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The physiology and pathophysiology of the nitric oxide/superoxide system

Physiologie und Pathophysiologie des Stickstoffmonoxid-Superoxid-Systems

  • Coronary Atherosclerosis
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Summary

The endothelium modulates vascular tone by producing vasodilator vasoconstrictor substances. Of these, the most well characterized and potentially important are NO and.O2 −. These small molecules exhibit opposing effects on vascular tone, and chemically react with each other in a fashion which negates their individual effects and leads to the production of potentially toxic substances. These dynamic interactions may likely have important implications, altering not only tissue perfusion but also contributing to the process of atherosclerosis..NO is produced in endothelial cells by an enzyme termed nitric oxide synthase. The endothelial.NO-synthase is activated when the intracellular level of calcium is increased. This occurs in response to neurohormonal stimuli and in response to shear stress. Acetylcholine and substance P are examples of neurohumoral substances that are able to stimulate the release of nitric oxide and to assess endothelial regulation of vasomotor tone. Importantly, the vasodilator potency of nitric oxide released by the endothelium is abnormal in a variety of diseased states such as hypercholesterolemia, atherosclerosis and diabetes mellitus. This may be secondary to decreased synthesis of nitric oxide or increased degradation of nitric oxide due to superoxide anions. More recent experimental observations demonstrate increased production of superoxide in atherosclerosis, diabetes mellitus and high renin hypertension suggesting that endothelial dysfunction in these states is rather secondary to increased.NO metabolism rather than due to decreased synthesis of.NO. Superoxide rapidly reacts with nitric oxide to form the highly reactive intermediate peroxynitrite (ONOO−). Peroxynitrite can be protonated to form peroxynitrous acid which in turn can yield the hydroxyl radical (OH.). These reactive species can oxidize lipids, damage cell membranes, and oxidize thiol groups..NO given locally, exerts potent antiatherosclerotic effects such as inhibition of platelet aggregation, inhibition of adhesion of leukocytes and the expression of leukocyte adhesion molecules. It is important to note, however, that in-vivo treatment with.NO (via organic nitrates) increases rather than decreases oxidant load within endothelial cells. It remains therefore questionable whether systemic treatment with.NO may have antiatherosclerotic properties or whether.NO may initiate or even accelerate the atherosclerotic process.

Zusammenfassung

Das Endothel reguliert durch die Produktion vasodilatierender und vaskonstriktorisch wirkender Substanzen in entscheidendem Maße den Gefäßtonus. Zu den am besten charakterisierten Molekülen gehören Stickstoffmonoxid (.NO) und das Superoxidanion (.O2 −)..NO wird im Endothel durch das Enzym.NO-Synthase aus der Aminosäure L-Arginin gebildet. Die wichtigsten physiologischen Stimuli zur.NO-Bildung sind die pulsatile Dehnung der Gefäßwand sowie die Scherkräfte, die auf das Endothel einwirken. Pharmakologisch kann die Freisetzung von.NO in vitro und in vivo durch die Gabe von Acetylcholin induziert werden, ein Verfahren, das mit Erfolg zur Endothelfunktionsdiagnostik in peripheren Arterien und Koronararterien eingesetzt wird. Die vasodilatierende Wirkung von.NO ist im Rahmen von verschiedenen Erkrankungen wie arterielle Hypertonie, Hypercholesterinämie und Diabetes mellitus deutlich abgeschwächt. Dies kann jedoch nicht auf eine verminderte.NO-Bildung zurückgeführt werden, da die Aktivität bzw. die Expression des Enzyms endotheliale.NO-Synthase bei diesen Erkrankungen eher kompensatorisch gesteigert als abgeschwächt ist. Neuere tierexperimentelle Untersuchungen konnten nachweisen, daß bei diesen Krankheitsbildern die endotheliale Superoxidproduktion ebenfalls angekurbelt ist. Somit kommt einem erhöhten.NO-Metabolismus durch.O2 − reagiert rasch mit.NO unter der Bildung des instabilen Metaboliten Peroxynitrit (ONOO−). Durch eine Protonierungsreaktion kann letztendlich das Hydroxylradikal entstehen, das wiederum Lipide und Thiolgruppen oxidieren und Membranen schädigen kann. In vitro konnten für.NO vielschichtige antiarteriosklerotische Eigenschaften. wie zum Beispiel Inhibition der Expression von Leukozytenadhäsionsmolekülen und Inhibition der Plättchenaggregation, nachgewiesen werden. In-vivo-Behandlung mit.NO (zum Beispiel in Form von Nitroglycerin) führt in Tiermodellen nachweislich eher zu einer Steigerung als zu einer Reduktion der endothelialen Superoxidbildung. Somit bleibt abzuwarten, ob durch eine Therapie mit.NO der bei Patienten mit manifester koronarer Herzkrankheit (und somit erhöhtem oxidativen Streß in der Gefäßwand) die Arteriosklerose positiv beeinflußt wird oder ob durch die Invivo-.NO-Gabe der arteriosklerotische Prozeß nicht eher beschleunigt wird.

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  1. the Emory University, Atlanta, GA, USA

    T. Münzel, T. Heitzer & D. G. Harrison

  2. Abteilung für Kardiologie, Universitätsklinik Eppendorf, Martinistraße 52, D-20246, Hamburg, Germany

    T. Münzel, T. Heitzer & D. G. Harrison

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  1. T. Münzel
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  2. T. Heitzer
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  3. D. G. Harrison
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Münzel, T., Heitzer, T. & Harrison, D.G. The physiology and pathophysiology of the nitric oxide/superoxide system. Herz 22, 158–172 (1997). https://doi.org/10.1007/BF03044353

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