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DOI: 10.1055/s-0028-1091272
© Georg Thieme Verlag KG Stuttgart · New York
Neue Erkenntnisse bei der Nitratwirkung, Nitratbioaktivierung und Toleranzentwicklung
Recent studies on nitrates: their action, bioactivation and development of tolerancePublication History
eingereicht: 10.1.2008
akzeptiert: 31.3.2008
Publication Date:
22 October 2008 (online)

Zusammenfassung
Nitrate stellen nach wie vor eine wichtige Säule in der Therapie des akuten Koronarsyndroms, der stabilen koronaren Herzerkrankung und der akuten und chronischen Herzinsuffizienz dar. Der prinzipielle Mechanismus der Vasodilatation beruht auf der Bildung des Stickstoffmonoxid (NO) oder einem chemisch verwandten Produkt, das die lösliche Guanylatzyklase aktiviert und über einen Abfall der intrazellulären Kalziumkonzentration den Gefäßtonus senkt und damit die Vasodilatation auslöst. Neuere Befunde zeigen, dass die Bioaktivierung hochreaktiver Nitrate wie des Nitroglyzerins (NTG) und des Pentaerthrityltetranitrat (PETN) durch ein mitochondrial lokalisiertes Enzym, der Aldehyddehydrogenase, kurz ALDH-2, bewerkstelligt wird. Das Bioaktivierungsenzym der Mono- und Dinitrate ist nach wie vor unbekannt. Trotz nachweislich guter antiischämischer Wirkung bei der Akut-Gabe ist die chronische Therapie mit organischen Nitraten durch 2 Nebenwirkungen limitiert: der Entwicklung einer Toleranz und einer endothelialen Dysfunktion. Sowohl die Toleranzentwicklung als auch die Nitrat-induzierte endotheliale Dysfunktion sind möglicherweise auf einen identischen Mechanismus, der vermehrten Bildung reaktiver Sauerstoffspezies zurückzuführen. In der Übersichtsarbeit werden neue Aspekte der Nitratbioaktivierung, die Ursachen der Toleranzentwicklung und der Entwicklung der endothelialen Dysfunktion sowie deren therapeutische Konsequenzen diskutiert. Ein weiterer Schwerpunkt sind neuere Ergebnisse bezüglich der NO-Donatoren Molsidomin, PETN, und der Kombinationstherapie bestehend aus dem Isosorbiddinitrat und Hydralazin in der Therapie der stabilen koronaren Herzerkrankung und der chronischen Herzinsuffizienz.
Summary
Organic nitrates still are one of the most important drug classes used in the treatment of an acute coronary syndrome and stable coronary artery disease as well as acute and chronic congestive heart failure. The mechanism of vasodilatation comprises the release of nitric oxide, which in turn activates soluble guanylate cyclase and lowers the intracellular calcium content leading to relaxation of vascular smooth muscle. Recent research has demonstrated that highly reactive nitrates, such as nitroglycerin (or glyceryl trinitrate) and pentaerthrityl tetranitrate (PETN) are bioactivated by aldehyde dehydrogenase 2 (ALDH-2), an enzyme located in mitochondria. The enzyme, which bioactivates mono- and dinitrates is not yet identified. Despite being effective in the acute treatment of patients, its long-term efficacy is limited by the development of tolerance to nitrates and of endothelial dysfunction. Both of these side effects of nitrate therapy are due to increased production of reactive oxygen species. This review focuses on new aspects of the process of bioactivation of organic nitrates, the conception of oxidative stress of endothelial dysfunction and of the development of tolerance and their therapeutic consequences. Also discussed are more recent findings on nitric oxide donors such as molsidomine, PETN and the combination treatment of isosorbide dinitrate and hydralazine of patients with coronary artery disease and chronic heart failure.
Schlüsselwörter
Nitrate - Nitroglyzerin - Stickstoffmonoxid - Pentaerythrityltetranitrat - Medikamententoleranz - Koronare Herzkrankheit
Keywords
nitrates - nitroglycerin - nitric oxide - pentaerythretyl tetranitrate - drug tolerance - coronary heart disease
Literatur
- 1
Abrams J.
Glyceryl trinitrate (nitroglycerin) and the organic nitrates. Choosing
the method of administration.
Drugs.
1987;
34
391-403
MissingFormLabel
- 2
Anand I S, Tam S W, Rector T S. et al .
