{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T15:39:54Z","timestamp":1781710794210,"version":"3.54.5"},"reference-count":104,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2021,10,30]],"date-time":"2021-10-30T00:00:00Z","timestamp":1635552000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Glyceryl trinitrate (GTN) is one of the earliest known treatments for angina with a fascinating history that bridges three centuries. However, despite its central role in the nitric oxide (NO) story as a NO-donating compound, establishing the precise mechanism of how GTN exerts its medicinal benefit has proven to be far more difficult. This review brings together the explosive and vasodilatory nature of this three-carbon molecule while providing an update on the likely in vivo pathways through which GTN, and the rest of the organic nitrate family, release NO, nitrite, or a combination of both, while also trying to explain nitrate tolerance. Over the last 20 years the alcohol detoxification enzyme, aldehyde dehydrogenase (ALDH), has undoubtedly emerged as the front runner to explaining GTN\u2019s bioactivation. This is best illustrated by reduced GTN efficacy in subjects carrying the single point mutation (Glu504Lys) in ALDH, which is also responsible for alcohol intolerance, as characterized by flushing. While these findings are significant for anyone following the GTN story, they appear particularly relevant for healthcare professionals, and especially so, if administering GTN to patients as an emergency treatment. In short, although the GTN puzzle has not been fully solved, clinical study data continue to cement the importance of ALDH, as uncovered in 2002, as a key GTN activator.<\/jats:p>","DOI":"10.3390\/molecules26216581","type":"journal-article","created":{"date-parts":[[2021,11,1]],"date-time":"2021-11-01T22:22:24Z","timestamp":1635805344000},"page":"6581","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Glyceryl Trinitrate: History, Mystery, and Alcohol Intolerance"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1705-5609","authenticated-orcid":false,"given":"Russell","family":"Pearson","sequence":"first","affiliation":[{"name":"School of Pharmacy & Bioengineering, Keele University, Newcastle-under-Lyme ST5 5BG, Staffordshire, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Butler","sequence":"additional","affiliation":[{"name":"School of Psychology & Neuroscience, University of St Andrews, St Andrews KY16 9JP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1038\/327524a0","article-title":"Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor","volume":"327","author":"Palmer","year":"1987","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"9265","DOI":"10.1073\/pnas.84.24.9265","article-title":"Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide","volume":"84","author":"Ignarro","year":"1987","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1038\/288373a0","article-title":"The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine","volume":"288","author":"Furchgott","year":"1980","journal-title":"Nature"},{"key":"ref_4","first-page":"175","article-title":"Properties and regulation of guanylate cyclase and some proposed functions for cyclic GMP","volume":"11","author":"Murad","year":"1979","journal-title":"Adv. Cyclic Nucleotide Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1016\/j.freeradbiomed.2004.06.013","article-title":"Nitrates and NO release: Contemporary aspects in biological and medicinal chemistry","volume":"37","author":"Thatcher","year":"2004","journal-title":"Free Rad. Biol. Med."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"McAninly, J., Williams, L.H., Askew, S.C., Butler, A.R., and Russell, C. (1993). Metal ion catalysis in nitrosothiol (RSNO) decomposition. J. Chem. Soc. Chem. Comm., 1758\u20131759.","DOI":"10.1039\/c39930001758"},{"key":"ref_7","unstructured":"Fant, K. (1993). Alfred Nobel: A Biography, Arcade Publishing."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1039\/QJ8591100245","article-title":"Contribution to the knowledge of the amyl group","volume":"11","author":"Guthrie","year":"1859","journal-title":"Q. J. Chem. Soc."},{"key":"ref_9","first-page":"120","article-title":"Report on the physiological action of nitrite of amyl","volume":"34","author":"Richardson","year":"1864","journal-title":"Rep. Brit. Assoc. Adv. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1046\/j.1440-1681.2000.03240.x","article-title":"A short history of nitroglycerine and nitric oxide in pharmacology and physiology","volume":"27","author":"Marsh","year":"2000","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1097\/00005344-198710000-00001","article-title":"Effect of in vivo nitroglycerin therapy on endothelium-dependent and independent vascular relaxation and cyclic GMP accumulation in rat aorta","volume":"10","author":"Molina","year":"1987","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1161\/01.RES.65.1.1","article-title":"Biological actions and properties of endothelium-derived nitric oxide formed and released from artery and vein","volume":"65","author":"Ignarro","year":"1989","journal-title":"Circ. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1038\/bjp.2008.263","article-title":"The enigma of nitroglycerin bioactivation and nitrate tolerance: News, views and troubles","volume":"155","author":"Mayer","year":"2008","journal-title":"Brit. J. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1146\/annurev.pharmtox.44.101802.121646","article-title":"Biochemical mechanism of nitroglycerin action and tolerance: Is this old mystery solved?","volume":"44","author":"Fung","year":"2004","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"205","DOI":"10.2165\/00003088-200342030-00001","article-title":"Clinical pharmacokinetics and pharmacodynamics of glyceryl trinitrate and its metabolites","volume":"42","author":"Hashimoto","year":"2003","journal-title":"Clin. Pharmacokinet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1002\/bdd.2510150210","article-title":"Pharmacokinetics of nitroglycerin and its four metabolites during nitroglycerin transdermal administration","volume":"15","author":"Han","year":"1994","journal-title":"Biopharm. Drug Dispos."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1462","DOI":"10.1016\/S0043-1354(96)00390-9","article-title":"Anaerobic biodegradation of nitroglycerin","volume":"31","author":"Christodoulatos","year":"1997","journal-title":"Wat. Res."},{"key":"ref_18","first-page":"324","article-title":"Sulfhydryl requirement for relaxation of vascular smooth muscle","volume":"187","author":"Needleman","year":"1973","journal-title":"J. Pharmacol. Exper. Therapeut."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/0304-4165(80)90297-4","article-title":"Requirement of thiols for activation of coronary arterial guanylate cyclase by glyceryl trinitrate and sodium nitrite: Possible involvement of S-nitrosothiols","volume":"631","author":"Ignarro","year":"1980","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_20","first-page":"739","article-title":"Mechanism of vascular smooth muscle relaxation by organic nitrates, nitrites, nitroprusside and nitric oxide: Evidence for the involvement of S-nitrosothiols as active intermediates","volume":"218","author":"Ignarro","year":"1981","journal-title":"J. Pharmacol. Exper. Therapeut."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"21664","DOI":"10.1016\/S0021-9258(17)31857-4","article-title":"Inactivation of human aldehyde dehydrogenase by isosorbide dinitrate","volume":"269","author":"Mukerjee","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Weiner, H., Holmes, R.S., and Wermuth, B. (1995). Nitrate esters as inhibitors and substrates of aldehyde dehydrogenase. Enzymology and Molecular Biology of Carbonyl Metabolism 5, Plenum Press.","DOI":"10.1007\/978-1-4615-1965-2"},{"key":"ref_23","first-page":"555","article-title":"The reaction between organic nitrates and sulhydryl compounds. A possible model system for the activation of organic nitrates","volume":"28","author":"Yeates","year":"1985","journal-title":"Mol. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.niox.2004.01.004","article-title":"Formation of nitric oxide from nitrous acid in ischemic tissue and skin","volume":"10","author":"Butler","year":"2004","journal-title":"Nitric Oxide"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Dicks, A.P., Swift, H.R., Williams, D.L.H., Butler, A.R., Al-Sa\u2019doni, H.H., and Cox, B.G. (1996). Identification of Cu+ as the effective reagent in nitric oxide formation from S-nitrosothiols (RSNO). J. Chem. Soc. Perkin Trans. 