The effect of vitamin C on nitroglycerin-mediated vasodilation in individuals with and without the aldehyde dehydrogenase 2 polymorphism.
aldehyde dehydrogenase 2
cardiovascular pharmacology
nitroglycerin bioactivation
vitamin C
Journal
British journal of clinical pharmacology
ISSN: 1365-2125
Titre abrégé: Br J Clin Pharmacol
Pays: England
ID NLM: 7503323
Informations de publication
Date de publication:
09 2023
09 2023
Historique:
revised:
10
04
2023
received:
01
02
2023
accepted:
12
04
2023
medline:
23
10
2023
pubmed:
27
4
2023
entrez:
27
4
2023
Statut:
ppublish
Résumé
To mediate its pharmacodynamic effects, glyceryl trinitrate (GTN) requires bioactivation, by which it releases nitric oxide or a nitric oxide moiety. The exact mechanism of GTN bioactivation remains uncertain. Mitochondrial aldehyde dehydrogenase (ALDH-2) has been proposed as the primary enzyme responsible for this bioactivation process. Evidence for the importance of ALDH-2 in GTN bioactivation has been inconsistent, particularly in human models. An alternative hypothesis suggests that decreased ALDH-2 activity leads to accumulation of reactive cytotoxic aldehydes, which either inhibit the vasoactive product(s) of GTN or impair other enzymatic pathways involved in the bioactivation of GTN. We investigated the effect of supplemental vitamin C on vascular responses to GTN in healthy volunteers of East Asian descent, of whom 12 with and 12 without the ALDH-2 polymorphism participated. Subjects underwent 2 sequential brachial artery infusions of GTN at rates of 5, 11 and 22 nmol/min, separated by a 30-min washout period. The GTN infusions were carried out in the presence and absence of vitamin C using a randomized, crossover design. Venous occlusion plethysmography was used to measure forearm blood flow responses to GTN. Compared to subjects with functional ALDH-2, the variant group exhibited blunted hemodynamic responses to intra-arterial GTN infusions, although this reduction in response was not statically significant. Contrary to our hypothesis, vitamin C had an inhibitory effect on GTN mediated vasodilation as compared to GTN during saline in both groups. We conclude that vitamin C did not augment the acute vascular response to GTN in those with the ALDH-2 polymorphism.
Substances chimiques
Ascorbic Acid
PQ6CK8PD0R
Nitric Oxide
31C4KY9ESH
Nitroglycerin
G59M7S0WS3
Vasodilator Agents
0
Vitamins
0
ALDH2 protein, human
EC 1.2.1.3
Aldehyde Dehydrogenase, Mitochondrial
EC 1.2.1.3
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2767-2774Subventions
Organisme : CIHR
Pays : Canada
Informations de copyright
© 2023 British Pharmacological Society.
Références
Parker JD, Parker JO. Nitrate therapy for stable angina pectoris. N Engl J Med. 1998;338(8):520-531. doi:10.1056/nejm199802193380807
Murrell W. Nitro-GLYCERINE as a remedy for angina pectoris. Lancet. 1879;113(2890):80-81. doi:10.1016/S0140-6736(02)46032-1
Divakaran S, Loscalzo J. The role of nitroglycerin and other nitrogen oxides in cardiovascular therapeutics. J am Coll Cardiol. 2017;70(19):2393-2410. doi:10.1016/j.jacc.2017.09.1064
Bogaert MG. Pharmacokinetics of organic nitrates in man: an overview. Eur Heart J. 1988;9(suppl A):33-37. doi:10.1093/eurheartj/9.suppl_A.33
Tarkin JM, Kaski JC. Vasodilator therapy: nitrates and Nicorandil. Cardiovasc Drugs Ther. 2016;30(4):367-378. doi:10.1007/s10557-016-6668-z
Fung H-L, Chung S-J, Bauer JA, Chong S, Kowaluk EA. Biochemical mechanism of organic nitrate action. Am J Cardiol. 1992;70(8):B4-B10. doi:10.1016/0002-9149(92)90588-P
Ahlner J, Andersson RG, Torfgard K, Axelsson KL. Organic nitrate esters: clinical use and mechanisms of actions. Pharmacol Rev. 1991;43(3):351-423.
