Cited by 141Nitric Oxide and Endothelin EffectsCardiovascular Health and Disease PreventionCardiovascular, Neuropeptides, and Oxidative Stress Research

Mechanisms of Inducible Nitric Oxide Synthase–Mediated Vascular Dysfunction

Gunnett, C.A., Lund, D.D., McDowell, A.K., Faraci, F.M., Heistad, D.D.·2005·Arteriosclerosis, Thrombosis, and Vascular Biology

Abstract

Objective— Inducible nitric oxide synthase (iNOS) is expressed in arteries during inflammation and may contribute to vascular dysfunction. Effects of gene transfer of iNOS to carotid arteries were examined in vitro in the absence of systemic inflammation to allow examination of mechanisms by which iNOS impairs contraction and relaxation. Methods and Results— After gene transfer of iNOS with an adenovirus (AdiNOS), constrictor responses to phenylephrine (PE) and U46619 were impaired. After AdiNOS, inhibition of soluble guanylate cyclase (sGC) with 1H-[1,2,4]oxadiazolo-[4,3,2]quinoxalin-1-one (ODQ) reduced the EC 50 for PE from 4.33±0.78 μmol/L to 1.15±0.43 μmol/L (mean±SEM). These results imply that iNOS impairs contraction by activation of the NO/cGMP pathway. Relaxation to acetylcholine (ACh) also was impaired after AdiNOS. Sepiapterin (300 μmol/L), the precursor for tetrahydrobiopterin (BH 4 ), improved relaxation to Ach. Because BH 4 is an essential cofactor for production of NO by both iNOS and endothelial nitric oxide synthase (eNOS), these results suggest that iNOS may reduce production of NO by eNOS by limiting availability of BH 4 . Next, we examined effects of expression of iNOS in endothelium and adventitia. Selective expression of iNOS in endothelium, but not adventitia, impaired contraction to phenylephrine and relaxation to acetylcholine. Conclusions— We conclude that: (1) iNOS may impair contraction in part by activation of sGC; (2) iNOS impairs relaxation, at least in part, by limiting availability of BH 4 ; and (3) expression of iNOS in endothelium may be a more important mediator of vascular dysfunction than expression of iNOS in adventitia.

Integrity signals

Registry

Crossref · 10.1161/01.atv.0000172626.00296.ba

Cites

42 of 42 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Cites

Flagged first, then by citations

Research works printed but not linked: 9

  1. 10.1161/str.27.8.1373 · DOI
  2. 10.1161/atvb.21.8.1281 · DOI
  3. 10.1161/res.34.3.317 · DOI
  4. 10.1161/hyp.33.5.1225 · DOI
  5. 2000, Physiol Res, 49, 19
  6. 1995, Mol Pharmacol, 48, 184
  7. 10.1161/atvb.17.11.2479 · DOI
  8. 1999, Proc Natl Acad Sci, 95, 9220
  9. 2004, Biochem Biophys, 41, 415

Cited by

Sorted by citations

Authors
Gunnett, C. A., Lund, D. D., McDowell, A. K., Faraci, F. M., & Heistad, D. D.
Affiliations
University of Iowa (US)
Venue
Arteriosclerosis, Thrombosis, and Vascular Biology
Published
2005-08
Volume
25
Issue
8
Pages
1617-1622
ISSN
  • 1079-5642 (ISSN-L)
  • 1524-4636
OpenAlex
W2122779791
Cited by
141
References
42
Citations by year
2026: 3 · 2025: 9 · 2024: 8 · 2023: 10 · 2022: 13 · 2021: 5 · 2020: 4 · 2019: 6 · 2018: 6 · 2017: 7 · 2016: 6 · 2015: 10 · 2014: 11 · 2013: 5 · 2012: 3
FWCI
3.21
Type
journal article
Language
en
Open access
closed
Locations
  • Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • U.S. Department of Veterans Affairs
  • Roy J. Carver Charitable Trust
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (HL-16066, P01HL062984, HL-62984, HL38901)
  • National Institute of Neurological Disorders and Stroke (NS24621, P01NS024621)
Topics
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
  • Health Sciences › Medicine › Surgery › Cardiovascular, Neuropeptides, and Oxidative Stress Research
Keywords
inducible nitric oxide synthase, vascular dysfunction, gene transfer, adenoviral vector, soluble guanylate cyclase, NO-cGMP pathway, tetrahydrobiopterin, endothelial nitric oxide synthase, endothelium, adventitia, vasoconstriction, vasorelaxation, acetylcholine, phenylephrine, sepiapterin, inflammation
MeSH terms
Adenoviridae, Animals, Carotid Arteries, Carotid Artery Diseases, Endothelium, Vascular, Male, Rabbits, Vasculitis, Vasoconstriction, Vasodilation, Gene Expression Regulation, Enzymologic, Gene Transfer Techniques, Nitric Oxide Synthase Type II

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review