Skip to main content
SpringerLink
Log in

Influence of the aldehyde dehydrogenase 2 polymorphism on the vasodilatory effect of nitroglycerin in infants with congenital heart disease and pulmonary arterial hypertension

  • Clinical Trial
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

The influence of the aldehyde dehydrogenase 2 (ALDH2) gene polymorphism on the pharmacokinetics and haemodynamics of nitroglycerin (GTN) was determined in human subjects.

Methods

Eighteen infants (nine each with and without ALDH2 gene polymorphism) with congenital heart disease and pulmonary arterial hypertension participated in this study. GTN treatment started at a dose of 2 μg/kg/min, and the dose was escalated by 1–2 μg/kg/min until pulmonary vascular resistance (PVR) was reduced by more than 30%. The plasma GTN concentration and PVR were measured at the end of each infusion period.

Results

Plasma GTN concentrations were significantly higher in patients with the ALDH2 gene polymorphism than in those without the polymorphism. Conversely, the reduction in PVR was smaller in patients with the ALDH2 gene polymorphism than in those without.

Conclusions

These data suggest that the ALDH2 gene polymorphism influences the pharmacokinetics and haemodynamics of GTN in human subjects.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Abman SH, Hansmann G, Archer SL, Ivy DD, Adatia I, Chung WK et al (2015) Pediatric pulmonary hypertension: guidelines from the American Heart Association and American Thoracic Society. Circulation 132:2037–2099

    Article  PubMed  Google Scholar 

  2. Cheng JW, Tonelli AR, Pettersson G, Krasuski RA (2014) Pharmacologic management of perioperative pulmonary hypertension. J Cardiovasc Pharmacol 63:375–384

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Chen Z, Zhang J, Stamler JSI (2002) Dentification of the enzymatic mechanism of nitroglycerin bioactivation. Proc Natl Acad Sci U S A 99:8306–8311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Lang BS, Gorren ACF, Oberdorfer G, Wenzl MV, Furdui CM, Poole LB et al (2012) Vascular bioactivation of nitroglycerin by aldehyde dehydrogenase-2. Reaction in intermediates revealed by crystallography and mass spectrometry. J Biol Chem 287:38124–38134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Duell EJ, Sala N, Travier N, Munoz X, Boutron-Ruault MC, Clavel-Chapelon F et al (2012) Genetic variation in alcohol dehydrogenase (ADH1A, ADH1B, ADH1C, ADH7) and aldehyde dehydrogenase (ALDH2), alcohol consumption and gastric cancer risk in the European prospective investigation into Cancer and nutrition (EPIC) cohort. Carcinogenesis 33:361–367

    Article  CAS  PubMed  Google Scholar 

  6. Idewaki Y, Iwase M, Fujii H, Ohkuma T, Ide H, Kaizu S et al (2015) Association of genetically determined aldehyde dehydrogenase 2 activity with diabetic complications in relation to alcohol consumption in Japanese patients with type 2 diabetes mellitus: the Fukuoka diabetes registry. PLoS One 10:e0143288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Li Y, Zhang D, Jin W, Shao C, Yan P, Xu C et al (2006) Mitochondrial aldehyde dehydrogenase-2 (ALDH2) Glu504Lys polymorphism contributes to the variation in efficacy of sublingual nitroglycerin. J Clin Invest 116:506–511

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sakata S, Yoshihara T, Arima H, Shiraishi F, Oniki H, Takahashi-Yanaga F et al (2011) Differential effects of organic nitrates on arterial diameter among healthy Japanese participants with different mitochondrial aldehyde dehydrogenase 2 genotypes: randomized crossover trial. BMJ Open 1:e000133

    Article  PubMed  PubMed Central  Google Scholar 

  9. Miura T, Nishinaka T, Terada T, Yonezawa K (2017) Vasodilatory effect of nitroglycerin in Japanese subjects with different aldehyde dehydrogenase 2 (ALDH2) genotypes. Chem Biol Interact 276:40–45

    Article  CAS  PubMed  Google Scholar 

  10. Wippermann CF, Huth RG, Schmidt FX, Thul J, Betancor M, Schranz D (1996) Continuous measurement of cardiac output by the Fick principle in infants and children: comparison with the thermodilution method. Intensive Care Med 22:467–471

    Article  CAS  PubMed  Google Scholar 

  11. Amamoto K, Okamura T, Tamaki S, Kita Y, Tsujita Y, Kadowaki T et al (2002) Epidemiologic study of the association of low-km mitochondrial acetaldehyde dehydrogenase genotypes with blood pressure level and the prevalence of hypertension in a general population. Hypertens Res 25:857–864

    Article  CAS  PubMed  Google Scholar 

  12. Opelt M, Eroglu E, Waldeck-Weiermair M, Russwurm M, Koesling D, Malli R et al (2016) Formation of nitric oxide by aldehyde dehydrogenase-2 is necessary and sufficient for vascular bioactivation of nitroglycerin. J Biol Chem 291:24076–24084