2, 481\u2013487.","DOI":"10.1039\/p29960000481"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1126\/science.177.4043.65","article-title":"Ascorbate-nitrite reaction: Possible means of blocking the formation of carcinogenic N-nitroso compounds","volume":"177","author":"Mirvish","year":"1972","journal-title":"Science"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1093\/jnci\/54.5.1203","article-title":"Reaction of nitrite with ascorbate and its relation to nitrosamine formation","volume":"54","author":"Archer","year":"1975","journal-title":"J. Nation. Cancer Instit."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1124\/mol.107.035642","article-title":"Bioactivation of nitroglycerin by ascorbate","volume":"72","author":"Kollau","year":"2007","journal-title":"Mol. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/0014-2999(87)90493-6","article-title":"Correlation between nitric oxide formation during degradation of organic nitrates and activation of guanylate cyclase","volume":"139","author":"Feelisch","year":"1987","journal-title":"Eur. J. Pharmacol."},{"key":"ref_30","first-page":"629","article-title":"Requirement for reduced, unliganded hemoprotein for the hemoglobin- and myoglobin-mediated biotransformation of glyceryl trinitrate","volume":"237","author":"Bennett","year":"1986","journal-title":"J. Pharmacol. Exp. Therapeut."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"7816","DOI":"10.1073\/pnas.132271799","article-title":"After 130 years, the molecular mechanism of action of nitroglycerin is revealed","volume":"99","author":"Ignarro","year":"2002","journal-title":"Proc. Nat. Acad. Sci. USA"},{"key":"ref_32","first-page":"185","article-title":"The heart less bounding: Treating angina pectoris","volume":"36","author":"Butler","year":"2006","journal-title":"J. R. Coll. Physians Edinb."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1111\/j.1463-1318.2007.01322.x","article-title":"GTN headaches and reduction of natural banding?","volume":"10","author":"Nash","year":"2008","journal-title":"Colorectal Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1111\/j.1463-1318.2006.01134.x","article-title":"Rectogesic (glyceryl trinitrate 0.2%) ointment relieved symptoms of haemorrhoids associated with high resting anal canal pressures","volume":"9","author":"Tjandra","year":"2007","journal-title":"Colorectal Dis."},{"key":"ref_35","first-page":"1386","article-title":"Reversible chemical sphincterotomy by local application of glyceryl trinitrate","volume":"9","author":"Loder","year":"1994","journal-title":"Brit. J. Surg."},{"key":"ref_36","first-page":"216","article-title":"The nitrites and nitrates","volume":"25","author":"Dipalma","year":"1982","journal-title":"Am. Fam. Physician"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"8306","DOI":"10.1073\/pnas.122225199","article-title":"Identification of the enzymatic mechanism of nitroglycerin bioactivation","volume":"99","author":"Chen","year":"2002","journal-title":"Proc. Nat. Acad. Sci. USA"},{"key":"ref_38","first-page":"145","article-title":"Guanylate cyclase: Activation by azide, nitro compounds, nitric oxide, and hydroxyl radical and inhibition by hemoglobin and myoglobin. Adv","volume":"9","author":"Murad","year":"1978","journal-title":"Cyclic Nucleotide Res."},{"key":"ref_39","first-page":"77","article-title":"The transformation of glyceryl trinitrate and other nitrates by glutathione-organic nitrate reductase","volume":"1","author":"Needleman","year":"1965","journal-title":"Mol. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"7150","DOI":"10.1016\/S0021-9258(19)39092-1","article-title":"Purification and characterization of glutathione transferases with an activity toward nitroglycerin from human aorta and heart","volume":"265","author":"Tsuchida","year":"1990","journal-title":"J. Biol. Chem."},{"key":"ref_41","first-page":"1527","article-title":"Isoform-specific biotransformation of glyceryl trinitrate by rat aortic glutathione S-transferases","volume":"279","author":"Nigam","year":"1996","journal-title":"J. Pharmacol. Exper. Therapeut."