Influence of blood pressure
on the effectiveness of a fixed-dose combination of isosorbide dinitrate
and hydralazine in the African-American Heart Failure Trial.
J
Am Coll Cardiol.
2007;
49
32-39
MissingFormLabel
- 3
Azevedo E R, Schofield A M, Kelly S, Parker J D.
Nitroglycerin
withdrawal increases endothelium-dependent vasomotor response to
acetylcholine.
J Am Coll Cardiol.
2001;
37
505-509
MissingFormLabel
- 4
Caramori P R, Adelman A G, Azevedo E R. et al .
Therapy with nitroglycerin
increases coronary vasoconstriction in response to acetylcholine.
J Am Coll Cardiol.
1998;
32
1969-1974
MissingFormLabel
- 5
Chen Z, Zhang J, Stamler J S.
Identification of the enzymatic mechanism of nitroglycerin bioactivation.
Proc Natl Acad Sci U S A.
2002;
99
8306-8311
MissingFormLabel
- 6
Cohn J N, Archibald D G, Ziesche S. et al .
Effect of vasodilator therapy on mortality
in chronic congestive heart failure. Results of a Veterans Administration
Cooperative Study.
The New England journal of medicine.
1986;
314
1547-1552
MissingFormLabel
- 7
Cohn J N, Johnson G, Ziesche S. et al .
A comparison of enalapril with hydralazine-isosorbide
dinitrate in the treatment of chronic congestive heart failure.
The New England journal of medicine.
1991;
325
303-310
MissingFormLabel
- 8
Daiber A, Oelze M, Coldewey M. et
al .
Hydralazine is a powerful inhibitor of peroxynitrite
formation as a possible explanation for its beneficial effects on
prognosis in patients with congestive heart failure.
Biochem
Biophys Res Commun.
2005;
338
1865-1874
MissingFormLabel
- 9
Daiber A, Oelze M, Coldewey M. et
al .
Oxidative stress and mitochondrial aldehyde dehydrogenase
activity: a comparison of pentaerythritol tetranitrate with other
organic nitrates.
Mol Pharmacol.
2004;
66
1372-1382
MissingFormLabel
- 10
Esplugues J V, Rocha M, Nunez C. et
al .
Complex I dysfunction and tolerance to nitroglycerin:
an approach based on mitochondrial-targeted antioxidants.
Circ
Res.
2006;
99
1067-1075
MissingFormLabel
- 11
Franciosa J A, Blank R C, Cohn J N.
Nitrate effects on cardiac output and left
ventricular outflow resistance in chronic congestive heart failure.
Am J Med.
1978;
64
207-213
MissingFormLabel
- 12
Franciosa J A, Cohn J N.
Hemodynamic responsiveness
to short- and long-acting vasodilators in left ventricular failure.
Am J Med.
1978;
65
126-133
MissingFormLabel
- 13
Gogia H, Mehra A, Parikh S. et
al .
Prevention of tolerance to hemodynamic effects
of nitrates with concomitant use of hydralazine in patients with
chronic heart failure.
J Am Coll Cardiol.
1995;
26
1575-1580
MissingFormLabel
- 14
Gori T, Burstein J M, Ahmed S. et al .
Folic acid prevents nitroglycerin-induced
nitric oxide synthase dysfunction and nitrate tolerance: a human
in vivo study.
Circulation.
2001;
104
1119-1123
MissingFormLabel
- 15
Gori T, Mak S S, Kelly S, Parker J D.
Evidence supporting
abnormalities in nitric oxide synthase function induced by nitroglycerin
in humans.
J Am Coll Cardiol.
2001;
38
1096-1101
MissingFormLabel
- 16
Heitzer T, Schlinzig T, Krohn K, Meinertz T, Munzel T.
Endothelial dysfunction, oxidative stress, and risk of cardiovascular
events in patients with coronary artery disease.
Circulation.
2001;
104
2673-2678
MissingFormLabel
- 17
Hink U, Oelze M, Kolb P. et
al .
Role for peroxynitrite in the inhibition of prostacyclin
synthase in nitrate tolerance.
J Am Coll Cardiol.
2003;
42
1826-1834
MissingFormLabel
- 18
Jurt U, Gori T, Ravandi A. et
al .
Differential effects of pentaerythritol tetranitrate
and nitroglycerin on the development of tolerance and evidence of
lipid peroxidation: a human in vivo study.
