsomal prostaglandin E synthase-1, and cardiovascular function

Nitric oxide is the primary mediator of cytotoxicity induced by GSH depletion in neuronal cells

Prostaglandins inhibit cytochrome P450 4A activity and contribute to endotoxin-induced hypotension in rats via nitric oxide production

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