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1702","DOI":"10.1016\/j.bcp.2009.02.022","article-title":"Role of microsomal glutathione transferase 1 in the mechanism-based biotransformation of glyceryl trinitrate in LLC-PK1 cells","volume":"77","author":"Ji","year":"2009","journal-title":"Biochem. Pharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.ejphar.2009.06.043","article-title":"Comparing the role of glutathione-S-transferase and mitochondrial aldehyde dehydrogenase in nitroglycerin biotransformation and the correlation with calcitonin gene-related peptide","volume":"617","author":"Zhang","year":"2009","journal-title":"Euro. J. Pharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1016\/0006-291X(89)91106-6","article-title":"Nitric oxide formation during microsomal hepatic denitration of glyceryl trinitrate: Involvement of cytochrome P-450","volume":"163","author":"Servent","year":"1989","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1552","DOI":"10.1139\/y90-236","article-title":"Cytochrome P-450-mediated biotransformation of organic nitrates","volume":"68","author":"McDonald","year":"1990","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/0006-2952(93)90403-J","article-title":"Biotransformation of glyceryl trinitrate by rat aortic cytochrome P450","volume":"45","author":"McDonald","year":"1993","journal-title":"Biochem. Pharmacol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1495","DOI":"10.1111\/bph.15362","article-title":"Vascular biotransformation of organic nitrates is independent of cytochrome P450 monooxygenases","volume":"178","author":"Lopez","year":"2021","journal-title":"Br. J. Pharmacol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"12546","DOI":"10.1074\/jbc.M511803200","article-title":"Characterization of the mechanism of cytochrome P450 reductase-cytochrome P450-mediated nitric oxide and nitrosothiol generation from organic nitrates","volume":"281","author":"Li","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/S0014-5793(98)00430-X","article-title":"Xanthine oxidoreductase catalyses the reduction of nitrates and nitrite to nitroc oxide under hypoxic conditions","volume":"427","author":"Millar","year":"1998","journal-title":"FEBS Lett."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/S0304-4165(01)00148-9","article-title":"Reduction of organic nitrates catalysed by xanthine oxidoreductase under anaerobic conditions","volume":"1527","author":"Doel","year":"2001","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"24482","DOI":"10.1074\/jbc.M011648200","article-title":"Characterization of the magnitude and kinetics of xanthine oxidase-catalysed nitrite reduction","volume":"276","author":"Li","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"17855","DOI":"10.1074\/jbc.M801785200","article-title":"Nitric oxide production from nitrite occurs primarily in tissues not in the blood","volume":"283","author":"Li","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_53","first-page":"61","article-title":"The new organic nitrate 2-nitrate-1,3-diocthanoxy propan (NDOP) induces nitric oxide production and vasorelaxation via activation of inward-rectifier potassium channels (KIR)","volume":"104\u2013105","author":"Cavalcanti","year":"2020","journal-title":"Nitric Oxide"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.3389\/fphar.2018.01085","article-title":"Metabolomics-driven elucidation of cellular nitrate tolerance reveals ascorbic acid prevents nitroglycerin-induced inactivation of xanthine oxidase","volume":"9","author":"Axton","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.1139\/Y09-101","article-title":"Vascular responses to nitrite are mediated by xanthine oxidoreductase and mitochondrial aldehyde dehydrogenase in the rat","volume":"87","author":"Golwala","year":"2009","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"96","DOI":"10.15288\/jsa.1977.38.96","article-title":"The disulfiram-ethanol reaction","volume":"38","author":"Kitson","year":"1977","journal-title":"J. Stud. Alc."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1124\/pr.111.005538","article-title":"Aldehyde dehydrogenase inhibitors: A comprehensive review of the pharmacology, mechanism of action, substrate specificity, and clinical application","volume":"64","author":"Koppaka","year":"2012","journal-title":"Pharmacol. Rev."