Effects of four different antihypertensive drugs on plasma metabolomic profiles in patients with essential hypertension

Timo P Hiltunen, Jenni M Rimpelä, Robert P Mohney, Steven M Stirdivant, Kimmo K Kontula, Timo P Hiltunen, Jenni M Rimpelä, Robert P Mohney, Steven M Stirdivant, Kimmo K Kontula

Abstract

Objective: In order to search for metabolic biomarkers of antihypertensive drug responsiveness, we measured >600 biochemicals in plasma samples of subjects participating in the GENRES Study. Hypertensive men received in a double-blind rotational fashion amlodipine, bisoprolol, hydrochlorothiazide and losartan, each as a monotherapy for one month, with intervening one-month placebo cycles.

Methods: Metabolomic analysis was carried out using ultra high performance liquid chromatography-tandem mass spectrometry. Full metabolomic signatures (the drug cycles and the mean of the 3 placebo cycles) became available in 38 to 42 patients for each drug. Blood pressure was monitored by 24-h recordings.

Results: Amlodipine (P values down to 0.002), bisoprolol (P values down to 2 x 10-5) and losartan (P values down to 2 x 10-4) consistently decreased the circulating levels of long-chain acylcarnitines. Bisoprolol tended to decrease (P values down to 0.002) the levels of several medium- and long-chain fatty acids. Hydrochlorothiazide administration was associated with an increase of plasma uric acid level (P = 5 x 10-4) and urea cycle metabolites. Decreases of both systolic (P = 0.06) and diastolic (P = 0.04) blood pressure after amlodipine administration tended to associate with a decrease of plasma hexadecanedioate, a dicarboxylic fatty acid recently linked to blood pressure regulation.

Conclusions: Although this systematic metabolomics study failed to identify circulating metabolites convincingly predicting favorable antihypertensive response to four different drug classes, it provided accumulating evidence linking fatty acid metabolism to human hypertension.

Conflict of interest statement

Competing Interests: TPH, JMR and KKK declare no competing interest. RPM and SMS are employees of Metabolon Inc. and, as such, have affiliations with or financial involvement with Metabolon Inc. RPM and SMS have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. The commercial affiliation of RPM and SMS does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Effect of antihypertensive drugs on…
Fig 1. Effect of antihypertensive drugs on selected plasma acylcarnitines.
Plasma metabolite level is presented as relative units: the median of all analyzed samples was set to 1. Box-and-whisker plots are presented. P values

Fig 2. Effect of antihypertensive drugs on…

Fig 2. Effect of antihypertensive drugs on selected plasma long-chain fatty acids.

Plasma metabolite level…

Fig 2. Effect of antihypertensive drugs on selected plasma long-chain fatty acids.
Plasma metabolite level is presented as relative units: the median of all analyzed samples was set to 1. Box-and-whisker plots are presented. P values

Fig 3. Effect of antihypertensive drugs on…

Fig 3. Effect of antihypertensive drugs on uric acid and its precursors.

Plasma metabolite level…

Fig 3. Effect of antihypertensive drugs on uric acid and its precursors.
Plasma metabolite level is presented as relative units: the median of all analyzed samples was set to 1. Box-and-whisker plots are presented. P values

Fig 4. Correlation of the change of…

Fig 4. Correlation of the change of plasma cysteinylglycine and hexadecanedioate levels with the antihypertensive…

Fig 4. Correlation of the change of plasma cysteinylglycine and hexadecanedioate levels with the antihypertensive effect of amlodipine.
Correlation coefficients (r) and P values from partial correlation, calculated with normalized metabolite change values and controlling for metabolite baseline level, are included. dASBP, change of 24-hour ambulatory systolic blood pressure; dADBP, change of 24-hour ambulatory diastolic blood pressure.
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References
    1. Lim SS, Vos T, Flaxman AD, Danaei G, Shibuya K, Adair-Rohani H, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380: 2224–2260. doi: 10.1016/S0140-6736(12)61766-8 - DOI - PMC - PubMed
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    1. Egan BM, Zhao Y, Axon RN. US trends in prevalence, awareness, treatment, and control of hypertension, 1988–2008. JAMA. 2010;303: 2043–2050. doi: 10.1001/jama.2010.650 - DOI - PubMed
    1. Banegas JR, Lopez-Garcia E, Dallongeville J, Guallar E, Halcox JP, Borghi C, et al. Achievement of treatment goals for primary prevention of cardiovascular disease in clinical practice across Europe: the EURIKA study. Eur Heart J. 2011;32: 2143–2152. doi: 10.1093/eurheartj/ehr080 - DOI - PMC - PubMed
    1. Ehret GB, Caulfield MJ. Genes for blood pressure: an opportunity to understand hypertension. Eur Heart J. 2013;34: 951–961. doi: 10.1093/eurheartj/ehs455 - DOI - PMC - PubMed
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The present study was supported by grants from The Sigrid Juselius Foundation and The Finnish Foundation for Cardiovascular Research. These foundations provided support in the form of salary to the study technician (but not to any of the authors) and in the form of full coverage of the metabolomic analyses, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Metabolon Inc. performed the metabolomic analyses on a fully commercial (fee per sample) basis. Metabolon Inc. had no role in the funding or planning of the study, nor did the authors (RPM and SMS) employed by it.
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Fig 2. Effect of antihypertensive drugs on…
Fig 2. Effect of antihypertensive drugs on selected plasma long-chain fatty acids.
Plasma metabolite level is presented as relative units: the median of all analyzed samples was set to 1. Box-and-whisker plots are presented. P values

