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Citations to this article

Evidence for enhanced vascular superoxide anion production in nitrate tolerance. A novel mechanism underlying tolerance and cross-tolerance.
T Münzel, … , M M Tarpey, D G Harrison
T Münzel, … , M M Tarpey, D G Harrison
Published January 1, 1995
Citation Information: J Clin Invest. 1995;95(1):187-194. https://doi.org/10.1172/JCI117637.
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Research Article Article has an altmetric score of 9

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

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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.

Authors

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

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Total citations by year

Year: 2025 2023 2022 2021 2020 2019 2018 2017 2016 2015 2014 2013 2012 2011 2010 2009 2008 2007 2006 2005 2004 2003 2002 2001 2000 1999 1998 1997 1996 1995 1991 1970 Total
Citations: 1 2 1 5 3 3 7 13 8 4 8 21 16 11 16 34 19 24 18 28 27 29 38 33 29 32 49 27 23 6 4 1 540
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Citations to this article in year 2015 (4)

Title and authors Publication Year
Organic nitrate therapy, nitrate tolerance and nitrate induced endothelial dysfunction – emphasis on redox biology and oxidative stress
A Daiber, T Münzel
Antioxidants & Redox Signaling 2015
Effect of soluble guanylyl cyclase activator and stimulator therapy on nitroglycerin-induced nitrate tolerance in rats
A Jabs, M Oelze, Y Mikhed, P Stamm, S Kröller-Schön, P Welschof, T Jansen, M Hausding, M Kopp, S Steven, E Schulz, JP Stasch, T Münzel, A Daiber
Vascular Pharmacology 2015
Factors Associated with Nitric Oxide-mediated β 2 Integrin Inhibition of Neutrophils
VM Bhopale, M Yang, K Yu, SR Thom
The Journal of biological chemistry 2015
Effects of Alpha-Lipoic Acid on Oxidative Stress and Kinin Receptor Expression in Obese Zucker Diabetic Fatty Rats
AE Midaoui
Journal of Diabetes & Metabolism 2015

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