On the Mechanism of Antihypertensive Action of Hydrochlorothiazide in Rats

• Chlorothiazide and congeners, such as hydrochlorothiazide, have been shown to decrease the blood pressure in hypertensive patients' and animals. Indeed, all potent diuretics have been suggested to possess some antihypei-tensive properties either alone or in combination with other agents.' B Two consequences of the diuretic action of chlorothiazide have been postulated to account for its hypotensive effects: reduction in plasma volume and extracellular fluid volume (ECPV) and reduction in cellular sodium concentration with consequent alteration in the sodium gradient and in cellular function." Although reduction in ECPV following chlorothiazide has been repeatedly demonstrated, continued treatment may result in restoration of ECFV but not of the original blood pressure." Direct evidence for reduction of cellular sodium concentration is lacking. As has been recently emphasized, the mechanisms whereby blood pressure may be lowered are limited and involve usually either reduction in cardiac output or decrease in vascular resistance to flow. If the hypotensive action of chlorothiazide operated through reduction in extracellular sodium and fluid, it might act by decreasing cardiac output, and this has been reported to occur in hypertensive patients treated with the drug." However, reduction in plasma volume or extracellular fluid volume is not alone sufficient condition for causing reduced blood pressure since a similar reduction in ECFV in normotensive patients does not lower blood pressure. Further reduction of cardiac output does not