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1038\/sj.bjp.0707116","article-title":"Number of nitrate groups determines reactivity and potency of organic nitrates: A proof of concept study in ALDH-2-\/- mice","volume":"150","author":"Wenzel","year":"2007","journal-title":"Brit. J. Pharmacol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"12159","DOI":"10.1073\/pnas.0503723102","article-title":"An essential role for mitochondria aldehyde dehydrogenase in nitroglycerin bioactivation","volume":"102","author":"Chen","year":"2005","journal-title":"Proc. Nat. Acad. Sci. USA"},{"key":"ref_60","first-page":"548","article-title":"Differential metabolism of organic nitrates by aldehyde dehydrogenase 1a1 and 2: Substrate selectivity, enzyme inactivation, and active cysteine sites","volume":"13","author":"Tsou","year":"2011","journal-title":"Amer. Assoc. Pharmaceut. Sci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.niox.2013.09.005","article-title":"In vitro organic nitrate bioactivation to nitric oxide by recombinant aldehyde dehydrogenase 3A1","volume":"35","author":"Lin","year":"2013","journal-title":"Nitric Oxide"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1161\/CIRCRESAHA.111.245837","article-title":"Vascular bioactivation of nitroglycerin is catalyzed by cytosolic aldehyde dehydrogenase-2","volume":"110","author":"Beretta","year":"2012","journal-title":"Circ. Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"17873","DOI":"10.1074\/jbc.M801182200","article-title":"Bioactivation of nitroglycerin by purified mitochondrial and cytosolic aldehyde dehydrogenases","volume":"283","author":"Baretta","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1042\/bj2750207","article-title":"Identification of a catalytically essential nucleophilic residue in sheep liver cytoplasmic aldehyde dehydrogenase","volume":"275","author":"Kitson","year":"1991","journal-title":"Biochem. J."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"19878","DOI":"10.1074\/jbc.M109.005652","article-title":"Role of the general base Glu-268 in nitroglycerin bioactivation and superoxide formation by aldehyde dehydrogenase-2","volume":"284","author":"Wenzl","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.tcm.2006.05.001","article-title":"Bioactivation of nitroglycerin by mitochondrial aldehyde dehydrogenase","volume":"16","author":"Chen","year":"2006","journal-title":"Trends Cardiovasc. Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1016\/S0006-2952(00)00435-4","article-title":"Role of disulfiram in the in vitro inhibition of rat liver mitochondrial aldehyde dehydrogenase","volume":"60","author":"Shen","year":"2000","journal-title":"Biochem. Pharmacol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1161\/01.RES.0000184694.03262.6d","article-title":"Explaining the phenomenon of nitrate tolerance","volume":"97","author":"Daiber","year":"2005","journal-title":"Circ. Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1124\/mol.111.071704","article-title":"Site-directed mutagenesis of aldehyde dehydrogenase-2 suggests three distinct pathways of nitroglycerin biotransformation","volume":"80","author":"Wenzl","year":"2011","journal-title":"Mol. Pharmacol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"38124","DOI":"10.1074\/jbc.M112.371716","article-title":"Vascular bioactivation of nitroglycerin by aldehyde dehydrogenase-2","volume":"287","author":"Lang","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"711227","DOI":"10.3389\/fmolb.2021.711227","article-title":"Role of copper on mitochondrial function and metabolism","volume":"8","author":"Ruiz","year":"2021","journal-title":"Front. Mol. Biosci."},{"key":"ref_72","first-page":"709","article-title":"Mechanism of tolerance development to organic nitrates","volume":"184","author":"Needleman","year":"1973","journal-title":"J. Pharmacol. Exper. Therapeut."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1124\/mol.117.110783","article-title":"Sustained formation of nitroglycerin-derived nitric oxide by aldehyde dehydrogenase-2 in vascular smooth muscle without added reductants: Implications for the development of nitrate tolerance","volume":"93","author":"Opelt","year":"2018","journal-title":"Mol. Pharmacol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1074\/jbc.M606477200","article-title":"Role of reduced lipoic acid in the redox regulation of mitochondrial aldehyde dehydrogenase (ALDH-2) activity","volume":"282","author":"Wenzel","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_75","first-page":"627","article-title":"Is the mechanism of nitroglycerin tolerance associated with aldehyde dehydrogenase activity? A contribution to the ongoing discussion","volume":"66","author":"Kotanska","year":"2019","journal-title":"Acta Biochim. Polon."