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Cited by 102Nitric Oxide and Endothelin EffectsInflammatory mediators and NSAID effectsEicosanoids and Hypertension Pharmacology

Cyclooxygenase-2 Inhibition Improves Vascular Endothelial Dysfunction in a Rat Model of Endotoxic Shock: Role of Inducible Nitric-Oxide Synthase and Oxidative Stress

Virdis, Agostino, Colucci, Rocchina, Fornai, Matteo, Blandizzi, Corrado, Duranti, Emiliano, Pinto, Stefania, Bernardini, Nunzia, Segnani, Cristina +4 more·2005·The Journal of Pharmacology and Experimental Therapeutics
DOI 10.1124/jpet.104.077644
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Abstract

We investigated whether cyclooxygenase (COX) isoforms (COX-1 and COX-2) and decreased NO availability contribute to endothelial dysfunction in endotoxemic rats. The involvement of reactive oxygen species (ROS) was also evaluated. Rats were injected with Salmonella-derived lipopolysaccharide or saline. After 6 h, endothelial function of mesenteric resistance arteries was evaluated. In controls, acetylcholine (ACh)-induced relaxation was inhibited by the nitric-oxide synthase inhibitor N(G)-monomethyl-l-arginine (l-NMMA) and unaffected by 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl)-phenyl-2(5H)-furanone (DFU) (COX-2 inhibitor). In lipopolysaccharide (LPS)-treated rats, the response to ACh was blunted compared with controls, less sensitive to l-NMMA, and enhanced by DFU. COX-2 blockade also improved the inhibitory effect of l-NMMA on cholinergic relaxation. SC-560 [5-(4-clorophenyl)-1-(4-metoxyphenyl)-3-trifluoromethylpirazole] (COX-1 inhibitor) did not modify the response to ACh in both groups. LPS-induced endothelial dysfunction was unaffected by the thromboxane A(2) (TxA(2)) receptor antagonist SQ-29548 (7-[3-[[2-[(phenylamino)carbonyl]hydrazino]methyl]-7-oxabicyclo[2.2.1] hept-2-yl]-[1S(1alpha,2alpha(Z),3alpha,4alpha)]-5-heptenoic acid). In vivo inducible nitric-oxide synthase (iNOS) inhibition by S-methylisothiourea partly attenuated LPS-induced endothelial dysfunction. The antioxidants ascorbic acid and superoxide dismutase normalized endothelium-dependent relaxation and restored the inhibitory action of l-NMMA on ACh. Responses to sodium nitroprusside were similar in both groups. In LPS-treated rats, reverse transcription-polymerase chain reaction showed a marked increase in mesenteric iNOS and COX-2 expressions, whereas endothelial nitric-oxide synthase and COX-1 were unchanged. LPS-induced COX-2 overexpression was reduced but not abrogated by S-methylisothiourea. LPS-induced COX-2 up-regulation was also documented by immunohistochemistry. In conclusion, mesenteric resistance vessels from endotoxemic rats show impaired endothelial function due to reduced NO availability, a condition that is partly ascribable to an iNOS-dependent enhanced COX-2 expression, whereas TxA(2) does not seem to be involved. Oxidative stress is the main mechanism responsible for reduced NO availability, and COX-2 might act as a source of ROS.

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  • Supplementation of folic acid (5-methyltetrahydrofolate) shows positive effects on eNOS function.

    “Supplementation of folic acid (5-methyltetrahydrofolate) shows positive effects on eNOS function (900, 978) and has been shown to prevent nitroglycerin tolerance in short-term human studies (375).”

    From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [978]

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Authors
Virdis, A., Colucci, R., Fornai, M., Blandizzi, C., Duranti, E., Pinto, S., Bernardini, N., Segnani, C., Antonioli, L., Taddei, S., Salvetti, A., & Del Tacca, M.
Affiliations
University of Pisa (IT)
ORCID
Venue
The Journal of Pharmacology and Experimental Therapeutics
Publisher
Elsevier BV
Published
2005-03
Volume
312
Issue
3
Pages
945-953
ISSN
0022-3565 (ISSN-L)
DOI
10.1124/jpet.104.077644
OpenAlex
W2162932559
Cited by
102
References
39
Citations by year
2026: 1 · 2025: 4 · 2024: 3 · 2023: 5 · 2022: 1 · 2021: 3 · 2020: 2 · 2019: 1 · 2018: 5 · 2017: 3 · 2016: 6 · 2015: 8 · 2014: 5 · 2013: 4 · 2012: 2
FWCI
5.91
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
  • PubMed (publishedVersion)
  • CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
  • Padua Research Archive (University of Padova) (submittedVersion)
Topics
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Health Sciences › Medicine › Pharmacology › Inflammatory mediators and NSAID effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
Keywords
COX-2 inhibition, endothelial dysfunction, endotoxic shock, lipopolysaccharide, inducible nitric oxide synthase, oxidative stress, reactive oxygen species, nitric oxide, mesenteric resistance arteries, acetylcholine-induced relaxation, thromboxane A2 receptor, S-methylisothiourea, superoxide dismutase, vitamin C
MeSH terms
Acetylcholine, Animals, Ascorbic Acid, Endothelium, Vascular, Male, Norepinephrine, Prostaglandin-Endoperoxide Synthases, Pyrazoles, Shock, Septic, Superoxide Dismutase, Vascular Resistance, Vasoconstriction, Cytokines, Cyclooxygenase Inhibitors, Rats, Sprague-Dawley, Oxidative Stress, Nitric Oxide Synthase, omega-N-Methylarginine, Reverse Transcriptase Polymerase Chain Reaction, Rats, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, Nitric Oxide Synthase Type II

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