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Erschienen in: Clinical Research in Cardiology 2/2010

01.02.2010 | Original Paper

Effects of pentaerythritol tetranitrate on endothelial function in coronary artery disease: results of the PENTA study

verfasst von: Boris Schnorbus, Robert Schiewe, Mir Abolfazl Ostad, Christoph Medler, Daniel Wachtlin, Philip Wenzel, Andreas Daiber, Thomas Münzel, Ascan Warnholtz

Erschienen in: Clinical Research in Cardiology | Ausgabe 2/2010

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Abstract

Background

Pentaerythritol tetranitrate (PETN) differs from other organic nitrates by the lack of tolerance induction and by antioxidative properties. The purpose of this study was to determine the effect of PETN on endothelial function in patients with coronary artery disease (CAD). We hypothesized that the treatment with PETN improves endothelial function in patients with CAD.

Methods

In a prospective, double-blind study, we randomly assigned 80 patients to treatment for 8 weeks with oral PETN 80 mg t.i.d. (PETN) or placebo (C). The primary endpoint was the absolute change in brachial artery flow-mediated dilation (FMD) from baseline to follow-up. Furthermore, changes in nitroglycerin-mediated dilation (NMD), digital peripheral arterial tonometry (PAT) index, vascular shear stress, mean flow velocity, plasma bilirubin, C-reactive protein (CRP) and thiobarbituric acid reactive substances (TBARS), serum ferritin, and the activity of the PETN bioactivating enzyme aldehyde dehydrogenase-2 (ALDH-2) in peripheral blood mononuclear cells were analyzed. Raw data entry, data monitoring and statistical analysis were performed independently.

Results

The treatment groups were comparable regarding demographics, cardiovascular risk and concomitant medication. There was no difference in the change in FMD between the two treatment groups (mean ± SD: PETN: +1.6 ± 3.3% vs. C: +1.4 ± 4.1%; P = 0.7). NMD increased after treatment with PETN and was higher compared with C (PETN: +3.8 ± 5.5% vs. C: +0.6 ± 4.2%; P = 0.004). Mean PAT index and ALDH-2 activity remained unchanged. Relative changes in mean flow volume (P = 0.04) and mean flow velocity (P = 0.01) upon ischemia increased in the PETN group versus C. Changes in bilirubin, ferritin, TBARS and CRP did not differ between the groups.