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wenzl MV, Beretta M, Gorren AC, Zeller A, Baral PK, Gruber K et al (2009) Role of the general base glu-268 in nitroglycerin bioactivation and superoxide formation by aldehyde dehydrogenase-2. J Biol Chem 284:19878–19886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hill KE, Hunt RW, Jones R, Hoover RL, Burk RF (1992) Metabolism of nitroglycerin by smooth muscle cells. Involvement of glutathione and glutathione S-transferase. Biochem Pharmacol 43:561–566

    Article  CAS  PubMed  Google Scholar 

  15. Schroder H (1992) Cytochrome P-450 mediates bioactivation of organic nitrates. J Pharmacol Exp Ther 262:298–302

    CAS  PubMed  Google Scholar 

  16. Sulica R, Dinh HV, Dunsky K, Fuster V, Poon M (2005) The acute hemodynamic effect of iv nitroglycerin and dipyridamole in patients with pulmonary arterial hypertension: comparison with iv epoprostenol. Congest Heart Fail 11:139–144

    Article  CAS  PubMed  Google Scholar 

  17. Stewart MJ, Malek K, Crabb DW (1996) Distribution of messenger RNAs for aldehyde dehydrogenase 1, aldehyde dehydrogenase 2, and aldehyde dehydrogenase 5 in human tissues. J Investig Med 44:42–46

    CAS  PubMed  Google Scholar 

  18. Guo R, Chen X-P, Guo X, Chen L, Li D, Peng J et al (2008) 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 52:953–960

    Article  CAS  PubMed  Google Scholar 

  19. Chen Z, Foster MW, Zhang J, Mao L, Rockman HA, Kawamoto T et al (2005) An essential role for mitochondrial aldehyde dehydrogenase in nitroglycerin bioactivation. Proc Natl Acad Sci U S A 102:12159–12164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Mackenzie I, Maki-Petaja KM, McEniery CM, Bao YP, Wallace SM, Cheriyan J et al (2005) Aldehyde dehydrogenase 2 plays a role in the bioactivation of nitroglycerin in humans. Arterioscler Thromb Vasc Biol 25:1891–1895

    Article  CAS  PubMed  Google Scholar 

  21. Xia J, Song J, Zhang Y, An N, Ding L, Zhang Z (2015) Effect of aldehyde dehydrogenase 2 gene polymorphism on hemodynamics after nitroglycerin intervention in northern Chinese Han population. Chin Med J 128:180–184

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Islam MM, Iqbal U, Walther BA, Nguyen PA, Li YJ, Dubey NK et al (2017) Gender-based personalized pharmacotherapy: a systematic review. Arch Gynecol Obstet 295:1305–1317

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by a research grant from the Japan Research Foundation for Clinical Pharmacology (K.U.).

We thank the following collaborators for their kind support: Dr. Koichi Kataoka, Dr. Yoji Otsuka, Dr. Hidetaka Iwai and Dr. Kohei Sunoki (Department of Anesthesiology and Critical Care Medicine, Jichi Medical University); Dr. Ko Yoshizumi and Dr. Shinya Ugaki (Division of Paediatric and Congenital Cardiovascular Surgery, Jichi Children’s Medical Center Tochigi, Jichi Medical University); and Ms. Hisae Shiokawa (Division of Clinical Pharmacology, Department of Pharmacology, Jichi Medical University).

We thank Joe Barber Jr., PhD, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.

Author information

Author notes

  1. Kentaro Ushijima

    Present address: Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, Yamaguchi, Japan

Authors and Affiliations

  1. Division of Clinical Pharmacology, Department of Pharmacology, Jichi Medical University, Tochigi, 329-0498, Japan

    Tatsuya Nagano, Kentaro Ushijima, Kenichi Aizawa, Yasushi Imai & Akio Fujimura

  2. Department of Anesthesiology and Critical Care Medicine, Jichi Medical University, Tochigi, Japan

    Tatsuya Nagano, Naoyuki Taga & Mamoru Takeuchi

  3. Division of Pediatric and Congenital Cardiovascular Surgery, Jichi Children’s Medical Center Tochigi, Jichi Medical University, Tochigi, Japan

    Masa-aki Kawada

Authors
  1. Tatsuya Nagano
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kentaro Ushijima
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Naoyuki Taga
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mamoru Takeuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Masa-aki Kawada
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kenichi Aizawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yasushi Imai
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Akio Fujimura
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceived of or designed study: Tatsuya Nagano, Kentaro Ushijima, Kenichi Aizawa, Yasushi Imai, Akio Fujimura.

Performed research: Tatsuya Nagano, Naoyuki Taga, Mamoru Takeuchi, Masa-aki Kawada.

Analysed data: Tatsuya Nagano, Kentaro Ushijima.

Contributed new methods or models: Tatsuya Nagano, Kentaro Ushijima.

Wrote the paper: Tatsuya Nagano, Kentaro Ushijima, Yasushi Imai, Akio Fujimura.

Corresponding author

Correspondence to Akio Fujimura.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest in relation to this work.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(DOCX 27 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nagano, T., Ushijima, K., Taga, N. et al. Influence of the aldehyde dehydrogenase 2 polymorphism on the vasodilatory effect of nitroglycerin in infants with congenital heart disease and pulmonary arterial hypertension. Eur J Clin Pharmacol 75, 1361–1367 (2019). https://doi.org/10.1007/s00228-019-02709-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-019-02709-x

Keywords

Search

Navigation