Chlorothiazide in Hypertensive and Normotensive Patients

Abstract

Chlorothiazide was synthesized by Novello and Sprague' and found to be a potent, orally effective diuretic and saluretic agent by Beyer, Baer, RUSSO, and Haimbach.2 Ford, Moyer, and Spurr3 have reported on its diuretic and saluretic properties in patients with edema. Because of its pronounced saluretic action a clinical trial of this agent was undertaken in hypertensive patients.The present report covers our experience to date in 105 patients, 90 of whom were hypertensive. In the beginning our major interest was in the attempt to potentiate the action of other antihypertensive drugs. A summary of early results was submitted as an abstract to

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.…”

“…The addition of 20 Gm. of salt daily to Circulation, Volume XXIII, February 1961 hydrochlorothiazide therapy in nine patients and chlorotlliazide therapy in one patient returned body weight and blood pressure to pretreatment levels, but further lowered 24-hour exchangeable potassium.…”

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.…”

The Effects of Hydrochlorothiazide and Frusemide on Noradrenaline Sensitivity and Blood Pressure of Salt‐loaded Rats Before and After Nephrectomy

“…Hydrochlorothiazide has also been shown to lower the resting blood pressure of rats made hypertensive by treatment with both deoxycorticosterone acetate and a high salt intake (Friedman et al, 1960) but there are no prior reports available of the antihypertensive effect either of hydrochlorothiazide or of frusemide in rats made hypertensive by administration of salt alone. Whereas the benzothiadiazines lower the blood pressure solely in hypertensive subjects (Freis et al, 1958) they depress vascular sensitivity to catecholamines in both hypertensive and normotensive man (Freis et al, 1958), in normotensive dogs (Beavers & Blackmore, 1958) and in normotensive rats (Cession, 1964). This action of the benzothiadiazines has now been demonstrated for hydrochlorothiazide and for frusemide in rats made hypertensive solely by chronic salt loading.…”

“…It was at first assumed that these drugs were hypotensive in man by consequence of their diuretic action because the initial fall in the resting blood pressure of hypertensive patients was accompanied by reduction in plasma volume, cardiac output and plasma concentration of sodium (Freis, Wanko, Wilson & Parrish, 1958;Fuchs, Moyer & Newman, 1960). After approximately 5 days of continuous therapy with a benzothiadiazine, however, refractoriness to the diuretic effect develops; plasma volume, cardiac output and plasma electrolytes are restored, but the hypotensive action remains (Gifford, Mattox, Orvis, Sones & Rosenvear, 1961;Talso & Carballo, 1960;Freis et al, 1958;Fuchs et al, 1960;Conway & Lauwers, 1961). The similarity of the diuretic effects of these compounds in normal and hypertensive patients (Hollander, Chobanian & Wilkins, 1960) contrasts with their ability to lower the blood pressure solely in the hypertensives (Freis et al, 1958;Friedman, Nakashima & Friedman, 1960) and again stresses the dissociation of these two actions.…”