Mechanisms and pharmacogenetic signals underlying thiazide diuretics blood pressure response

Abstract

Thiazide (TZD) diuretics are among the most commonly prescribed antihypertensives globally; however their chronic blood pressure (BP) lowering mechanism remains unclear. Herein we discuss the current evidence regarding specific mechanisms regulating the antihypertensive effects of TZDs, suggesting that TZDs act via multiple complex and interacting mechanisms, including natriuresis with short term use and direct vasodilatory effects chronically. Additionally, we review pharmacogenomics signals that have been associated with TZDs BP-response in several cohorts (i.e. NEDD4L, PRKCA, EDNRA-GNAS, and YEATS4) and discuss how these genes might be related to TZD BP-response mechanism. Understanding the association between these genes and TZD BP mechanism might facilitate the development of new drugs and therapeutic approaches based on a deeper understanding of the determinants of BP-response.

Copyright © 2016. Published by Elsevier Ltd.

Figures

Figure 1

Known and theoretical blood pressure lowering mechanisms of thiazide diuretics.

Figure 2

Blood pressure response to hydrochlorothiazide by NEDD4L rs4149601 genotype for White participants in PEAR study. Solid gray bars indicate change in systolic blood pressure (SBP), gray and white lined bars indicate change in diastolic blood pressure (DBP). Values are shown as mean ± standard error. Add; additive, DOM; dominant. Used with permission [34].

Figure 3

Blood pressure response to hydrochlorothiazide by PRKCA rs16960228 genotype for White participants from five independent studies. (a) Diastolic blood pressure response; (b) systolic blood pressure response. The blood pressure responses are adjusted for pretreatment blood pressure levels, age, and sex; P-values are for contrast of adjusted means between genotype groups. Used with permission [37].

Figure 4

Blood pressure response to hydrochlorothiazide by GNAS-EDN3 rs2273359 genotype for White participants from five independent studies. (a) Diastolic blood pressure response; (b) systolic blood pressure response. The blood pressure responses are adjusted for pretreatment blood pressure levels, age, and sex; P-values are for contrast of adjusted means between genotype groups. Used with permission [37].