Murad F. Cellular signaling with nitric oxide and cyclic GMP. Braz J Med Biol Res = Rev Bras Pesquis Med Biol. 1999;32(11):1317-1327. doi:10.1590/S0100-879X1999001100001
Lincoln TM, Dey N, Sellak H. Invited review: cGMP-dependent protein kinase signaling mechanisms in smooth muscle: from the regulation of tone to gene expression. J Appl Physiol. 2001;91(3):1421-1430. doi:10.1152/jappl.2001.91.3.1421
Bennett BM, McDonald BJ, St James MJ. Hepatic cytochrome P-450-mediated activation of rat aortic guanylyl cyclase by glyceryl trinitrate. J Pharmacol Exp Ther. 1992;261(2):716-723.
Lau DT, Chan EK, Benet LZ. Glutathione S-transferase-mediated metabolism of glyceryl trinitrate in subcellular fractions of bovine coronary arteries. Pharm Res. 1992;9(11):1460-1464. doi:10.1023/A:1015867031004
Seabra AB, Ouellet M, Antonic M, Chrétien MN, English AM. Catalysis of nitrite generation from nitroglycerin by glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Nitric Oxide. 2013;35:116-122. doi:10.1016/j.niox.2013.09.003
O'Byrne S, Shirodaria C, Millar T, Stevens C, Blake D, Benjamin N. Inhibition of platelet aggregation with glyceryl trinitrate and xanthine oxidoreductase. J Pharmacol Exp Ther. 2000;292(1):326-330.
Chen Z, Zhang J, Stamler JS. Identification of the enzymatic mechanism of nitroglycerin bioactivation. Proc Natl Acad Sci U S A. 2002;99(12):8306-8311. doi:10.1073/pnas.122225199
Beretta M, Gruber K, Kollau A, et al. Bioactivation of nitroglycerin by purified mitochondrial and cytosolic aldehyde dehydrogenases. J Biol Chem. 2008;283(26):17873-17880. doi:10.1074/jbc.M801182200
Kollau A, Beretta M, Gorren ACF, et al. Bioactivation of nitroglycerin by ascorbate. Mol Pharmacol. 2007;72(1):191-196. doi:10.1124/mol.107.035642
Zhang J, Chen Z, Cobb FR, Stamler JS. Role of mitochondrial aldehyde dehydrogenase in nitroglycerin-induced vasodilation of coronary and systemic vessels: an intact canine model. Circulation. 2004;110(6):750-755. doi:10.1161/01.CIR.0000138105.17864.6B
Kollau A, Hofer A, Russwurm M, et al. Contribution of aldehyde dehydrogenase to mitochondrial bioactivation of nitroglycerin: evidence for the activation of purified soluble guanylate cyclase through direct formation of nitric oxide. Biochem J. 2005;385(3):769-777. doi:10.1042/bj20041354
Wenzel P, Hink U, Oelze M, et al. Number of nitrate groups determines reactivity and potency of organic nitrates: a proof of concept study in ALDH-2−/− mice. Br J Pharmacol. 2007;150(4):526-533. doi:10.1038/sj.bjp.0707116
Li H, Borinskaya S, Yoshimura K, et al. Refined geographic distribution of the oriental ALDH2*504Lys (nee 487Lys) variant. Ann Hum Genet. 2009;73(3):335-345. doi:10.1111/j.1469-1809.2009.00517.x
Miura T, Nishinaka T, Terada T, Yonezawa K. Vasodilatory effect of nitroglycerin in Japanese subjects with different aldehyde dehydrogenase 2 (ALDH2) genotypes. Chem Biol Interact. 2017;276:40-45. doi:10.1016/j.cbi.2017.03.012
Sakata S, Yoshihara T, Arima H, et al. Differential effects of organic nitrates on arterial diameter among healthy Japanese participants with different mitochondrial aldehyde dehydrogenase 2 genotypes: randomised crossover trial. BMJ Open. 2011;1(1):e000133. doi:10.1136/bmjopen-2011-000133
Mackenzie IS, Maki-Petaja KM, McEniery CM, et al. Aldehyde dehydrogenase 2 plays a role in the bioactivation of nitroglycerin in humans. Arterioscler Thromb Vasc Biol. 2005;25(9):1891-1895. doi:10.1161/01.atv.0000179599.71086.89
