Das NO/cGMP-Signaltransduktionssystem: Ein zentraler Angriffspunkt von Anästhetika?

Zusammenfassung.

Stickstoffmonoxid (NO) ist ein inter- und intrazellulärer Botenstoff, dessen Identität und physiologische Funktion erst innerhalb der letzten Jahre beschrieben worden ist. NO wird von vielen Geweben einschließlich neuronalem Gewebe durch das Enzym NO-Synthase synthetisiert. Bisher sind drei Isoformen der NO-Synthase beschrieben worden: die endotheliale NO-Synthase, die immunologische NO-Synthase sowie die neuronale NO-Synthase. In der Zelle bewirkt NO über eine Aktivierung der Guanylylcyclase einen Anstieg der Konzentration von zyklischem Guanosinmonophosphat (cGMP). Sowohl volatile, als auch intravenös applizierte Allgemeinanästhetika können den Metabolismus von NO beeinflussen. Darüber hinaus wurde demonstriert, daß Inhalationsanästhetika, intravenöse Anästhetika aber auch andere Substanzen, die einen hypnotischen Effekt hervorrufen wie zum Beispiel α₂-Adrenozeptoragonisten, in ihrer hypnotisch-anästhetischen Wirkung durch eine Inhibition der NO-Synthase verstärkt werden. Verschiedene Interaktionen von Anästhetika auf den NO/cGMP-Metabolismus sind denkbar: auf Rezeptorebene, an der NO-Synthase sowie an der Guanylylcyclase. Gemeinsame Endstrecke des NO/cGMP-Signaltransduktionswegs ist die Konzentration von cGMP. Dieser second messenger reguliert die Aktivität von Proteinkinasen, Phosphodiesterasen und Ionenkanälen. Die Bedeutung dieser Strukturen für die hypnotisch-anästhetische Wirkung von Anästhetika ist bislang noch nicht ausreichend geklärt. Neuere Befunde an Knockout-Mäusen, die keine neuronale NO-Synthaseaktivität aufweisen sowie an chronisch mit NO-Synthaseinhibitoren behandelten Tieren deuten darauf hin, daß neben dem NO/cGMP-Metabolismus andere für die Wirkung von Anästhetika notwendige Signaltransduktionsmechanismen existieren.

Abstract

The identity and physiologic function of nitric oxide (NO) as an intra- and intercellular transmitter substance have only been recogniced during the last years. A variety of tissues including neuronal tissue is able to synthesize NO catalysed by the enzyme NO-synthase. Three isoforms of this enzyme have been described: the endothelial NO-synthase, the immunologic NO-synthase, and the neuronal NO-synthase. Within the cell NO binds to a haeme-moiety of the enzyme guanylyl cyclase thus increasing concentrations of cyclic guanosine monophosphate (cGMP). The NO metabolism is influenced by volatile as well as intravenous anaesthetics. The action of inhalational and intravenous anesthetics as well as other substances with hypnotic properties such as α₂-adrenoceptor agonists has been demonstrated to be increased after disruption of NO-synthase activity by NO-synthase inhibitors. Different mechanisms of interaction of anaesthetics with the NO/cGMP signal transduction pathway are conceivable: at the receptor level, at the NO-synthase, or at the guanylyl cyclase. Common denominator of the NO/cGMP pathway is the control of cGMP. This second messenger regulates the activity of protein kinases, phosphodiesterases, and ion channels. However, the relevance of these structures for the hypnotic-anaesthetic action of general anaesthetics is currently unclear. Recent findings in mice deficient of neuronal NO-synthase activity and in animals chronically treated with NO-synthase inhibitors suggest that in addition to the NO/cGMP-metabolism other signal transduction pathways exist that are necessary for the action of general anaesthetics.

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