Mechanism of Thiazide Diuretic Arterial Pressure Reduction: The Search Continues

Abstract

Thiazide diuretic (TZD)-mediated chronic reduction of arterial pressure is thought to occur through decreased total peripheral vascular resistance. Further, the decreased peripheral vascular resistance is accomplished through TZD activation of an extrarenal target, resulting in inhibition of vascular constriction. However, despite greater than five decades of investigation, little progress has been made into the identification of the TZD extrarenal target. Proposed mechanisms range from direct inhibition of constrictor and activation of relaxant signaling pathways in the vascular smooth muscle to indirect inhibition through decreased neurogenic and hormonal regulatory pathways. Surprisingly, particularly in view of this lack of progress, comprehensive reviews of the subject are absent. Moreover, even though it is well recognized that 1) several types of hypertension are insensitive to TZD reduction of arterial pressure and, further, TZD fail to reduce arterial pressure in normotensive subjects and animals, and 2) different mechanisms underlie acute and chronic TZD, findings derived from these models and parameters remain largely undifferentiated. This review 1) comprehensively describes findings associated with TZD reduction of arterial pressure; 2) differentiates between observations in TZD-sensitive and TZD-insensitive hypertension, normotensive subjects/animals, and acute and chronic effects of TZD; 3) critically evaluates proposed TZD extrarenal targets; 4) proposes guiding parameters for relevant investigations into extrarenal TZD target identification; and 5) proposes a working model for TZD chronic reduction of arterial pressure through vascular dilation.

Effect of drug interventions on cerebral hemodynamics in ischemic stroke patients

“…The precise mechanism for diuretics such as thiazides to lower blood pressure remains elusive (recently reviewed by Rapoport 43 ) but diuretic treatment is an effective antihypertensive strategy that reduces BP via renal excretion of salts and water. The three types of diuretics (thiazide, loop, potassium-sparing) will each target a different site of the kidney to reduce blood volume and reduce blood pressure.…”

Congenital Heart Disease: The State-of-the-Art on Its Pharmacological Therapeutics

“…These diuretics cause a natriuretic effect and a decrease in extracellular volume, venous return, cardiac output, and peripheral vascular resistance at high doses by targeting the reabsorption of sodium in the distal renal tubules [ 69 ]. Furthermore, both extracellular volume and cardiac output return to normal when administered chronically, but peripheral vascular resistance continues to decrease [ 70 ].…”

Independent relationships between renal mechanisms and systemic flow, but not resistance to flow in primary hypertension in Africa

“…Rather the present study suggests that alterations in renal function in some populations translate into chronic increases in systemic flow which sustain hypertension. Although current antihypertensives mediate their benefits in-part through renal mechanisms [4], the lack of evidence to show sustained decreases in systemic blood flow [4,5], suggest that alternative approaches to targeting the renal mechanisms of hypertension are critical in some populations.…”

“…In support of the importance of renal mechanisms in mediating sustained hypertension, most antihypertensives mediate renal effects that modify the pressure-natriuresis relationship [4]. However, antihypertensives, including diuretic gents, have no proven ability to reduce BP through sustained decreases in blood volume and hence systemic blood flow [5]. Nevertheless, renal mechanisms and abnormalities in Na + intake are thought to produce increases in BP through an enhanced systemic vascular resistance (SVR), with only transient increases in systemic blood flow accounting for renal effects [6].…”

“…Importantly, these effects were noted even in treated hypertensive individuals, the majority of whom were receiving thiazide diuretics as therapy [12]. As there are no antihypertensives, including diuretic agents [5], with a proven ability to produce sustained decreases in systemic blood flow, this raises the question of whether renal mechanisms indeed account for increases in systemic flow in some populations. If so, this would suggest that identifying novel renal targets for drug development may be necessary in some populations.…”