J Am Coll Cardiol.
2001;
38
854-859
MissingFormLabel
- 19
Kuzkaya N, Weissmann N, Harrison D G, Dikalov S.
Interactions
of peroxynitrite, tetrahydrobiopterin, ascorbic acid, and thiols:
implications for uncoupling endothelial nitric-oxide synthase.
J Biol Chem.
2003;
278
22546-22554
MissingFormLabel
- 20
Munzel T, Daiber A, Mulsch A.
Explaining the phenomenon of nitrate tolerance.
Circ
Res.
2005;
97
618-628
MissingFormLabel
- 21
Munzel T, Feil R, Mulsch A. et
al .
Physiology and pathophysiology of vascular signaling
controlled by guanosine 3’,5’-cyclic monophosphate-dependent
protein kinase [corrected].
Circulation.
2003;
108
2172-2183
MissingFormLabel
- 22
Munzel T, Giaid A, Kurz S, Stewart D J, Harrison D G.
Evidence for a role of endothelin 1 and protein kinase C in
nitroglycerin tolerance.
Proc Natl Acad Sci U S A.
1995;
92
5244-5248
MissingFormLabel
- 23
Munzel T, Heitzer T, Kurz S. et
al .
Dissociation of coronary vascular tolerance and
neurohormonal adjustments during long-term nitroglycerin therapy
in patients with stable coronary artery disease.
J Am Coll
Cardiol.
1996;
27
297-303
MissingFormLabel
- 24
Munzel T, Sayegh H, Freeman B A, Tarpey M M, Harrison D G.
Evidence for enhanced vascular superoxide
anion production in nitrate tolerance. A novel mechanism underlying
tolerance and cross-tolerance.
J Clin Invest.
1995;
95
187-194
MissingFormLabel
- 25
Oberle S, Abate A, Grosser N. et
al .
Endothelial protection by pentaerithrityl trinitrate:
bilirubin and carbon monoxide as possible mediators.
Exp
Biol Med (Maywood).
2003;
228
529-534
MissingFormLabel
- 26
Pfeifer A, Klatt P, Massberg S. et al .
Defective smooth muscle regulation in cGMP
kinase I-deficient mice.
Embo J.
1998;
17
3045-3051
MissingFormLabel
- 27
Silber S.
Nitrates: why and how should they be used today? Current status
of the clinical usefulness of nitroglycerin, isosorbide dinitrate and
isosorbide-5-mononitrate.
Eur J Clin Pharmacol.
1990;
38 Suppl 1
S35-51
MissingFormLabel
- 28
Taylor A L, Ziesche S, Yancy C. et al .
Combination of isosorbide dinitrate and
hydralazine in blacks with heart failure.
The New England journal
of medicine.
2004;
351
2049-2057
MissingFormLabel
- 29
Thomas G R, DiFabio J M, Gori T, Parker J D.
Once daily
therapy with isosorbide-5-mononitrate causes endothelial dysfunction
in humans: evidence of a free-radical-mediated mechanism.
J
Am Coll Cardiol.
2007;
49
1289-1295
MissingFormLabel
- 30
Thum T, Fraccarollo D, Thum S, Schultheiss M, Daiber A, Wenzel P, Munzel T, Ertl G, Bauersachs J.
Differential effects of organic nitrates on endothelial progenitor
cells are determined by oxidative stress.
Arterioscler
Thromb Vasc Biol..
2007;
27
748-754
MissingFormLabel
- 31
Wenzel P, Hink U, Oelze M. et
al .
Number of nitrate groups determines reactivity
and potency of organic nitrates: a proof of concept study in ALDH-2-/-
mice.
Br J Pharmacol.
2007;
150
526-533
MissingFormLabel
- 32
Wenzel P, Oelze M, Coldewey M. et
al .
Heme oxygenase-1: a novel key player in the development
of tolerance in response to organic nitrates.
Arterioscler
Thromb Vasc Biol.
2007;
27
1729-1735
MissingFormLabel
Prof. Dr. Thomas Münzel
II Medizinische Klinik für Kardiologie, Angiologie
und internistische Intensivmedizin, Johannes Gutenberg Universität
Mainz
Langenbeckstrasse 1
55131 Mainz
Phone: 06131/17-7250
Fax: 06131/17-6613
Email: tmuenzel@uni-mainz.de