Mechanisms for blood pressure lowering and metabolic effects of thiazide and thiazide-like diuretics

Abstract

Thiazide and thiazide-like diuretics are among the most commonly used antihypertensives and have been available for over 50 years. However, the mechanism by which these drugs chronically lower blood pressure is poorly understood. Possible mechanisms include direct endothelial- or vascular smooth muscle-mediated vasodilation and indirect compensation to acute decreases in cardiac output. In addition, thiazides are associated with adverse metabolic effects, particularly hyperglycemia, and the mechanistic underpinnings of these effects are also poorly understood. Thiazide-induced hypokalemia, as well as other theories to explain these metabolic disturbances, including increased visceral adiposity, hyperuricemia, decreased glucose metabolism and pancreatic β-cell hyperpolarization, may play a role. Understanding genetic variants with differential responses to thiazides could reveal new mechanistic candidates for future research to provide a more complete understanding of the blood pressure and metabolic response to thiazide diuretics.

Keywords::

• chlorthalidone
• epithelial sodium channel
• hydrochlorothiazide
• hypertension
• metabolic syndrome
• pharmacogenetics
• potassium
• sodium–chloride cotransporter
• thiazide

Financial & competing interests disclosure

This work is supported in part by NIH grants T32DK007518, K23HL086558 and GM074492. The authors 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.

No writing assistance was utilized in the production of this manuscript.