Conclusions

We conclude that chronic PETN therapy in patients with CAD may be established for symptomatic treatment without adverse effects on endothelial function and with beneficial effects on the microcirculation.
Literatur
1.
Zurück zum Zitat Daiber A, Oelze M, Coldewey M et al (2004) Oxidative stress and mitochondrial aldehyde dehydrogenase activity: a comparison of pentaerythritol tetranitrate with other organic nitrates. Mol Pharmacol 66:1372–1382CrossRefPubMed Daiber A, Oelze M, Coldewey M et al (2004) Oxidative stress and mitochondrial aldehyde dehydrogenase activity: a comparison of pentaerythritol tetranitrate with other organic nitrates. Mol Pharmacol 66:1372–1382CrossRefPubMed
2.
Zurück zum Zitat Daiber A, Wenzel P, Oelze M, Munzel T (2008) New insights into bioactivation of organic nitrates, nitrate tolerance and cross-tolerance. Clin Res Cardiol 97:12–20CrossRefPubMed Daiber A, Wenzel P, Oelze M, Munzel T (2008) New insights into bioactivation of organic nitrates, nitrate tolerance and cross-tolerance. Clin Res Cardiol 97:12–20CrossRefPubMed
3.
Zurück zum Zitat Dikalov S, Fink B, Skatchkov M et al (1998) Formation of reactive oxygen species by pentaerithrityltetranitrate and glyceryl trinitrate in vitro and development of nitrate tolerance. J Pharmacol Exp Ther 286:938–944PubMed Dikalov S, Fink B, Skatchkov M et al (1998) Formation of reactive oxygen species by pentaerithrityltetranitrate and glyceryl trinitrate in vitro and development of nitrate tolerance. J Pharmacol Exp Ther 286:938–944PubMed
4.
Zurück zum Zitat 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 91:1392–1394CrossRefPubMed 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 91:1392–1394CrossRefPubMed
5.
Zurück zum Zitat Gori T, Harvey P, Floras JS, Parker JD (2004) Continuous therapy with nitroglycerin impairs endothelium-dependent vasodilation but does not cause tolerance in conductance arteries: a human in vivo study. J Cardiovasc Pharmacol 44:601–606CrossRefPubMed Gori T, Harvey P, Floras JS, Parker JD (2004) Continuous therapy with nitroglycerin impairs endothelium-dependent vasodilation but does not cause tolerance in conductance arteries: a human in vivo study. J Cardiovasc Pharmacol 44:601–606CrossRefPubMed
6.
Zurück zum Zitat 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 132:1707–1714CrossRefPubMed 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 132:1707–1714CrossRefPubMed
7.
Zurück zum Zitat Hamburg NM, Keyes MJ, Larson MG et al (2008) Cross-sectional relations of digital vascular function to cardiovascular risk factors in the Framingham Heart Study. Circulation 117:2467–2474CrossRefPubMed Hamburg NM, Keyes MJ, Larson MG et al (2008) Cross-sectional relations of digital vascular function to cardiovascular risk factors in the Framingham Heart Study. Circulation 117:2467–2474CrossRefPubMed
8.
Zurück zum Zitat Hayoz D, Weber R, Rutschmann B et al (1995) Postischemic blood flow response in hypercholesterolemic patients. Hypertension 26:497–502PubMed Hayoz D, Weber R, Rutschmann B et al (1995) Postischemic blood flow response in hypercholesterolemic patients. Hypertension 26:497–502PubMed
9.
Zurück zum Zitat Hink U, Daiber A, Kayhan N et al (2007) Oxidative inhibition of the mitochondrial aldehyde dehydrogenase promotes nitroglycerin tolerance in human blood vessels. J Am Coll Cardiol 50:2226–2232CrossRefPubMed Hink U, Daiber A, Kayhan N et al (2007) Oxidative inhibition of the mitochondrial aldehyde dehydrogenase promotes nitroglycerin tolerance in human blood vessels. J Am Coll Cardiol 50:2226–2232CrossRefPubMed
10.
Zurück zum Zitat Huang AL, Silver AE, Shvenke E et al (2007) Predictive value of reactive hyperemia for cardiovascular events in patients with peripheral arterial disease undergoing vascular surgery. Arterioscler Thromb Vasc Biol 27:2113–2119CrossRefPubMed Huang AL, Silver AE, Shvenke E et al (2007) Predictive value of reactive hyperemia for cardiovascular events in patients with peripheral arterial disease undergoing vascular surgery. Arterioscler Thromb Vasc Biol 27:2113–2119CrossRefPubMed
