It has been observed that the saluretic agent chlorothiazide (6-chloro-7-sulfamyl-1,2,4-benzothiadiazine-1,1 dioxide) and its analogs produce alterations in the process of urinary dilution which differ from those expected from a simple increase in electrolyte excretion (1-3). Heinemann, Demartini and Laragh (2) observed in human subjects undergoing water diiuresis that the augmented electrolyte excretion resulting from the injection of chlorothiazide was associated with no increase, or a fall, in the clearance of free water. In a single experiment the authors observed no effect of the drug on the elaboration of a concentrated urine, and suggested that chlorothiazide may in part interfere with the reabsorption of electrolyte at sites in the distal convoluted tubule where urinary dilution normallv occurs. The absence of an effect on the concentrating mechanism has been confirmed by others (4).Crawford and Kennedy (3) found that the continuous administration of chlorothiazide (or hv-(lrochlorothiazide) per cent dextrose in water was infused at a constant rate of 10 to 14 ml per minute. Urine was collected by free flow through an indwelling catheter with the dog in the upright position. After at least 1 hour had been allowed for equilibration, urine specimens were collected and the rate of flow and osmolality determined. \Vchen these were stable for 3 consecutive 10-minute periods collection of "control" periods was begun. Venous blood samples were collected every 30 to 40 minutes by free flo\w through an indwelling needle into a heparinized tube.In 4 experiments, after the collection of 3 "control"periods, chlorothiazide (50 mg per kg body weight) was administered intravenously and a like amount was given by constant infusion each hour. Four 10-minute periods were then collected. The acute change in solute excret.on and free water clearance produced by the drug under these conditions was thus determined. In order to examine the relationship between Cos.g and Ci12o during water diuresis, 2.5 per cent mannitol in water was infused in 3 experiments to produce progressively increasing rates of solute excretion. The relationship was re-examined during the administration of chloro-.hiazide. The drug was administered either before the 2.5 per cent mannitol infusion was begun or after the mannitol had been infused and a high rate of solute excretion attained. In the former instance the mannitol infusion was then started in order to increase solute excretion, and in the later instance it was then stopped in order to decrease solute excretion. The effect of chlorothiazide was thus examined under conditions of both increasinog and decreasing rates of solute excretion.Thle effect of an equivalent dose of acetazolamide was examined in the same manner.Maximial hydropenia and aWtidincretc hlormiione. In order to examine the effects of chlorothiazide on urinary concentration, 11 experiments were performed on 5 trained unanesthetized mongrel female dogs. The dogs w\ere 857

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