Neue Erkenntnisse bei der Nitratwirkung, Nitratbioaktivierung und Toleranzentwicklung

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

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