11.
Zurück zum Zitat Jurt U, Gori T, Ravandi A et al (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 38:854–859CrossRefPubMed Jurt U, Gori T, Ravandi A et al (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 38:854–859CrossRefPubMed
12.
Zurück zum Zitat Kojda G, Stein D, Kottenberg E et al (1995) In vivo effects of pentaerythrityl-tetranitrate and isosorbide-5-mononitrate on the development of atherosclerosis and endothelial dysfunction in cholesterol-fed rabbits. J Cardiovasc Pharmacol 25:763–773CrossRefPubMed Kojda G, Stein D, Kottenberg E et al (1995) In vivo effects of pentaerythrityl-tetranitrate and isosorbide-5-mononitrate on the development of atherosclerosis and endothelial dysfunction in cholesterol-fed rabbits. J Cardiovasc Pharmacol 25:763–773CrossRefPubMed
13.
Zurück zum Zitat Li C, Hossieny P, Wu BJ et al (2007) Pharmacologic induction of heme oxygenase-1. Antioxid Redox Signal 9:2227–2239CrossRefPubMed Li C, Hossieny P, Wu BJ et al (2007) Pharmacologic induction of heme oxygenase-1. Antioxid Redox Signal 9:2227–2239CrossRefPubMed
14.
Zurück zum Zitat Meredith IT, Currie KE, Anderson TJ et al (1996) Postischemic vasodilation in human forearm is dependent on endothelium-derived nitric oxide. Am J Physiol 270:H1435–H1440PubMed Meredith IT, Currie KE, Anderson TJ et al (1996) Postischemic vasodilation in human forearm is dependent on endothelium-derived nitric oxide. Am J Physiol 270:H1435–H1440PubMed
15.
Zurück zum Zitat Mitchell GF, Parise H, Vita JA et al (2004) Local shear stress and brachial artery flow-mediated dilation: the Framingham Heart Study. Hypertension 44:134–139CrossRefPubMed Mitchell GF, Parise H, Vita JA et al (2004) Local shear stress and brachial artery flow-mediated dilation: the Framingham Heart Study. Hypertension 44:134–139CrossRefPubMed
16.
Zurück zum Zitat Morita T (2005) Heme oxygenase and atherosclerosis. Arterioscler Thromb Vasc Biol 25:1786–1795CrossRefPubMed Morita T (2005) Heme oxygenase and atherosclerosis. Arterioscler Thromb Vasc Biol 25:1786–1795CrossRefPubMed
17.
Zurück zum Zitat Munzel T, Daiber A, Mulsch A (2005) Explaining the phenomenon of nitrate tolerance. Circ Res 97:618–628CrossRefPubMed Munzel T, Daiber A, Mulsch A (2005) Explaining the phenomenon of nitrate tolerance. Circ Res 97:618–628CrossRefPubMed
18.
Zurück zum Zitat Nakamura Y, Moss AJ, Brown MW et al (1999) Long-term nitrate use may be deleterious in ischemic heart disease: A study using the databases from two large-scale postinfarction studies. Multicenter Myocardial Ischemia Research Group. Am Heart J 138:577–585CrossRefPubMed Nakamura Y, Moss AJ, Brown MW et al (1999) Long-term nitrate use may be deleterious in ischemic heart disease: A study using the databases from two large-scale postinfarction studies. Multicenter Myocardial Ischemia Research Group. Am Heart J 138:577–585CrossRefPubMed
19.
Zurück zum Zitat Oberle S, Abate A, Grosser N et al (2002) Heme oxygenase-1 induction may explain the antioxidant profile of pentaerythrityl trinitrate. Biochem Biophys Res Commun 290:1539–1544CrossRefPubMed Oberle S, Abate A, Grosser N et al (2002) Heme oxygenase-1 induction may explain the antioxidant profile of pentaerythrityl trinitrate. Biochem Biophys Res Commun 290:1539–1544CrossRefPubMed
20.
Zurück zum Zitat Ostad MA, Eggeling S, Tschentscher P et al (2009) Flow-mediated dilation in patients with coronary artery disease is enhanced by high dose atorvastatin compared to combined low dose atorvastatin and ezetimibe: results of the CEZAR study. Atherosclerosis 205:227–232CrossRefPubMed Ostad MA, Eggeling S, Tschentscher P et al (2009) Flow-mediated dilation in patients with coronary artery disease is enhanced by high dose atorvastatin compared to combined low dose atorvastatin and ezetimibe: results of the CEZAR study. Atherosclerosis 205:227–232CrossRefPubMed
