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Cardiovascular medicine
Research
Differential effects of organic nitrates on arterial diameter among healthy Japanese participants with different mitochondrial aldehyde dehydrogenase 2 genotypes: randomised crossover trial
  1. Satoko Sakata1,
  2. Tatsuya Yoshihara2,
  3. Hisatomi Arima3,
  4. Fumie Shiraishi2,
  5. Hideyuki Oniki1,
  6. Fumi Takahashi-Yanaga2,
  7. Kiyoshi Matsumura1,
  8. Toshiyuki Sasaguri2
  1. 1Department of Medicine and Clinical Science, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
  2. 2Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
  3. 3George Institute for Global Health, The University of Sydney, Sydney, Australia
  1. Correspondence to Professor Toshiyuki Sasaguri; sasaguri{at}med.kyushu-u.ac.jp

Abstract

Objectives To determine whether polymorphisms at codon 487 (*1, GAA=Glu; *2, AAA=Lys) of mitochondrial aldehyde dehydrogenase 2 (ALDH2) influence nitroglycerine (glyceryl trinitrate (GTN))-induced vasodilation, and whether GTN or isosorbide dinitrate (ISDN) is a more effective antianginal agent in each ALDH2 genotype.

Design A randomised, open-label, crossover trial with 117 healthy Japanese (20–39 years) whose genotypes were determined (*1/*1, n=47; *1/*2, n=48; *2/*2, n=22) was performed at Kyushu University Hospital, Fukuoka, Japan. Participants were randomly assigned to treatment: sublingual spray of GTN (0.3 mg) or ISDN (1.25 mg). After ≥1 week, measurements were repeated using the other drug. The main outcome measures were the maximal rate of increase in the brachial artery diameter determined by ultrasonography, the time required to attain maximal dilation (Tmax) and the time required to attain 90% maximal dilation (T0.9).

Results The maximal artery diameter increase in response to GTN or ISDN did not differ among genotypes. However, GTN Tmax was significantly longer for *2/*2 (299.7 s, 269.0–330.4) than *1/*1 (254.7 s, 238.6–273.4; p=0.0190). GTN T0.9 was significantly longer in the *1/*2 (206.1 s, 191.7–219.3) and *2/*2 (231.4 s, 211.8–251.0) genotypes than *1/*1 (174.9 s, 161.5–188.3; p=0.0068, p<0.0001, respectively). In contrast, the time-course of ISDN-induced vasodilation did not differ among genotypes. GTN Tmax and T0.9 among *1 allele carriers (*1/*1 and *1/*2) were significantly shorter than those of ISDN, whereas the time course of GTN and ISDN vasodilation did not differ among participants carrying *2/*2.

Conclusions The amplitude of GTN-induced vasodilation was not influenced by the ALDH2 genotype, but the response was significantly delayed in *2 allele carriers, especially *2/*2. GTN dilated the artery more quickly than ISDN in *1/*1 and *1/*2, but not in *2/*2.

Trial registration number UMIN000001492 (UMIN-CTR database).

  • Clinical pharmacology
  • therapeutics
  • hypertension
  • ischaemic heart disease
  • heart failure

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.

https://doi.org/10.1136/bmjopen-2011-000133

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    Footnotes

    • To cite: 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:e000133. doi:10.1136/bmjopen-2011-000133

    • Funding This work was supported by Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan (grant number 20390160).

    • Competing interests None.

    • Ethics approval Ethics approval was provided by the Institutional Review Board for Clinical Trials, Kyushu University Hospital.

    • Contributors TS, KM, HA and FT-Y conceived and designed the study and wrote the protocol. SS, TY, HO and TS recruited participants, obtained informed consent and acquired the data. FS determined participants' genotypes. SS, TY, KM, and TS analysed and interpreted the data. HA undertook sample size calculation, randomisation, and statistical analyses. TS obtained funding. All authors wrote and revised the manuscript, and all approved the publication of the final version. All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. TS is guarantor.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement The full study protocol and data will not be publicly accessible. Interested individuals may contact the authors.