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

Abstract

ObjectiveIn 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.MethodsMetabolomic 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.ResultsAmlodipine (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.ConclusionsAlthough 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.

Metabolite Changes in Maternal and Fetal Plasma Following Spontaneous Labour at Term in Humans Using Untargeted Metabolomics Analysis: A Pilot Study

“…The samples were transported on dry ice to Metabolon, Inc. (Morrisville, NC, USA) for ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC/MS) [26,27,28]. All samples were analysed together in order to reduce risk of batch bias.…”

An Overview of Metabolic Phenotyping in Blood Pressure Research

“…Applications of metabolic phenotyping to blood pressure research have been multifaceted, including the study of lifestyle and environmental factors on blood pressure levels through biomarkers of exposure [ 50 – 61 ], investigation of disease pathophysiological processes [ 62 – 70 ] and evaluation of drug response to treatment for high blood pressure and associated side effects [ 71 – 77 ]. However, despite increasing interest in this area, most studies are still small, cross-sectional, and limited to targeted metabolic platforms.…”

“…Several studies have attempted to identify potential biomarkers of drug responsiveness and to understand the molecular mechanisms that lead to drug response variation in blood pressure. For example, 313 Finnish men with high blood pressure (aged 35 to 60 years) from the Genetics of Drug Responsiveness in Essential Hypertension (GENRES) study received in a double-blind rotational design amlodipine, bisoprolol, hydrochlorothiazide (HCTZ), and losartan, each as monotherapy for 1 month, with 1-month placebo cycles between each treatment [ 71 ]. Treatment led to decreased long-chain acyl carnitines (amlodipine, bisoprolol, losartan) and medium and long-chain fatty acids (bisoprolol).…”

Sexual Dimorphism of Metabolomic Profile in Arterial Hypertension

“…A variety of lipids were also reported to be quantitatively modified in hypertension, such as phosphatidylcholines, ceramides, phosphatidylinositols, diacylglycerols, and fatty acids 14,16,18,19 . Changes in these signatures under the influence of dietary interventions in hypertensive patients (proline-betaine, carnitine, hippurate, cresyl sulfate, phenylacetylglutamine, N-methyl-2-pyridone-5-carboxyamide, methionine sulfone, and β-hydroxyisovalerate) 20,21 or under various antihypertensive therapies (acylcarnitines, hexadecanedioate uric acid, lysophosphatidylcholines, triacylglycerols, and cholesterol esters) have also been reported [22][23][24] .…”