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

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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.

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References

  1. 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 66:1372–1382

    Article  CAS  PubMed  Google Scholar 

  2. Daiber A, Wenzel P, Oelze M, Munzel T (2008) New insights into bioactivation of organic nitrates, nitrate tolerance and cross-tolerance. Clin Res Cardiol 97:12–20

    Article  CAS  PubMed  Google Scholar 

  3. 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 286:938–944

    CAS  PubMed  Google Scholar 

  4. 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

    Article  CAS  PubMed  Google Scholar 

  5. 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 44:601–606

    Article  CAS  PubMed  Google Scholar 

  6. 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

    Article  CAS  PubMed  Google Scholar 

  7. 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 117:2467–2474

    Article  PubMed  Google Scholar 

  8. Hayoz D, Weber R, Rutschmann B et al (1995) Postischemic blood flow response in hypercholesterolemic patients. Hypertension 26:497–502

    CAS  PubMed  Google Scholar 

  9. 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 50:2226–2232

    Article  CAS  PubMed  Google Scholar 

  10. 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 27:2113–2119

    Article  CAS  PubMed  Google Scholar 

  11. 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 38:854–859

    Article  CAS  PubMed  Google Scholar 

  12. 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 25:763–773

    Article  CAS  PubMed  Google Scholar 

  13. Li C, Hossieny P, Wu BJ et al (2007) Pharmacologic induction of heme oxygenase-1. Antioxid Redox Signal 9:2227–2239

    Article  CAS  PubMed  Google Scholar 

  14. 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–H1440

    CAS  PubMed  Google Scholar 

  15. Mitchell GF, Parise H, Vita JA et al (2004) Local shear stress and brachial artery flow-mediated dilation: the Framingham Heart Study. Hypertension 44:134–139

    Article  CAS  PubMed  Google Scholar 

  16. Morita T (2005) Heme oxygenase and atherosclerosis. Arterioscler Thromb Vasc Biol 25:1786–1795

    Article  CAS  PubMed  Google Scholar 

  17. Munzel T, Daiber A, Mulsch A (2005) Explaining the phenomenon of nitrate tolerance. Circ Res 97:618–628

    Article  PubMed  Google Scholar 

  18. 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 138:577–585

    Article  CAS  PubMed  Google Scholar 

  19. 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 290:1539–1544

    Article  CAS  PubMed  Google Scholar 

  20. 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 205:227–232

    Article  CAS  PubMed  Google Scholar 

  21. Philpott A, Anderson TJ (2007) Reactive hyperemia and cardiovascular risk. Arterioscler Thromb Vasc Biol 27:2065–2067

    Article  CAS  PubMed  Google Scholar 

  22. Pyke KE, Tschakovsky ME (2007) Peak vs. total reactive hyperemia: which determines the magnitude of flow-mediated dilation? J Appl Physiol 102:1510–1519

    Article  PubMed  Google Scholar 

  23. 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 46:63–67

    Article  CAS  PubMed  Google Scholar 

  24. 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 49:1289–1295

    Article  CAS  PubMed  Google Scholar 

  25. 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 20:37–44

    Article  CAS  PubMed  Google Scholar 

  26. 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 40:1356–1363

    Article  CAS  PubMed  Google Scholar 

  27. 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 95:20–23

    Article  CAS  PubMed  Google Scholar 

  28. 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 27:1729–1735

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank Dr Stalleicken from Actavis Deutschland GmbH & Co., KG, Langenfeld, Germany for discussion of the study results, Jessica Wisniewski (IZKS) for supporting the statistical analysis and the presentation of the results and Hannelore Seiler for the performance of the vascular function studies. The study was supported by Actavis Deutschland GmbH & Co., KG, Langenfeld, Germany. Contribution of IZKS was supported by grant “Clinical Trial Centers, funding number FKN 01KN0703, IZKS Mainz” of German Federal Ministry of Education and Research.

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Correspondence to Ascan Warnholtz.

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B. Schnorbus and R. Schiewe have contributed equally to this study.

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Schnorbus, B., Schiewe, R., Ostad, M.A. et al. Effects of pentaerythritol tetranitrate on endothelial function in coronary artery disease: results of the PENTA study. Clin Res Cardiol 99, 115–124 (2010). https://doi.org/10.1007/s00392-009-0096-z

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  • DOI: https://doi.org/10.1007/s00392-009-0096-z

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