Guo R, Chen XP, Guo X, et al. Evidence for involvement of calcitonin gene-related peptide in nitroglycerin response and association with mitochondrial aldehyde dehydrogenase-2 (ALDH2) Glu504Lys polymorphism. J Am Coll Cardiol. 2008;52(11):953-960. doi:10.1016/j.jacc.2008.05.049
Li Y, Zhang D, Jin W, et al. Mitochondrial aldehyde dehydrogenase-2 (ALDH2) Glu504Lys polymorphism contributes to the variation in efficacy of sublingual nitroglycerin. J Clin Invest. 2006;116(2):506-511. doi:10.1172/JCI26564
D'Souza Y, Kawamoto T, Bennett BM. Role of the lipid peroxidation product, 4-hydroxynonenal, in the development of nitrate tolerance. Chem Res Toxicol. 2014;27(4):663-673. doi:10.1021/tx4004787
Esterbauer H, Schaur RJ, Zollner H. Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med. 1991;11(1):81-128. doi:10.1016/0891-5849(91)90192-6
Uchida K. 4-Hydroxy-2-nonenal: a product and mediator of oxidative stress. Prog Lipid Res. 2003;42(4):318-343. doi:10.1016/S0163-7827(03)00014-6
Wolkart G, Wenzl MV, Beretta M, Stessel H, Schmidt K, Mayer B. Vascular tolerance to nitroglycerin in ascorbate deficiency. Cardiovasc Res. 2008;79(2):304-312. doi:10.1093/cvr/cvn107
Bassenge E, Fink N, Skatchkov M, Fink B. Dietary supplement with vitamin C prevents nitrate tolerance. J Clin Invest. 1998;102(1):67-71. doi:10.1172/JCI977
Daniel TA, Nawarskas JJ. Vitamin C in the prevention of nitrate tolerance. Ann Pharmacother. 2000;34(10):1193-1197. doi:10.1345/aph.19415
Wilkinson IB, Webb DJ. Venous occlusion plethysmography in cardiovascular research: methodology and clinical applications. Br J Clin Pharmacol. 2001;52(6):631-646. doi:10.1046/j.0306-5251.2001.01495.x
Thomas GR, DiFabio JM, Gori T, Parker JD. Once daily therapy with isosorbide-5-mononitrate causes endothelial dysfunction in humans: evidence of a free-radical-mediated mechanism. J Am Coll Cardiol. 2007;49(12):1289-1295. doi:10.1016/j.jacc.2006.10.074
Pleiner J, Schaller G, Mittermayer F, et al. Intra-arterial vitamin C prevents endothelial dysfunction caused by ischemia-reperfusion. Atherosclerosis. 2008;197(1):383-391. doi:10.1016/j.atherosclerosis.2007.06.011
Heitzer T, Schlinzig T, Krohn K, Meinertz T, Munzel T. Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation. 2001;104(22):2673-2678. doi:10.1161/hc4601.099485
Pleiner J, Mittermayer F, Schaller G, MacAllister RJ, Wolzt M. High doses of vitamin C reverse Escherichia coli endotoxin-induced hyporeactivity to acetylcholine in the human forearm. Circulation. 2002;106(12):1460-1464. doi:10.1161/01.CIR.0000030184.70207.FF
Zhou K, Parker JD. The role of vascular endothelium in nitroglycerin-mediated vasodilation. Br J Clin Pharmacol. 2019;85(2):377-384. doi:10.1111/bcp.13804
DiFabio JM, Gori T, Thomas G, Jedrzkiewicz S, Parker JD. Daily low-dose folic acid supplementation does not prevent nitroglycerin-induced nitric oxide synthase dysfunction and tolerance: a human in vivo study. Can J Cardiol. 2010;26(9):461-465. doi:10.1016/S0828-282X(10)70448-7
Gori T, Burstein JM, Ahmed S, et al. Folic acid prevents nitroglycerin-induced nitric oxide synthase dysfunction and nitrate tolerance: a human in vivo study. Circulation. 2001;104(10):1119-1123. doi:10.1161/hc3501.095358
Alexander SPH, Fabbro D, Kelly E, et al. The concise guide to pharmacology 2019/20: enzymes. Br J Pharmacol. 2019;176(Suppl 1):S297-S396. doi:10.1111/bph.14752
