Abstract
Organic nitrates still represent a group of very effective anti-ischemic drugs used for the treatment of patients with stable angina, acute myocardial infarction and chronic congestive heart failure. Long-term therapy with organic nitrates, however, results in a rapid development of nitrate tolerance blunting their hemodynamic and antiischemic efficacy. Recent studies revealed that mitochondrial reactive oxygen species (ROS) formation and a subsequent oxidative inactivation of nitrate reductase, the mitochondrial aldehyde dehydrogenase (ALDH-2), play an important role for the development of nitrate and crosstolerance. The present review focuses firstly on the role of ALDH-2 for organic nitrate bioactivation and secondly on the role of oxidative stress in the development of tolerance and cross-tolerance (endothelial dysfunction) in response to various organic nitrates. Finally, we would like to draw the reader’s attention to the protective properties of the organic nitrate pentaerithrityl tetranitrate (PETN), which, in contrast to all other organic nitrates, is able to upregulate enzymes with a strong antioxidative capacity thereby preventing tolerance and the development of endothelial dysfunction.
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References
Ahlner J, Andersson RG, Torfgard K, Axelsson KL (1991) Organic nitrate esters: clinical use and mechanisms of actions. Pharmacol Rev 43:351–423
Bossert T, Bittner HB, Gummert JF, Mohr FW (2006) Coronary artery spasm of the native right coronary artery during off-pump coronary surgery of the left coronary artery system. Clin Res Cardiol 95:115–118
Chen Z, Foster MW, Zhang J, Mao L, Rockman HA, Kawamoto T, Kitagawa K, Nakayama KI, Hess DT, Stamler JS (2005) An essential role for mitochondrial aldehyde dehydrogenase in nitroglycerin bioactivation. Proc Natl Acad Sci USA 102:12159–12164
Chen Z, Zhang J, Stamler JS (2002) Identification of the enzymatic mechanism of nitroglycerin bioactivation. Proc Natl Acad Sci USA 99:8306–8311
Daiber A, Oelze M, Coldewey M, Bachschmid M, Wenzel P, Sydow K, Wendt M, Kleschyov AL, Stalleicken D, Ullrich V, Mulsch A, Munzel T (2004) Oxidative stress and mitochondrial aldehyde dehydrogenase activity: a comparison of pentaerythritol tetranitrate with other organic nitrates. Mol Pharmacol 66:1372–1382
Daiber A, Oelze M, Sulyok S, Coldewey M, Schulz E, Treiber N, Hink U, Mulsch A, Scharffetter-Kochanek K, Munzel T (2005) Heterozygous deficiency of manganese superoxide dismutase in mice (Mn-SOD±): a novel approach to assess the role of oxidative stress for the development of nitrate tolerance. Mol Pharmacol 68:579–588
Elkayam U, Kulick D, McIntosh N, Roth A, Hsueh W, Rahimtoola SH (1987) Incidence of early tolerance to hemodynamic effects of continuous infusion of nitroglycerin in patients with coronary artery disease and heart failure. Circulation 76:577–584
Fung HL (2004) Biochemical mechanism of nitroglycerin action and tolerance: is this old mystery solved? Annu Rev Pharmacol Toxicol 44:67–85
Gori T, Al-Hesayen A, Jolliffe C, Parker JD (2003) Comparison of the effects of pentaerythritol tetranitrate and nitroglycerin on endothelium-dependent vasorelaxation in male volunteers. Am J Cardiol 91:1392–1394
Hacker A, Muller S, Meyer W, Kojda G (2001) The nitric oxide donor pentaerythritol tetranitrate can preserve endothelial function in established atherosclerosis. Br J Pharmacol 132:1707–1714
Hink U, Oelze M, Kolb P, Bachschmid M, Zou MH, Daiber A, Mollnau H, August M, Baldus S, Tsilimingas N, Walter U, Ullrich V, Munzel T (2003) Role for peroxynitrite in the inhibition of prostacyclin synthase in nitrate tolerance. J Am Coll Cardiol 42:1826–1834
Jurt U, Gori T, Ravandi A, Babaei S, Zeman P, Parker JD (2001) Differential effects of pentaerythritol tetranitrate and nitroglycerin on the development of tolerance and evidence of lipid peroxidation: a human in vivo study. J Am Coll Cardiol 38:854–859
Kleschyov AL, Oelze M, Daiber A, Huang Y, Mollnau H, Schulz E, Sydow K, Fichtlscherer B, Mulsch A, Munzel T (2003) Does nitric oxide mediate the vasodilator activity of nitroglycerin? Circ Res 93:e104–112
Li Y, Zhang D, Jin W, Shao C, Yan P, Xu C, Sheng H, Liu Y, Yu J, Xie Y, Zhao Y, Lu D, Nebert DW, Harrison DC, Huang W, Jin L (2006) Mitochondrial aldehyde dehydrogenase-2 (ALDH2) Glu504Lys polymorphism contributes to the variation in efficacy of sublingual nitroglycerin. J Clin Invest 116:506–511
Mackenzie IS, Maki-Petaja KM, Mc- Eniery CM, Bao YP, Wallace SM, Cheriyan J, Monteith S, Brown MJ, Wilkinson IB (2005) Aldehyde dehydrogenase 2 plays a role in the bioactivation of nitroglycerin in humans. Arterioscler Thromb Vasc Biol 25:1891–1895
