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.
T Münzel, H Sayegh, B A Freeman, M M Tarpey, D G Harrison
Title and authors | Publication | Year |
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Pulmonary surfactant: an immunological perspective
ZC Chroneos, Z Sever-Chroneos, VL Shepherd |
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology | 2009 |
Pharmacological induction of vascular extracellular superoxide dismutase expressionin vivo
M Oppermann, V Balz, V Adams, VT Dao, M Bas, T Suvorava, G Kojda |
Journal of Cellular and Molecular Medicine | 2009 |
cGMP: Generators, Effectors and Therapeutic Implications
HH Schmidt, F Hofmann, JP Stasch |
Handbook of experimental pharmacology | 2009 |
cGMP: Generators, Effectors and Therapeutic Implications
HH Schmidt, F Hofmann, JP Stasch |
Handbook of experimental pharmacology | 2009 |
cGMP: Generators, Effectors and Therapeutic Implications
HH Schmidt, F Hofmann, JP Stasch |
Handbook of experimental pharmacology | 2009 |
cGMP: Generators, Effectors and Therapeutic Implications
HH Schmidt, F Hofmann, JP Stasch |
Handbook of experimental pharmacology | 2009 |
cGMP: Generators, Effectors and Therapeutic Implications
HH Schmidt, F Hofmann, JP Stasch |
Handbook of experimental pharmacology | 2009 |
cGMP: Generators, Effectors and Therapeutic Implications
HH Schmidt, F Hofmann, JP Stasch |
Handbook of experimental pharmacology | 2009 |
cGMP: Generators, Effectors and Therapeutic Implications
HH Schmidt, F Hofmann, JP Stasch |
Handbook of experimental pharmacology | 2009 |
cGMP: Generators, Effectors and Therapeutic Implications
HH Schmidt, F Hofmann, JP Stasch |
Handbook of experimental pharmacology | 2009 |
cGMP: Generators, Effectors and Therapeutic Implications
HH Schmidt, F Hofmann, JP Stasch |
Handbook of experimental pharmacology | 2009 |
cGMP: Generators, Effectors and Therapeutic Implications
HH Schmidt, F Hofmann, JP Stasch |
Handbook of experimental pharmacology | 2009 |
cGMP: Generators, Effectors and Therapeutic Implications
HH Schmidt, F Hofmann, JP Stasch |
Handbook of experimental pharmacology | 2009 |
cGMP: Generators, Effectors and Therapeutic Implications
HH Schmidt, F Hofmann, JP Stasch |
Handbook of experimental pharmacology | 2009 |
cGMP: Generators, Effectors and Therapeutic Implications
HH Schmidt, F Hofmann, JP Stasch |
Handbook of experimental pharmacology | 2009 |
cGMP: Generators, Effectors and Therapeutic Implications
HH Schmidt, F Hofmann, JP Stasch |
Handbook of experimental pharmacology | 2009 |
cGMP: Generators, Effectors and Therapeutic Implications
HH Schmidt, F Hofmann, JP Stasch |
Handbook of experimental pharmacology | 2009 |
cGMP: Generators, Effectors and Therapeutic Implications
HH Schmidt, F Hofmann, JP Stasch |
Handbook of experimental pharmacology | 2009 |
A new class of organic nitrates: investigations on bioactivation, tolerance and cross-tolerance phenomena
S Schuhmacher, E Schulz, M Oelze, A König, C Roegler, K Lange, L Sydow, T Kawamoto, P Wenzel, T Münzel, J Lehmann, A Daiber |
British Journal of Pharmacology | 2009 |
Monitoring white blood cell mitochondrial aldehyde dehydrogenase activity: implications for nitrate therapy in humans
P Wenzel, E Schulz, T Gori, MA Ostad, F Mäthner, S Schildknecht, S Göbel, M Oelze, D Stalleicken, A Warnholtz, T Münzel, A Daiber |
The Journal of pharmacology and experimental therapeutics | 2009 |
Advanced Protocols in Oxidative Stress II
D Armstrong |
2009 | |
Advanced Protocols in Oxidative Stress II
D Armstrong |
2009 | |
Effect of Chronic Inhibition of Nitric Oxide on Hypertension, Insulin Resistance, and Cardiovascular Remodeling in Glucose-fed Rats
M Pilon, R Wu, JÉ Huot-Marchand, D deBlois, J Champlain, R Couture |
Journal of Cardiovascular Pharmacology | 2009 |
Understanding organic nitrates - a vein hope?
MR Miller, RM Wadsworth |
British Journal of Pharmacology | 2009 |
Degradation of leucine zipper-positive isoform of MYPT1 may contribute to development of nitrate tolerance
D Dou, H Ma, X Zheng, L Ying, Y Guo, X Yu, Y Gao |
Cardiovascular Research | 2009 |
Nitroglycerin Headache and Nitroglycerin-Induced Primary Headaches From 1846 and Onwards: A Historical Overview and an Update
PC Tfelt-Hansen, J Tfelt-Hansen |
Headache: The Journal of Head and Face Pain | 2009 |
Continuous therapy with transdermal nitroglycerin does not affect biomarkers of vascular inflammation and injury in healthy volunteers
GR Thomas, JM DiFabio, T Gori, DJ Jenkins, JD Parker |
Canadian Journal of Physiology and Pharmacology | 2009 |
Mitochondrial aldehyde dehydrogenase (ALDH-2)—Maker of and marker for nitrate tolerance in response to nitroglycerin treatment
A Daiber, P Wenzel, M Oelze, S Schuhmacher, T Jansen, T Münzel |
Chemico-Biological Interactions | 2009 |
Non-Hemodynamic Effects of Organic Nitrates and the Distinctive Characteristics of Pentaerithrityl Tetranitrate
T Gori, A Daiber |
American Journal Cardiovascular Drugs | 2009 |
Statins for post resuscitation syndrome
A Kämäräinen, I Virkkunen, T Silfvast, J Tenhunen |
Medical Hypotheses | 2009 |
Nitrate tolerance as a model of vascular dysfunction: Roles for mitochondrial aldehyde dehydrogenase and mitochondrial oxidative stress
A Daiber, M Oelze, P Wenzel, JM Wickramanayake, S Schuhmacher, T Jansen, KJ Lackner, M Torzewski, T Münzel |
Pharmacological Reports | 2009 |
New biomaterials for the sustained release of nitric oxide: past, present and future
A Friedman, J Friedman |
Expert Opinion on Drug Delivery | 2009 |
Effects of nitroglycerin or pentaerithrityl tetranitrate treatment on the gene expression in rat hearts: evidence for cardiotoxic and cardioprotective effects
A Pautz, P Rauschkolb, N Schmidt, J Art, M Oelze, P Wenzel, U Förstermann, A Daiber, H Kleinert |
Physiological genomics | 2009 |
Role of Glutaredoxin-Mediated Protein S -Glutathionylation in Cellular Nitroglycerin Tolerance
PS Tsou, V Addanki, JA Haas, NA Page, HL Fung |
The Journal of pharmacology and experimental therapeutics | 2009 |