Fig 3. Effect of antihypertensive drugs on…

Fig 3. Effect of antihypertensive drugs on uric acid and its precursors.

Plasma metabolite level…

Fig 3. Effect of antihypertensive drugs on uric acid and its precursors.
Plasma metabolite level is presented as relative units: the median of all analyzed samples was set to 1. Box-and-whisker plots are presented. P values

Fig 4. Correlation of the change of…

Fig 4. Correlation of the change of plasma cysteinylglycine and hexadecanedioate levels with the antihypertensive…

Fig 4. Correlation of the change of plasma cysteinylglycine and hexadecanedioate levels with the antihypertensive effect of amlodipine.
Correlation coefficients (r) and P values from partial correlation, calculated with normalized metabolite change values and controlling for metabolite baseline level, are included. dASBP, change of 24-hour ambulatory systolic blood pressure; dADBP, change of 24-hour ambulatory diastolic blood pressure.
Similar articles
Cited by
References
    1. Lim SS, Vos T, Flaxman AD, Danaei G, Shibuya K, Adair-Rohani H, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380: 2224–2260. doi: 10.1016/S0140-6736(12)61766-8 - DOI - PMC - PubMed
    1. Poulter NR, Prabhakaran D, Caulfield M. Hypertension. Lancet. 2015;386: 801–812. doi: 10.1016/S0140-6736(14)61468-9 - DOI - PubMed
    1. Egan BM, Zhao Y, Axon RN. US trends in prevalence, awareness, treatment, and control of hypertension, 1988–2008. JAMA. 2010;303: 2043–2050. doi: 10.1001/jama.2010.650 - DOI - PubMed
    1. Banegas JR, Lopez-Garcia E, Dallongeville J, Guallar E, Halcox JP, Borghi C, et al. Achievement of treatment goals for primary prevention of cardiovascular disease in clinical practice across Europe: the EURIKA study. Eur Heart J. 2011;32: 2143–2152. doi: 10.1093/eurheartj/ehr080 - DOI - PMC - PubMed
    1. Ehret GB, Caulfield MJ. Genes for blood pressure: an opportunity to understand hypertension. Eur Heart J. 2013;34: 951–961. doi: 10.1093/eurheartj/ehs455 - DOI - PMC - PubMed
Show all 42 references
Publication types
MeSH terms
Substances
Related information
Grant support
The present study was supported by grants from The Sigrid Juselius Foundation and The Finnish Foundation for Cardiovascular Research. These foundations provided support in the form of salary to the study technician (but not to any of the authors) and in the form of full coverage of the metabolomic analyses, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Metabolon Inc. performed the metabolomic analyses on a fully commercial (fee per sample) basis. Metabolon Inc. had no role in the funding or planning of the study, nor did the authors (RPM and SMS) employed by it.
[x]
Cite
Copy Download .nbib
Format: AMA APA MLA NLM
Fig 3. Effect of antihypertensive drugs on…
Fig 3. Effect of antihypertensive drugs on uric acid and its precursors.
Plasma metabolite level is presented as relative units: the median of all analyzed samples was set to 1. Box-and-whisker plots are presented. P values

Fig 4. Correlation of the change of…

Fig 4. Correlation of the change of plasma cysteinylglycine and hexadecanedioate levels with the antihypertensive…

Fig 4. Correlation of the change of plasma cysteinylglycine and hexadecanedioate levels with the antihypertensive effect of amlodipine.
Correlation coefficients (r) and P values from partial correlation, calculated with normalized metabolite change values and controlling for metabolite baseline level, are included. dASBP, change of 24-hour ambulatory systolic blood pressure; dADBP, change of 24-hour ambulatory diastolic blood pressure.
Fig 4. Correlation of the change of…
Fig 4. Correlation of the change of plasma cysteinylglycine and hexadecanedioate levels with the antihypertensive effect of amlodipine.
Correlation coefficients (r) and P values from partial correlation, calculated with normalized metabolite change values and controlling for metabolite baseline level, are included. dASBP, change of 24-hour ambulatory systolic blood pressure; dADBP, change of 24-hour ambulatory diastolic blood pressure.

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