The vasodilatory and antianginal effects of organic nitrates and other nitrovasodilators are mediated by the nitric oxide free radical (NO) and its second messenger cyclic guanosine monophosphate (cGMP). Prior to their pharmacological action, organic nitrates such as glyceryl trinitrate have to be transformed into the active metabolite NO. According to recent results, this reaction is catalyzed by a cytochrome P-450-dependent enzyme with reductase activity. Other previously suggested mechanisms such as NO release by cysteine or glutathione S-transferase do not seem to play a crucial role for the pharmacological action of organic nitrates. Since nitrate tolerance is caused by a decreased NO formation from organic nitrates it may be assumed that the mechanism underlying this clinically relevant desensitization involves down-regulation or irreversible inactivation of the bioactivating cytochrome P-450. Nitrovasodilators with spontaneous NO release such as molsidomine, i.e. its active metabolite 3-morpholinosydnonimine (SIN-1), do not require enzymatic bioactivation and thus do not induce tolerance.
|Translated title of the contribution||New results on the molecular mechanism of nitrovasodilators and their clinical relevance|
|Number of pages||6|
|State||Published - Jan 1 1994|
- cyclic GMP
- cytochrome P-450
- glycerol trinitrate
- nitric oxide