A potential role for extracellular nitric oxide generation in cGMP‐independent inhibition of human platelet aggregation: biochemical and pharmacological considerations

Crane, Michael S; Rossi, Adriano G.; Megson, Ian L.

doi:10.1038/sj.bjp.0706110

Cited by 52 publications

(35 citation statements)

References 62 publications

(72 reference statements)

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“…Similar to its role in smooth muscle, NO has been postulated to mediate platelet inhibition by cGMP-dependent as well as cGMPindependent mechanisms (9,(21)(22)(23). The Western blot in Fig.…”

Section: Lack Of Glycerol Trinitrate (Gtn)-induced Decrease In Systolmentioning

confidence: 94%

Fatal gastrointestinal obstruction and hypertension in mice lacking nitric oxide-sensitive guanylyl cyclase

Friebe

Mergia

Dangel

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

215

225

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The signaling molecule nitric oxide (NO), first described as endothelium-derived relaxing factor (EDRF), acts as physiological activator of NO-sensitive guanylyl cyclase (NO-GC) in the cardiovascular, gastrointestinal, and nervous systems. Besides NO-GC, other NO targets have been proposed; however, their particular contribution still remains unclear. Here, we generated mice deficient for the ␤1 subunit of NO-GC, which resulted in complete loss of the enzyme. GC-KO mice have a life span of 3-4 weeks but then die because of intestinal dysmotility; however, they can be rescued by feeding them a fiber-free diet. Apparently, NO-GC is absolutely vital for the maintenance of normal peristalsis of the gut. GC-KO mice show a pronounced increase in blood pressure, underlining the importance of NO in the regulation of smooth muscle tone in vivo. The lack of an NO effect on aortic relaxation and platelet aggregation confirms NO-GC as the only NO target regulating these two functions, excluding cGMP-independent mechanisms. Our knockout model completely disrupts the NO/cGMP signaling cascade and provides evidence for the unique role of NO-GC as NO receptor.cardiovascular ͉ knockout mice ͉ cGMP ͉ platelet aggregation ͉ smooth muscle relaxation T he nitric oxide (NO)/cGMP signaling cascade regulates a plethora of physiological functions in the cardiovascular, neuronal, and gastrointestinal systems (1-3). In the vascular system, NO, first recognized as endothelium-derived relaxing factor (EDRF; ref. 4), has been shown to mediate smooth muscle relaxation and inhibition of platelet aggregation. NO is synthesized by the family of NO synthases which exist in endothelial, neuronal, and inducible forms. The prominent receptor known to date is the enzyme NO-sensitive guanylyl cyclase (NO-GC). Stimulation of NO-GC by NO results in the production of the second messenger, cGMP, which exerts its effects via cGMPdependent kinases, channels, or phosphodiesterases (5-8). Besides these cGMP-mediated effects, NO is thought to mediate a variety of effects via cGMP-independent mechanisms in the cardiovascular system (for a review, see ref. 9).To gain further insight into the NO/cGMP signaling cascade, mice deficient in NO synthases (NOS) have been generated (10)(11)(12)(13)(14). Although these mouse lines have tremendously helped to understand NO/cGMP signaling, it is still not known which of NO's effects are mediated via NO-GC and thus cGMP, or alternatively, via pathways not involving cGMP.To address this point and to further investigate the physiological role of the enzyme and of the NO/cGMP signaling cascade in vivo, we generated an NO-GC-deficient mouse line. NO-GC is a heterodimer made up of two subunits, ␣ and ␤. Two isoforms are known to exist (␣ 1 ␤ 1 and ␣ 2 ␤ 1 ; ref. 15) in which the ␤ 1 subunit acts as the dimerizing partner for either ␣ subunit. ␣ subunits in the absence of the ␤ 1 subunit do not form dimers and are not catalytically active. Thus, deletion of the ␤ 1 subunit should completely eliminate NO-GC and yield a mouse line ...

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Section: Lack Of Glycerol Trinitrate (Gtn)-induced Decrease In Systolmentioning

confidence: 94%

Fatal gastrointestinal obstruction and hypertension in mice lacking nitric oxide-sensitive guanylyl cyclase

Friebe

Mergia

Dangel

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

215

225

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“…This does not exclude other mechanisms of cGMP-independent action such as inhibition of intracellular calcium entry [37] or direct nitrosation of α IIb β 3 [33,38].…”

