Relationship Between Plasma and Extracellular Fluid Volume Depletion and the Antihypertensive Effect of Chlorothiazide

Abstract

The importance of plasma and extracellular fluid volumes in the mechanism of the antihypertensive effect of chlorothiazide is disputed. The present investigation indicates that the lowering of blood pressure is accompanied by reductions in plasma and extracellular fluid volumes and in body weight. Furthermore, re-expansion of plasma volume with salt-free dextran reverses the antihypertensive effect. However, since gradual reaccumulation of extracellular fluid occurs during 1 year of continuous treatment, the late antihypertensive effects of chlorothiazide cannot be explained by the volume-depletion mechanism.T HE discovery of the antihypertensive action of chlorothiazide" 2 raised certain questions as to its mechanism of action. These questions included (1) whether the hypotensive response was caused by salt depletion or by some independent factor; (2) if produced by salt loss, by what mechanism it reduced blood pressure; (3) the factors that lead to increased reactivity to other antihypertensive agents; and (4) the reason for the moderate antihypertensive action of the drug when used alone in hypertensive patients and the absence of such activity in normotensive subjects.3 4 Complete answers to these questions cannot yet be given. This report concerns an attempt to elucidate some of the factors involved. MATERIALS AND METHODSTwenty male hypertensive patients with no symptoms or signs of congestive heart failure or edema were hospitalized and placed on a standard diet containing 1.5 Gm. of salt per day plus a supplement of 3 Gm. of salt in tablet form. This supplied a sodium intake of approximately 75 mEq. per day. Most of these patients were From the Veterans Administration Hospital and

The Antihypertensive Actions of Benzothiadiazines

“…20 The degree of oligemia Circulation, Volume XXIII, February 1961 lessens in the course of several months. The reduction in plasma volume averaged 6 per cent after 2 months of continuous diuretic therapy in the present study (p<.05) and was insignificant after 6 months in another study.6 Right heart pressure and cardiac output were reduced and peripheral vascular resistance increased in the first few weeks in several studies21-23 but not in the study of Aleksandrow et al 19 After 1 month of chlorothiazide therapy, peripheral vascular resistance was decreased. 24 Oligemia and reduced cardiac output will exaggerate the effects of other drugs or pathophysiologic states influencing venous return, cardiac output, or vascular capacity.…”

How do thiazide and thiazide-like diuretics lower blood pressure?

“…37 At first sight, the blood pressure lowering action of thiazides seems obvious; diuretics will cause a reduction in plasma volume, diminish venous return and depress cardiac output and blood pressure. This mechanism does seem sufficient to explain most or all of the reduction in blood pressure seen in hypertensive subjects following acute administration of thiazides, [38][39][40][41][42] and re-expansion of plasma volume by infusion of dextran, with or without sodium, restores blood pressure to pre-treatment levels. 39,40 In association with the fall in cardiac output following acute administration of thiazide, there is a rise in total peripheral vascular resistance (TPR) that is mediated largely by the sympathetic nervous system (SNS) 43 and activation of the reninangiotensin-aldosterone system.…”

“…This mechanism does seem sufficient to explain most or all of the reduction in blood pressure seen in hypertensive subjects following acute administration of thiazides, [38][39][40][41][42] and re-expansion of plasma volume by infusion of dextran, with or without sodium, restores blood pressure to pre-treatment levels. 39,40 In association with the fall in cardiac output following acute administration of thiazide, there is a rise in total peripheral vascular resistance (TPR) that is mediated largely by the sympathetic nervous system (SNS) 43 and activation of the reninangiotensin-aldosterone system. 44,45 Activation of the SNS may persist after chronic use, 43 but variability in reflex responses may contribute to differences in blood pressure lowering, at least in the short term.…”

Invited Review

“…27,28 The fall in BP with chlorothiazide was associated with a reduction of approximately 25 mEq body sodium and 1 to 2 L of extracellular water, which included 15% of the plasma volume. 29 This loss occurred during the first 2 to 3 days of daily drug administration. No further reduction occurred with longer continuation of chlorothiazide.…”