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Research Article Free access | 10.1172/JCI117637

Evidence for enhanced vascular superoxide anion production in nitrate tolerance. A novel mechanism underlying tolerance and cross-tolerance.

T Münzel, H Sayegh, B A Freeman, M M Tarpey, and D G Harrison

Department of Medicine, Emory University School of Medicine, Atlanta Veterans Administration Medical Center, Georgia 30322.

Find articles by Münzel, T. in: JCI | PubMed | Google Scholar

Department of Medicine, Emory University School of Medicine, Atlanta Veterans Administration Medical Center, Georgia 30322.

Find articles by Sayegh, H. in: JCI | PubMed | Google Scholar

Department of Medicine, Emory University School of Medicine, Atlanta Veterans Administration Medical Center, Georgia 30322.

Find articles by Freeman, B. in: JCI | PubMed | Google Scholar

Department of Medicine, Emory University School of Medicine, Atlanta Veterans Administration Medical Center, Georgia 30322.

Find articles by Tarpey, M. in: JCI | PubMed | Google Scholar

Department of Medicine, Emory University School of Medicine, Atlanta Veterans Administration Medical Center, Georgia 30322.

Find articles by Harrison, D. in: JCI | PubMed | Google Scholar

Published January 1, 1995 - More info

Published in Volume 95, Issue 1 on January 1, 1995
J Clin Invest. 1995;95(1):187–194. https://doi.org/10.1172/JCI117637.
© 1995 The American Society for Clinical Investigation
Published January 1, 1995 - Version history
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Abstract

We sought to examine mechanisms underlying nitroglycerin (NTG) tolerance and "cross-tolerance" to other nitrovasodilators. Rabbits were treated for 3 d with NTG patches (0.4 mg/h) and their aortic segments studied in organ chambers. Relaxations were examined after preconstriction with phenylephrine. In NTG tolerant rabbit aorta, relaxations to cGMP-dependent vasodilators such as NTG (45 +/- 6%), SIN-1 (69 +/- 7%), and acetylcholine (ACh, 64 +/- 5%) were attenuated vs. controls, (90 +/- 2, 94 +/- 3, and 89 +/- 2% respectively, P < 0.05 for all), while responses to the cAMP-dependent vasodilator forskolin remained unchanged. In tolerant aorta, endothelial removal markedly enhanced relaxations to NTG and SIN-1 (82 +/- 4 and 95 +/- 3%, respectively). Other studies were performed to determine how the endothelium enhances tolerance. Vascular steady state .-O2 levels (assessed by lucigenin chemiluminescence) was increased twofold in tolerant vs. control vessels with endothelium (0.31 +/- 0.01 vs. 0.61 +/- 0.01 nmol/mg per minute). This difference was less in vessels after denudation of the endothelium. Diphenylene iodonium, an inhibitor of flavoprotein containing oxidases, and Tiron a direct .-O2 scavenger normalized .-O2 levels. In contrast, oxypurinol (1 mM) an inhibitor of xanthine oxidase, rotenone (50 microM) an inhibitor of mitochondrial electron transport and NG-nitro-L-arginine (100 microM) an inhibitor of nitric oxide synthase did not affect the chemiluminescence signals from NTG-tolerant aortas. Pretreatment of tolerant aorta with liposome-entrapped, pH sensitive superoxide dismutase (600 U/ml) significantly enhanced maximal relaxation in response to NTG, SIN-1, and ACh, and effectively reduced chemiluminescence signals. These studies show that continuous NTG treatment is associated with increased vascular .-O2-production and consequent inhibition of NO. mediated vasorelaxation produced by both exogenous and endogenous nitrovasodilators.

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