Alexander SPH, Fabbro D, Kelly E, et al. The concise guide to pharmacology 2019/20: catalytic receptors. Br J Pharmacol. 2019;176(Suppl 1):S247-S296. doi:10.1111/bph.14751
Mayer B, Beretta M. The enigma of nitroglycerin bioactivation and nitrate tolerance: news, views and troubles. Br J Pharmacol. 2008;155(2):170-184. doi:10.1038/bjp.2008.263
Daiber A, Munzel T. Organic nitrate therapy, nitrate tolerance, and nitrate-induced endothelial dysfunction: emphasis on redox biology and oxidative stress. Antioxid Redox Signal. 2015;23(11):899-942. doi:10.1089/ars.2015.6376
Chen Z, Foster MW, Zhang J, et al. An essential role for mitochondrial aldehyde dehydrogenase in nitroglycerin bioactivation. Proc Natl Acad Sci U S A. 2005;102(34):12159-12164. doi:10.1073/pnas.0503723102
Lai CL, Yao CT, Chau GY, et al. Dominance of the inactive Asian variant over activity and protein contents of mitochondrial aldehyde dehydrogenase 2 in human liver. Alcohol Clin Exp Res. 2014;38(1):44-50. doi:10.1111/acer.12215
Cross JM, Donald AE, Nuttall SL, Deanfield JE, Woolfson RG, Macallister RJ. Vitamin C improves resistance but not conduit artery endothelial function in patients with chronic renal failure. Kidney Int. 2003;63(4):1433-1442. doi:10.1046/j.1523-1755.2003.00852.x
Nimse SB, Pal D. Free radicals, natural antioxidants, and their reaction mechanisms. RSC Adv. 2015;5(35):27986-28006. doi:10.1039/C4RA13315C
Gori T, Di Stolfo G, Sicuro S, et al. Nitroglycerin protects the endothelium from ischaemia and reperfusion: human mechanistic insight. Br J Clin Pharmacol. 2007;64(2):145-150. doi:10.1111/j.1365-2125.2007.02864.x
Skyschally A, Schulz R, Gres P, Korth HG, Heusch G. Attenuation of ischemic preconditioning in pigs by scavenging of free oxyradicals with ascorbic acid. Am J Physiol Heart Circ Physiol. 2003;284(2):H698-H703. doi:10.1152/ajpheart.00693.2002
Sun JZ, Tang XL, Park SW, Qiu Y, Turrens JF, Bolli R. Evidence for an essential role of reactive oxygen species in the genesis of late preconditioning against myocardial stunning in conscious pigs. J Clin Invest. 1996;97(2):562-576. doi:10.1172/jci118449
de Queiroz TM, Monteiro MM, Braga VA. Angiotensin-II-derived reactive oxygen species on baroreflex sensitivity during hypertension: new perspectives. Front Physiol. 2013;4:105. doi:10.3389/fphys.2013.00105
Wada A, Ueda S, Masumori-Maemoto S, Kuji N, Sugimoto K, Umemura S. Angiotensin II attenuates the vasodilating effect of a nitric oxide donor, glyceryl trinitrate: roles of superoxide and angiotensin II type 1 receptors. Clin Pharmacol Ther. 2002;71(6):440-447. doi:10.1067/mcp.2002.125293
Münzel T, Daiber A, Mülsch A. Explaining the phenomenon of nitrate tolerance. Circ Res. 2005;97(7):618-628. doi:10.1161/01.RES.0000184694.03262.6d
Watanabe H, Kakihana M, Ohtsuka S, Sugishita Y. Randomized, double-blind, placebo-controlled study of the preventive effect of supplemental oral vitamin C on attenuation of development of nitrate tolerance. J Am Coll Cardiol. 1998;31(6):1323-1329. doi:10.1016/S0735-1097(98)00085-0
Milone SD, Pace-Asciak CR, Reynaud D, Azevedo ER, Newton GE, Parker JD. Biochemical, hemodynamic, and vascular evidence concerning the free radical hypothesis of nitrate tolerance. J Cardiovasc Pharmacol. 1999;33(5):685-690. doi:10.1097/00005344-199905000-00002