21.
Zurück zum Zitat Philpott A, Anderson TJ (2007) Reactive hyperemia and cardiovascular risk. Arterioscler Thromb Vasc Biol 27:2065–2067CrossRefPubMed Philpott A, Anderson TJ (2007) Reactive hyperemia and cardiovascular risk. Arterioscler Thromb Vasc Biol 27:2065–2067CrossRefPubMed
22.
Zurück zum Zitat Pyke KE, Tschakovsky ME (2007) Peak vs. total reactive hyperemia: which determines the magnitude of flow-mediated dilation? J Appl Physiol 102:1510–1519CrossRefPubMed Pyke KE, Tschakovsky ME (2007) Peak vs. total reactive hyperemia: which determines the magnitude of flow-mediated dilation? J Appl Physiol 102:1510–1519CrossRefPubMed
23.
Zurück zum Zitat Sekiya M, Sato M, Funada J et al (2005) Effects of the long-term administration of nicorandil on vascular endothelial function and the progression of arteriosclerosis. J Cardiovasc Pharmacol 46:63–67CrossRefPubMed Sekiya M, Sato M, Funada J et al (2005) Effects of the long-term administration of nicorandil on vascular endothelial function and the progression of arteriosclerosis. J Cardiovasc Pharmacol 46:63–67CrossRefPubMed
24.
Zurück zum Zitat Thomas GR, DiFabio JM, Gori 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 49:1289–1295CrossRefPubMed Thomas GR, DiFabio JM, Gori 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 49:1289–1295CrossRefPubMed
25.
Zurück zum Zitat Thomas MK, Narang D, Lakshmy R et al (2006) Correlation between inflammation and oxidative stress in normocholesterolemic coronary artery disease patients ‘on’ and ‘off’ atorvastatin for short time intervals. Cardiovasc Drugs Ther 20:37–44CrossRefPubMed Thomas MK, Narang D, Lakshmy R et al (2006) Correlation between inflammation and oxidative stress in normocholesterolemic coronary artery disease patients ‘on’ and ‘off’ atorvastatin for short time intervals. Cardiovasc Drugs Ther 20:37–44CrossRefPubMed
26.
Zurück zum Zitat Warnholtz A, Mollnau H, Heitzer T et al (2002) Adverse effects of nitroglycerin treatment on endothelial function, vascular nitrotyrosine levels and cGMP-dependent protein kinase activity in hyperlipidemic Watanabe rabbits. J Am Coll Cardiol 40:1356–1363CrossRefPubMed Warnholtz A, Mollnau H, Heitzer T et al (2002) Adverse effects of nitroglycerin treatment on endothelial function, vascular nitrotyrosine levels and cGMP-dependent protein kinase activity in hyperlipidemic Watanabe rabbits. J Am Coll Cardiol 40:1356–1363CrossRefPubMed
27.
Zurück zum Zitat Warnholtz A, Ostad MA, Heitzer T et al (2005) Effect of tirofiban on percutaneous coronary intervention-induced endothelial dysfunction in patients with stable coronary artery disease. Am J Cardiol 95:20–23CrossRefPubMed Warnholtz A, Ostad MA, Heitzer T et al (2005) Effect of tirofiban on percutaneous coronary intervention-induced endothelial dysfunction in patients with stable coronary artery disease. Am J Cardiol 95:20–23CrossRefPubMed
28.
Zurück zum Zitat Wenzel P, Oelze M, Coldewey M et al (2007) Heme oxygenase-1: a novel key player in the development of tolerance in response to organic nitrates. Arterioscler Thromb Vasc Biol 27:1729–1735CrossRefPubMed Wenzel P, Oelze M, Coldewey M et al (2007) Heme oxygenase-1: a novel key player in the development of tolerance in response to organic nitrates. Arterioscler Thromb Vasc Biol 27:1729–1735CrossRefPubMed
Metadaten
Titel
Effects of pentaerythritol tetranitrate on endothelial function in coronary artery disease: results of the PENTA study
verfasst von
Boris Schnorbus
Robert Schiewe
Mir Abolfazl Ostad
Christoph Medler
Daniel Wachtlin
Philip Wenzel
Andreas Daiber
Thomas Münzel
Ascan Warnholtz
Publikationsdatum
01.02.2010
Verlag
Springer-Verlag
Erschienen in
Clinical Research in Cardiology / Ausgabe 2/2010
Print ISSN: 1861-0684
Elektronische ISSN: 1861-0692
DOI
https://doi.org/10.1007/s00392-009-0096-z

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