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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Profiles in Cardiology
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Clinical Cardiology | 2007 |
Once Daily Therapy With Isosorbide-5-Mononitrate Causes Endothelial Dysfunction in Humans
GR Thomas, JM DiFabio, T Gori, JD Parker |
Journal of the American College of Cardiology | 2007 |
Recent developments in nitric oxide donor drugs
MR Miller, IL Megson |
British Journal of Pharmacology | 2007 |
Oxidative Inhibition of the Mitochondrial Aldehyde Dehydrogenase Promotes Nitroglycerin Tolerance in Human Blood Vessels
U Hink, A Daiber, N Kayhan, J Trischler, C Kraatz, M Oelze, H Mollnau, P Wenzel, CF Vahl, KK Ho, H Weiner, T Munzel |
Journal of the American College of Cardiology | 2007 |
Nitroglycerin protects the endothelium from ischaemia and reperfusion: human mechanistic insight
T Gori, GD Stolfo, S Sicuro, S Dragoni, M Lisi, S Forconi, JD Parker |
British Journal of Clinical Pharmacology | 2007 |
New insights into bioactivation of organic nitrates, nitrate tolerance and cross-tolerance
A Daiber, P Wenzel, M Oelze, T Münzel |
Clinical Research in Cardiology | 2007 |
Number of nitrate groups determines reactivity and potency of organic nitrates: a proof of concept study in ALDH-2−/− mice
P Wenzel, U Hink, M Oelze, A Seeling, T Isse, K Bruns, L Steinhoff, M Brandt, AL Kleschyov, E Schulz, K Lange, H Weiner, J Lehmann, KJ Lackner, T Kawamoto, T Münzel, A Daiber |
British Journal of Pharmacology | 2007 |
Increased superoxide production in nitrate tolerance is associated with NAD(P)H oxidase and aldehyde dehydrogenase 2 downregulation
K Szöcs, B Lassègue, P Wenzel, M Wendt, A Daiber, M Oelze, T Meinertz, T Münzel, S Baldus |
Journal of Molecular and Cellular Cardiology | 2007 |
Desensitization of soluble guanylyl cyclase, the NO receptor, by S-nitrosylation
N Sayed, P Baskaran, X Ma, F Akker, A Beuve |
Proceedings of the National Academy of Sciences | 2007 |
The kinin B1receptor antagonist SSR240612 reverses tactile and cold allodynia in an experimental rat model of insulin resistance
JP Dias, MA Ismael, M Pilon, J Champlain, B Ferrari, P Carayon, R Couture |
British Journal of Pharmacology | 2007 |
Cellular, molecular and clinical aspects of vitamin E on atherosclerosis prevention
A Munteanu, JM Zingg |
Molecular Aspects of Medicine | 2007 |
Involvement of thromboxane A2 receptor in the cerebrovascular damage of salt-loaded, stroke-prone rats
T Ishizuka, A Niwa, M Tabuchi, Y Nagatani, K Ooshima, H Higashino |
Journal of Hypertension | 2007 |
Do We Still Need Organic Nitrates?⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology
T Münzel, P Wenzel, A Daiber |
Journal of the American College of Cardiology | 2007 |
Evaluation of Pharmacological Modulation of Nitroglycerin-Induced Impairment of Nitric Oxide Bioavailability by a Catheter-Type Nitric Oxide Sensor
T Imanishi, A Kuroi, H Ikejima, S Mochizuki, M Goto, T Akasaka |
Circulation Journal | 2007 |
Nitratbehandlung
T Münzel, F Post |
Clinical Research in Cardiology Supplements | 2007 |
Risk of Mortality with Vitamin E Supplements: The Cache County Study
KM Hayden, KA Welsh-Bohmer, HJ Wengreen, PP Zandi, CG Lyketsos, JC Breitner |
The American Journal of Medicine | 2007 |
Chronic nitrates blunt the effects of not only nitric oxide but also natriuretic peptides in cardiac myocytes
T Tan, Q Zhang, C Anyadike, PM Scholz, HR Weiss |
Pharmacological research : the official journal of the Italian Pharmacological Society | 2007 |
Role of endogenous hydrogen peroxide in the development of nitrate tolerance
S Ghatta, RB Hemmer, S Uppala, ST O'Rourke |
Vascular Pharmacology | 2007 |
Ozonized autohemotransfusion does not affect arterial vasodilation in patients with peripheral arterial disease
A Coppola, L Coppola, C Luongo, A Arciello, F Cacciapuoti, D Lama, M Luongo, L Ruggiero, A Pastore, G Gombos |
International Journal of Angiology | 2007 |
Cardiovascular Therapeutics
MJ Landzberg |
Cardiovascular Therapeutics | 2007 |
Reduction in soluble guanylyl cyclase-specific activity following prolonged treatment of porcine pulmonary artery with nitric oxide
WJ Perkins, M Taniguchi, DO Warner, EN Chini, KA Jones |
American journal of physiology. Lung cellular and molecular physiology | 2007 |
Organic Nitrates and Tolerance in Cardiovascular Diseases: Effects of Isosorbide-2-Mononitrate Compared to Traditional Nitrates
R Raddino, G Caretta, D Robba, G Zanini, I Bonadei, A Madureri, LD Cas |
Heart International | 2007 |
Endothelial Dysfunction in Heart Failure and Ischemic Heart Disease: Rationale for the Clinical use of Mononitrates
O Parodi, RD Maria, E Roubina |
Heart International | 2007 |
In Vitro Tolerance of Mononitrates and Effects on Aggregation of Blood Platelets
E Lampa, A Filippelli |
Heart International | 2007 |