Antihypertensive action of benzothiadiazines.

C HLOROTHIAZIDE and other diuretics of similar structure have become established as valuable therapeutic agents in the control of hypertension. While not entirely free of toxicity, these drugs produce few disturbing side-effects. In addition, they have a relatively flat dose response curve in the therapeutic range. This permits fairly uniform dose schedules, which is an important feature of drugs used in general practice. Finally, they have the valuable characteristic of enhancing the antihyper-tensive effects of other blood pressure-reducing drugs such as reserpine, hydralazine, guanethidine, and methyldopa. This permits lower and, hence, less toxic doses of the latter drugs. Three possible mechanisms have been advanced to explain the antihypertensive effects of the thiazide diuretics. The first two implicate the sodium-depleting effect of chlorothiazide while the third claims that thiazides act by a vasodilator mechanism that is independent of the saluretic effect. A specific vasodilator effect of chloro-thiazide discrete from its natriuretic action was first proposed by Hollander, Chobanian, and Wilkins. l Their evidence was based on the observation that normotensive control subjects did not exhibit an anti-hypertensive effect, despite a similar diure-sis, and that the reduction in blood pressure began prior to a significant diuresis. This view received some support by the later discovery of diazoxide, a chemically related benzothiadiazine compound.