Miche E, Herrmann G, Nowak M, Wirtz U, Tietz M, Hurst M, Zoller B, Radzewitz A (2006) Effect of an exercise training program on endothelial dysfunction in diabetic and non-diabetic patients with severe chronic heart failure. Clin Res Cardiol 95:i117–i124
Mullenheim J, Muller S, Laber U, Thamer V, Meyer W, Bassenge E, Fink B, Kojda G (2001) The effect of high-dose pentaerythritol tetranitrate on the development of nitrate tolerance in rabbits. Naunyn Schmiedebergs Arch Pharmacol 364:269–275
Mulsch A, Bara A, Mordvintcev P, Vanin A and Busse R (1995) Specificity of different organic nitrates to elicit NO formation in rabbit vascular tissues and organs in vivo. Br J Pharmacol 116:2743–2749
Munzel T, Daiber A, Mulsch A (2005) Explaining the phenomenon of nitrate tolerance. Circ Res 97:618–628
Munzel T, Sayegh H, Freeman BA, Tarpey MM, Harrison DG (1995) Evidence for enhanced vascular superoxide anion production in nitrate tolerance. A novel mechanism underlying tolerance and cross-tolerance. J Clin Invest 95:187–194
Needleman P, Hunter FE Jr (1966) Effects of organic nitrates on mitochondrial respiration and swelling: possible correlations with the mechanism of pharmacologic action. Mol Pharmacol 2:134–143
Nunez C, Victor VM, Tur R, Alvarez- Barrientos A, Moncada S, Esplugues JV, D’Ocon P (2005) Discrepancies between nitroglycerin and NO-releasing drugs on mitochondrial oxygen consumption, vasoactivity, and the release of NO. Circ Res 97:1063–1069
Oberle S, Abate A, Grosser N, Hemmerle A, Vreman HJ, Dennery PA, Schneider HT, Stalleicken D, Schroder H (2003) Endothelial protection by pentaerithrityl trinitrate: bilirubin and carbon monoxide as possible mediators. Exp Biol Med (Maywood) 228:529–534
Oberle S, Schwartz P, Abate A, Schroder H (1999) The antioxidant defense protein ferritin is a novel and specific target for pentaerithrityl tetranitrate in endothelial cells. Biochem Biophys Res Commun 261:28–34
Palmer RM, Ferrige AG, Moncada S (1987) Nitric oxide release accounts for the biological activity of endothelium- derived relaxing factor. Nature 327:524–526
Schmieder RE, Schrader J, Zidek W, Tebbe U, Paar WD, Bramlage P, Pittrow D, Bohm M (2007) Low-grade albuminuria and cardiovascular risk: what is the evidence? Clin Res Cardiol 96:247–257
Schulz E, Tsilimingas N, Rinze R, Reiter B, Wendt M, Oelze M, Woelken- Weckmuller S, Walter U, Reichenspurner H, Meinertz T, Munzel T (2002) Functional and biochemical analysis of endothelial (dys)function and NO/cGMP signaling in human blood vessels with and without nitroglycerin pretreatment. Circulation 105:1170–1175
Sekiya M, Sato M, Funada J, Ohtani T, Akutsu H, Watanabe K (2005) Effects of the long-term administration of nicorandil on vascular endothelial function and the progression of arteriosclerosis. J Cardiovasc Pharmacol 46:63–67
Stewart DD (1888) Remarkable tolerance to nitroglycerin. Philadelphia Polyclinic 6:43
Sydow K, Daiber A, Oelze M, Chen Z, August M, Wendt M, Ullrich V, Mulsch A, Schulz E, Keaney JF Jr, Stamler JS, Munzel T (2004) Central role of mitochondrial aldehyde dehydrogenase and reactive oxygen species in nitroglycerin tolerance and cross-tolerance. J Clin Invest 113:482–489
Thomas GR, DiFabio JM, Tommaso T, Parker JD (2007) Once daily therapy with isosorbide-5-mononitrate causes endothelial dysfunction in humans: evidence of a free radical mediated mechanism. J Am Coll Cardiol 49:1289–1295
Wang EQ, Lee WI, Fung HL (2002) Lack of critical involvement of endothelial nitric oxide synthase in vascular nitrate tolerance in mice. Br J Pharmacol 135:299–302
Wenzel P, Hink U, Oelze M, Schuppan S, Schaeuble K, Schildknecht S, Ho KK, Weiner H, Bachschmid M, Munzel T, Daiber A (2007) Role of reduced lipoic acid in the redox regulation of mitochondrial aldehyde dehydrogenase (ALDH-2) activity: implications for mitochondrial oxidative stress and nitrate tolerance. J Biol Chem 282:792–799
Wenzel P, Hink U, Oelze M, Seeling A, Isse T, Bruns K, Steinhoff L, Brandt M, Kleschyov AL, Schulz E, Lange K, Weiner H, Lehmann J, Lackner KJ, Kawamoto T, Munzel T, Daiber A (2007) Number of nitrate groups determines reactivity and potency of organic nitrates: a proof of concept study in ALDH-2–/– mice. Brit J Pharmacol 150:526–533
Wenzel P, Oelze M, Coldewey M, Hortmann M, Seeling A, Hink U, Mollnau H, Stalleicken D, Weiner H, Lehmann J, Li H, Forstermann U, Munzel T, Daiber A (2007) Heme oxygenase-1. A novel key player in the development of tolerance in response to organic nitrates. Arterioscler Thromb Vasc Biol 27:1729–1735
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Daiber, A., Wenzel, P., Oelze, M. et al. New insights into bioactivation of organic nitrates, nitrate tolerance and cross-tolerance. Clin Res Cardiol 97, 12–20 (2008). https://doi.org/10.1007/s00392-007-0588-7
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DOI: https://doi.org/10.1007/s00392-007-0588-7