Mechanisms of nitrate tolerance--influence of the metabolic activation pathways.
Nitrovasodilator drugs like nitroglycerin are broadly used for the treatment of coronary heart disease. They act by releasing nitric oxide, a gaseous substance that has substantial physiological importance for the regulation of vascular tone, and which is synthetized and released by the vascular endothelial cell layer. Nitrovasodilators thus are prodrugs for the release of nitric oxide (NO). Their pathways of bioactivation, however, are very different, depending on the individual chemical structure of the drugs. In the case of nitrate-containing vasodilators like nitroglycerin or ISDN an enzyme-catalyzed reduction or non-enzymatic interaction with thiol-containing compounds is a prerequisite for the liberation of NO. These specific pathways of chemical degradation are likely to trigger off the development of nitrate tolerance if sophisticated dosage regimens are not maintained, because drugs which directly release NO like sodium nitroprusside or amylinitrite do not show this phenomenon. Inhibition of enzymatic and nonenzymatic biotransformation due to oxidation of essential SH-containing compounds and/or to their cellular depletion may be, therefore, the reason for nitrate tolerance.
Noack
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Institut für Pharmakologie, Heinrich-Heine-Universität, Düsseldorf, FRG.
D000818:Animals; D001711:Biotransformation / Q000502:physiology; D003327:Coronary Disease / Q000097:blood* / Q000188:drug therapy; D004361:Drug Tolerance / Q000502:physiology; D006801:Humans; D007548:Isosorbide Dinitrate / Q000493:pharmacokinetics / Q000627:therapeutic use; D009566:Nitrates / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005996:Nitroglycerin / Q000493:pharmacokinetics / Q000627:therapeutic use
D009566:Nitrates; D005996:Nitroglycerin; D007548:Isosorbide Dinitrate