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1023\/A:1022982213484","article-title":"How to use nitrates","volume":"16","author":"Abrams","year":"2002","journal-title":"Cardiovasc. Drug Ther."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1007\/s00392-007-0588-7","article-title":"New insights into bioactivation of organic nitrates, nitrate tolerance and cross tolerance","volume":"97","author":"Daiber","year":"2008","journal-title":"Clin. Res. Cardiol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1161\/CIRCRESAHA.108.175133","article-title":"Nitroglycerin-induced S-nitrosylation and desensitization of soluble guanylyl cyclase contribute to nitrate tolerance","volume":"103","author":"Sayed","year":"2008","journal-title":"Circ. Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1161\/CIRCRESAHA.108.184341","article-title":"Nitroglycerin-mediated S-nitrosylation of proteins: A field comes full cycle","volume":"103","author":"Stamler","year":"2008","journal-title":"Circ. Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2241","DOI":"10.1161\/01.CIR.94.9.2241","article-title":"In vivo nitrate tolerance is not associated with reduced bioconversion of nitroglycerin to nitric oxide","volume":"94","author":"Laursen","year":"1996","journal-title":"Circulation"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1172\/JCI117637","article-title":"Evidence for enhanced vascular superoxide anion production in nitrate tolerance","volume":"95","author":"Sayegh","year":"1995","journal-title":"J. Clin. Investig."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.phrs.2014.07.007","article-title":"The effect of peroxynitrite decomposition catalyst MnTBAP on aldehyde dehydrogenase-2 nitration by organic nitrates: Role in nitrate tolerance","volume":"89","author":"Mollace","year":"2014","journal-title":"Pharmacol. Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1016\/j.bbabio.2012.02.013","article-title":"Evidence for a relationship between mitochondrial complex 1 activity and mitochondrial aldehyde dehydrogenase during nitroglycerin tolerance: Effects of mitochondrial antioxidants","volume":"1817","author":"Rocha","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_84","first-page":"11","article-title":"Bioactivation of organic nitrates and the mechanism of nitrate tolerance","volume":"16","author":"Klemenska","year":"2009","journal-title":"Cardiol. J."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"2545","DOI":"10.1161\/01.CIR.96.8.2545","article-title":"Randomized, double-blind, placebo-controlled study of supplemental vitamin E on attenuation of the development of nitrate tolerance","volume":"96","author":"Watanabe","year":"1997","journal-title":"Circulation"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/S0891-5849(99)00228-2","article-title":"A new approach for extracellular spin trapping of nitroglycerin-induced superoxide radicals both in vitro and in vivo","volume":"28","author":"Fink","year":"2000","journal-title":"Free Rad. Biol. Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1097\/01.fjc.0000211798.91023.14","article-title":"Effect of resveratrol on nitrate tolerance in isolated human internal mammary artery","volume":"47","author":"Coskun","year":"2006","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1021\/tx4004787","article-title":"Role of lipid peroxidation product, 4-hydroxynonenal, in the development of nitrate tolerance","volume":"27","author":"Kawamoto","year":"2014","journal-title":"Chem. Res. Toxicol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"12940","DOI":"10.1074\/jbc.M607959200","article-title":"Structural and functional consequences of coenzyme binding to the inactive Asian variant of mitochondrial aldehyde dehydrogenase","volume":"282","author":"Larson","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1172\/JCI26564","article-title":"Mitochondrial aldehyde dehydrogenase-2 (ALDH2) Glu504Lys polymorphism contributes to the variation in efficacy of sublingual nitroglycerin","volume":"116","author":"Li","year":"2006","journal-title":"J. Clin. Investig."