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Changes in the tubular reabsorption of sodium independent of aldosterone activity may play an important role in determining sodium excretion. Several studies in the dog employing clearance techniques have demonstrated that infusions of isotonic saline (1-5) or plasma-like solutions (1, 2) result in a depression of the over-all net tubular reabsorption of sodium as the excretion of sodium increases. Dirks, Cirksena, and Berliner have demonstrated by micropuncture studies in the dog that this depression of tubular reabsorption during the infusion of saline occurs specifically in the proximal tubule (6). These same authors reported that acute constriction of the thoracic inferior vena cava, a maneuver known to inhibit sodium excretion and to lead to chronic sodium retention and the formation of ascites (7), prevents this depression of proximal reabsorption during saline infusion (8). Such studies indicate that nonaldosterone factors determining the rate of sodium reabsorption by the proximal tubule could play a major role in the normal physiologic regulation of sodium balance and also may be involved in the pathogenesis of sodium retention in disorders characterized by the accumulation of ascites and edema.Although the factors that determine the rate of proximal tubular reabsorption are unknown, recent studies from our laboratory have demonstrated that renal vascular resistance and perfusion pressure may affect the over-all tubular reabsorp-

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

A B S T R A C T Micropuncture techniques in the rat were used to reinvestigate the possibility that intraluminal flow rate per se may influence net volume reabsorption by the proximal tubule. An experimental design was devised which lowered intraluminal flow without affecting filtration rate of the nephron under study or without directly affecting other renal hemodynamics. In 11 rats flow of tubular fluid between early and late proximal tubular sites was reduced by partially collecting tubular fluid at the early puncture site. In 42 nephrons the rate of flow of tubular fluid was reduced an average of 45% without changing nephron filtration rate and there was an associated reduction in reabsorption between the two sites which averaged 29%. This indicated 63% balance between delivery of tubular fluid and the rate of reabsorption between two sites along proximal tubules. The results of these studies indicate that a reduction in delivery of normal filtrate along the proximal tubule is associated with a concordant reduction in the absolute rate of reabsorption. Since this relationship occurred in the absence of changes in renal hemodynamics or even a change in filtration rate of the nephron under study it is concluded that changes in intraluminal load per se play an important role in the phenomenon of glomerulotubular balance.

Laragh, Heinemann, and Demartini first reported that the administration of chlorothiazide during water diuresis results in an increased rate of solute excretion without significant changes in the rate of urine flow (1,2 repeatedly confirmed (6-13), and the thiazide derivatives have now attained a place of therapeutic usefulness in patients with vasopressinresistant diabetes insipidus (13).Inhibition of solute reabsorption in the distal nephron alone does not account for the antidiuretic effect of the thiazide derivatives. As indicated above, such inhibition of solute reabsorption would merely increase urinary osmolality without affecting urinary volume. Therefore, the mechanism whereby volume is reduced must reside in some other direct or indirect action of these agents. The results of the present studies are consistent with the view that the antidiuretic effect of hydrochlorothiazide is a consequence of the losses of sodium induced by the agent and is not due to any unique property of the thiazide derivatives. The antidiuresis is enhanced by a low sodium intake. is diminished by a high sodium intake, and may also be produced by mercurial diuretics, despite apparent differences in the site and mode of action of the latter agents. METHODSMultiple studies were performed on four hospitalized male subj ects with vasopressin-resistant diabetes insipidus, ranging in age from seven to, seventeen years. Two were brothers, a third had an affected brother, and all had a history of polyuria and polydipsia dating from infancy. Maximal urine osmolalities after a 17-to 20-hour thirst were less than 100 mOsm per kg in three subjects, and not greater than 130 mOsm per kg in one subject (S. Z.). None of the four subjects demonstrated any increase in urinary concentration when dehydration was followed by the administration of vasopressin. All were free of other renal functional abnormalities. The intakes of sodium were controlled by the addition of weighed amounts of sodium chloride to a standard diet containing 9 mEq of sodium. In all instances in which the effects of hydrochlorothiazide were studied, the drug was administered orally, 25 mg every 8 hours. A mini-1988

Abstract. The importance of plasma protein concentration, renal vascular resistance, and arterial pressure as mediators of the natriuretic response to volume expansion was investigated in anesthetized dogs.Saline loading depressed plasma protein concentration and increased arterial pressure but did not decrease renal vascular resistance. Restoring plasma protein concentration by infusing hyperoncotic albumin increased sodium reabsorption and decreased sodium excretion during saline loading despite simultaneous decreases in renal vascular resistance and increases in arterial pressure.Infusion of "plasma" did not depress plasma protein concentration and produced natriuresis associated with increased arterial pressure and marked decreases in renal vascular resistance. Unilateral hemodynamic natriuresis was produced before "plasma" loading by the renal arterial infusion of acetylcholine, and the subsequent infusion of "plasma" resulted in much smaller increases in sodium excretion by the vasodilated kidney than by the control kidney. If perfusion pressure to both kidneys was then reduced by aortic constriction sodium excretion by the vasodilated kidney could be reduced to preloading (vasodilated) levels without reduced glomerular filtration, despite continued natriuresis in control kidneys which underwent vasodilatation in response to the infusion of plasma.Infusion of equilibrated whole blood did not alter plasma protein concentration or the hematocrit, and renal vascular resistance did not decrease. Sodium excretion was increased minimally or not at all by the infusion of blood despite increased arterial pressure and glomerular filtration. However, in kidneys vasodilated before infusing blood sodium excretion increased in response to tfie infusion in association with increased arterial pressure. This increased excretion of sodium by vasodilated kidneys during infusion of blood could be abolished by reducing perfusion pressure to the preloading level.These observations indicate that changes in plasma oncotic pressure, renal vascular resistance, and arterial pressure either alone or in combination are important variables determining the natriuretic response to volume expansion, and that the relative importance of each of these factors depends on the manner in which volume is expanded (viz., the infusion of saline, plasma, or blood).

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