The Effects of Infusions of Chlorothiazide on Urinary Dilution and Concentration in the Dog

Abstract

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

On the Concentrating Defect in Cirrhosis of the Liver*

“…The ability of normal subjects studied to maintain TCH2O for a given Cosm shortly after the peak of osmotic diuresis is consistent with the findings in normal dogs (12 abnormal in the present studies.…”

Further Studies on Segmental Sodium Transport in the Rat Kidney during Expansion of the Extracellular Fluid Volume

“…Clearance and micropuncture studies have suggested that the main sites of action of chlorothiazide are in the cortical portion of the ascending limb of Henle's loop and the distal convoluted tubule (24,25). If Ringer loading inhibited sodium transport in this chlorothiazide-sensitive portion of JMN to a greater extent than in SN, administration of this diuretic may reduce or abolish the net addition pattern.…”

Micropuncture Study of Diuretic Effects on Sodium and Calcium Reabsorption in the Dog Nephron

“…7), although reduced to 0.4, was still significant at P < 0.01. 6 of the 44 points illustrated in Fig. 7 have a TF/UFca ratio of more than twice the population mean.…”

“…Furosemide has also been reported as having no proximal effect in the rhesus monkey (40), although a more specific response has been demonstrated in the rat proximal tubule (41) The action of thiazides in more distal nephron segments has been more clearly elucidated, although much of the evidence is indirect. Several investigators have reported that thiazides reduce free water clearance (CH20) and have no effect on free water reabsorption (44)(45)(46). The usual interpretation has been that thiazides inhibit sodium reabsorption in the diluting segment in the ascending limb of Henle's loop.…”