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.
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