Bioactivation of organic nitrates and the mechanism of nitrate tolerance.
Organic nitrates, such as nitroglycerin, are commonly used in the therapy of cardiovascular disease. Long-term therapy with these drugs, however, results in the rapid development of nitrate tolerance, limiting their hemodynamic and anti-ischemic efficacy. In addition, nitrate tolerance is associated with the expression of potentially deleterious modifications such as increased oxidative stress, endothelial dysfunction, and sympathetic activation. In this review we discuss current concepts regarding the mechanisms of organic nitrate bioactivation, nitrate tolerance, and nitrate-mediated oxidative stress and endothelial dysfunction. We also examine how hydralazine may prevent nitrate tolerance and related endothelial dysfunction.
Klemenska
Emila
E
Department of Clinical Physiology, Medical Centre of Postgraduate Education, Warszawa, Poland.
Beresewicz
Andrzej
A
D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D001711:Biotransformation; D004359:Drug Therapy, Combination; D004361:Drug Tolerance; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D000431:Ethanol / Q000378:metabolism; D006801:Humans; D006830:Hydralazine / Q000627:therapeutic use; D008928:Mitochondria / Q000201:enzymology; D009566:Nitrates / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000503:physiopathology; D013618:Tachyphylaxis; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*
D009566:Nitrates; D017382:Reactive Oxygen Species; D014665:Vasodilator Agents; D006830:Hydralazine; D000431:Ethanol; D000444:Aldehyde Dehydrogenase