Section: Discussionmentioning

confidence: 98%

Interactions between cell surface protein disulphide isomerase and S-nitrosoglutathione during nitric oxide delivery

et al. 2007

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This is an electronic version of an article published in Nitric Oxide, 16 (1). pp. 135-142., February 2007. The definitive publisher-authenticated version is available from the journal homepage at:http://www.sciencedirect.com/science/journal/10898603The WestminsterResearch online digital archive at the University of Westminster aims to make the research output of the University available to a wider audience. Copyright and Moral Rights remain with the authors and/or copyright owners. Users are permitted to download and/or print one copy for non-commercial private study or research. Further distribution and any use of material from within this archive for profit-making enterprises or for commercial gain is strictly forbidden.Whilst further distribution of specific materials from within this archive is forbidden, you may freely distribute the URL of WestminsterResearch.(http://www.wmin.ac.uk/westminsterresearch).In case of abuse or copyright appearing without permission e-mail wattsn@wmin.ac.uk. 1 INTERACTIONS BETWEEN CELL SURFACE PROTEIN DISULPHIDE ISOMERASE AND S-NITROSOGLUTATHIONE DURING NITRIC OXIDE DELIVERY AbstractIn this study, we investigated the role of protein disulphide isomerase (PDI) in rapid metabolism of S-nitrosoglutathione (GSNO) and S-nitrosoalbumin (albSNO) and in NO delivery from these compounds into cells. Incubation of GSNO or albSNO (1 μM) with the megakaryocyte cell line MEG-01 resulted in a cell-mediated removal of each compound which was inhibited by blocking cell surface thiols with 5, 5'-dithiobis 2-nitrobenzoic acid (DTNB) (100 μM) or inhibiting PDI with bacitracin (5 mM). GSNO, but not albSNO, rapidly inhibited platelet aggregation and stimulated cyclic GMP (cGMP) accumulation (used as a measure of intracellular NO entry). cGMP accumulation in response to GSNO (1 μM) was inhibited by MEG-01 treatment with bacitracin or DTNB, suggesting a role for PDI and surface thiols in NO delivery. PDI activity was present in MEG-01 conditioned medium, and was inhibited by high concentrations of GSNO (500 μM). A number of cell surface thiol-containing proteins were labelled using the impermeable thiol specific probe 3-(N-maleimido-propionyl) biocytin (MPB). Pretreatment of cells with GSNO resulted in a loss of thiol reactivity on some but not all proteins, suggesting selective cell surface thiol modification.Immunoprecipitation experiments showed that GSNO caused a concentrationdependent loss of thiol reactivity of PDI. Our data indicate that PDI is involved in both rapid metabolism of GSNO and intracellular NO delivery and that during this process PDI is itself altered by thiol modification. In contrast, the relevance of PDI-mediated albSNO metabolism to NO signalling is uncertain.3

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“…NO is also known to have many other beneficial effects on the vascular endothelium, including inhibition of vascular smooth muscle cell proliferation, an inhibitory effect on platelet aggregation and adhesion, and inhibition of inflammatory cell activation [30][31][32] . A differentiated BP profile of naproxcinod compared to naproxen and rofecoxib has been shown in a previous phase 2 study 22 .…”

Section: Rheumatologymentioning

confidence: 99%

Efficacy, Safety, and Tolerability of the Cyclooxygenase-Inhibiting Nitric Oxide Donator Naproxcinod in Treating Osteoarthritis of the Hip or Knee

Karlsson¹,

Pivodic²,

Aguirre³

et al. 2009

J Rheumatol

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Objective.Naproxcinod, a cyclooxygenase-inhibiting nitric oxide donator antiinflammatory drug, was evaluated in this phase 2, double-blind, randomized, parallel group study to determine its optimal dose in patients with osteoarthritis (OA).Methods.In total 543 patients with OA of the hip or knee were randomized to receive naproxcinod 750 mg once daily (qd), 750 mg twice daily (bid), 1125 mg bid, rofecoxib 25 mg qd, or placebo for 6 weeks. The primary efficacy variable was the within-patient change from baseline to the average of Weeks 4 and 6 in WOMAC™ pain subscale score. Treatment-group differences were compared using ANCOVA with factors for treatment and country, and baseline pain subscale score as a covariate. Safety endpoints included vital signs and adverse events. Treatment-group differences in mean change from baseline to Week 6 in systolic blood pressure (SBP) were compared using an ANCOVA with treatment and country as fixed factors and baseline SBP as covariate.Results.All active treatments showed statistically significant reductions in WOMAC pain score compared to placebo (p ≤ 0.02). Naproxcinod was well tolerated. The 750 mg bid dose appeared to have the best balance of benefit versus safety. All 3 naproxcinod doses showed a reduction in SBP, while an increase was shown for rofecoxib. The changes for the naproxcinod groups were statistically significantly better compared to rofecoxib (p ≤ 0.02).Conclusion.This dose-finding study identified naproxcinod 750 mg bid as the upper dose for further therapeutic confirmatory clinical trials. Naproxcinod at all doses decreased mean SBP compared to an increase with rofecoxib.

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A potential role for extracellular nitric oxide generation in cGMP‐independent inhibition of human platelet aggregation: biochemical and pharmacological considerations

Cited by 52 publications

References 62 publications

Fatal gastrointestinal obstruction and hypertension in mice lacking nitric oxide-sensitive guanylyl cyclase

Fatal gastrointestinal obstruction and hypertension in mice lacking nitric oxide-sensitive guanylyl cyclase

Interactions between cell surface protein disulphide isomerase and S-nitrosoglutathione during nitric oxide delivery

Efficacy, Safety, and Tolerability of the Cyclooxygenase-Inhibiting Nitric Oxide Donator Naproxcinod in Treating Osteoarthritis of the Hip or Knee

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