},{"key":"ref_91","first-page":"769","article-title":"Population genetic studies on aldehyde dehydrogenase isozyme deficiency and alcohol sensitivity","volume":"35","author":"Goedde","year":"1983","journal-title":"Am. J. Hum. Genet."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1891","DOI":"10.1161\/01.ATV.0000179599.71086.89","article-title":"Aldehyde dehydrogenase 2 plays a role in the bioactivation of nitroglycerin in humans","volume":"25","author":"Mackenzie","year":"2005","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1007\/BF00286702","article-title":"Inheritance of mitochondrial aldehyde dehydrogenase: Genotyping in Chinese, Japanese and South Korean families reveals dominance of the mutant allele","volume":"83","author":"Singh","year":"1989","journal-title":"Hum. Gen."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1007\/s00228-019-02709-x","article-title":"Influence of the aldehyde dehydrogenase 2 polymorphism on the vasodilatory effect of nitroglycerin in infants with congenital heart disease and pulmonary arterial hypertension","volume":"75","author":"Nagano","year":"2019","journal-title":"Euro. J. Clin. Pharmacol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.cbi.2017.03.012","article-title":"Vasodilatory effect of nitroglycerin in Japanese subjects with different aldehyde dehydrogenase 2 (ALDH2) genotypes","volume":"276","author":"Miura","year":"2017","journal-title":"Chem.-Biol. Interact."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1097\/FJC.0000000000000673","article-title":"Role of mitochondrial aldehyde dehydrogenase in nitroglycerin-mediated vasodilation: Observations concerning the dose-response relationship","volume":"73","author":"He","year":"2019","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"180","DOI":"10.4103\/0366-6999.149192","article-title":"Effect of aldehyde dehydrogenase 2 gene polymorphism on hemodynamics after nitroglycerin intervention in Northern Chinese Han population","volume":"128","author":"Xia","year":"2015","journal-title":"Chin. Med. J."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"13854","DOI":"10.1016\/S0021-9258(17)36725-X","article-title":"Effects of changing glutamate 487 to lysine in rat and human liver mitochondrial aldehyde dehydrogenase","volume":"269","author":"Wang","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"3341","DOI":"10.1111\/bph.13122","article-title":"Role of aldehyde dehydrogenase in hypoxic vasodilator effects of nitrite in rats and humans","volume":"172","author":"Arif","year":"2015","journal-title":"Br. J. Pharmacol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1111\/j.1476-5381.2012.02220.x","article-title":"Effect of overexpression of human aldehyde dehydrogenase 2 in LL-PK1 cells on glyceryl trinitrate biotransformation and cGMP accumulation","volume":"168","author":"Ji","year":"2013","journal-title":"Br. J. Pharmacol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.niox.2013.09.003","article-title":"Catalysis of nitrite generation from nitroglycerin by glyceraldehyde-3-phosphate dehydrogenase (GAPDH)","volume":"35","author":"Seabra","year":"2013","journal-title":"Nitric Oxide"},{"key":"ref_102","first-page":"629","article-title":"The relationship between aldehyde dehydrogenase-2 gene polymorphisms and efficacy of nitroglycerin","volume":"46","author":"Zhang","year":"2007","journal-title":"Zhonghua Nei Ke Za Zhi"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1253\/circj.CJ-11-1133","article-title":"Nitroglycerin use in myocardial infarction patients: Risks and benefits","volume":"76","author":"Ferreira","year":"2012","journal-title":"Circ. J."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1007\/s00395-018-0681-2","article-title":"The GTN patch: A simple and effective new approach to cardioprotection?","volume":"113","author":"Yellon","year":"2018","journal-title":"Basic Res. Cardiol."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/21\/6581\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:23:28Z","timestamp":1760167408000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/21\/6581"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,30]]},"references-count":104,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["molecules26216581"],"URL":"https:\/\/doi.org\/10.3390\/molecules26216581","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,30]]}}}