Control of renal excretion of water in man is largely vested in the supra-optico-hypophyseal system. When the tonicity of the blood plasma and extracellular fluid rises, an increased secretion of antidiuretic hormone (ADH) leads to the conservation of water inasmuch as urinary solutes are excreted with a minimum of water. Conversely, when tonicity falls, a diminution of ADH output permits the excretion of a large volume of dilute urine. In both instances homeostasis is served.Many stimuli, in addition to hypertonicity, increase ADH production, including certain anaesthetic (1) and narcotic drugs (2), barbiturates (3), smoking (4, 5) and nicotine (6, 7), acetylcholine (8), exercise (9), emotion (9), syncope ( 10), pain ( 11 ) and conditioned reflexes ( 11 ), as well as the direct electrical (12) or acetylcholine (13) stimulation of nerve cells and fibers connected with the pars nervosa of the pituitary gland. Removal of amounts of blood insufficient to alter blood pressure significantly may nevertheless lead to increased ADH activity (9). There is also suggestive evidence that there may at times be increased ADH activity in patients with cirrhosis of the liver (14,15).In contrast to the many factors which may lead to increased antidiuretic activity few other than destructive lesions involving the supra-optico-hypophyseal system and hypotonicity of the plasma and extracellular fluid have been reported to cause a decline in ADH activity. These are hypnotic suggestion (1), alcohol administration (16-18), and exposure to cold (19).1 Reviewed in the Veterans Administration and published with the approval of the Chief Medical Director. The statements and conclusions published by the authors are the result of their own study and do not necessarily reflect the opinion or policy of the Veterans Administration.It is the purpose of this communication to present evidence that a rather rapid isotonic expansion of extracellular fluid volume (or some factor associated with such a volume increase) leads to a water diuresis of the type which follows diminished ADH activity. METHODSThe subjects were three essentially healthy male adults hospitalized for the investigation of minor symptoms for which no organic cause was found and which cleared rapidly. Without previous preparation2 they came to the laboratory one to two hours after breakfast, voided, and began the timed collection of urine specimens. When it became apparent that the flow of urine was diminishing, blood was collected without stasis from an antecubital vein after the arm had been immersed in hot water for five minutes to arterialize the blood (20), following which 3,000 ml. of 0.9 per cent solution of sodium chloride in water (Sp. Gr. 1.005 at 15°C.) was infused intravenously at a constant rate of 25 ml./min., the entire infusion requiring two hours. A blood sample was collected from the opposite arm immediately upon the completion of the infusion, and a third at a subsequent time. Urine was voided at intervals during and after the infusion, the subject standing for ...

The deficient diuretic response to water which is characteristic of patients with adrenal insufficiency can be rapidly corrected by the administration of cortisone (1-3). The mechanism of the defective diuresis and the precise nature of the response to hormonal replacement have not been established. A number of observations, chiefly in experimental animals, have suggested that administration of various adrenocortical preparations in large "pharmacologic" doses also influences water diuresis in the normal organism (4). However, no systematic study of the latter effect has been made in man. The present report describes the effects of large doses of cortisone and hydrocortisone on water diuresis, renal solute excretion, glomerular filtration rate, and effective renal plasma flow in man. Striking augmentation of the maximal rates of urine flow observed during maintained water loading was a regular occurrence. The steroids studied appear to have a specific influence upon water reabsorption by the renal tubules, an action which can be separated from their effect on renal hemodynamics. MATERIALS AND METHODSThe subjects were adult male patients free from cardiovascular, renal and endocrine disease. Three sets of studies concerning water diuresis were carried out.Group I-A-Intermittent studies during prolonged intramuscular administration of cortisone. In these experiments creatinine clearance was measured, but not inulin or para-aminohippurate clearances. Urinary total solute concentration was calculated from determined cations and urea; freezing point determinations were not made.1 Present address: Veterans Administration Hospital, Syracuse, New York.Group I-B--Serial studies at intervals of one to three days during prolonged oral cortisone and hydrocortisone administration. Clearances of inulin and para-aminohippurate, as well as of creatinine, were determined. Urinary osmolality was measured cryoscopically.Group II-The acute response to intravenous infusion of hydrocortisone during water diuresis. Renal clearances and urinary total solute concentrations were measured as in I-B.Details of experimental procedure will be given together with the results in each group. Chemical methods and calculationsUrine and serum were analyzed for sodium, potassium, chloride and creatinine by methods previously described (5). Serum creatinine was determined after adsorption on Lloyd's reagent (6). Total solute concentration in urine and serum was measured by freezing point depression using a Fiske osmometer (Advanced Instruments, Inc., Needham, Mass.

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The administration of a large amount of water to the normal subject results in the copious excretion of a dilute urine. An extensive body of evidence indicates that this response is primarily dependent upon a decrease in the effective osmotic pressure of the plasma and extracellular fluid, with resultant inhibition of the secretion of antidiuretic hormone (ADH) by the neurohypophysis and decreased facultative reabsorption of water by the renal tubules (2-5).Although alterations of this normal response to water loading have been studied in a variety of abnormal conditions, factors which influence the magnitude of water diuresis in normal man have received scant attention, even though Haldane and Priestley in 1916 noted that the initial high rates of urine flow which followed the ingestion of water subsequently underwent a gradual moderate decline despite a continued large fluid intake (6). Depletion of body sodium in man and experimental animals has been shown to diminish the excretion of administered water, but under the conditions of these studies general impairment of renal excretory function was evident (7-9) or was not excluded (10, 11).The present communication describes observations which indicate that in man the maintenance of a large water load evokes a diuresis the magnitude of which is. greatly influenced by factors which evoke concomitant changes in the renal excretion of solutes, particularly sodium. These influences include the dietary intake of sodium, postural effects, and the administration of various solute loads. METHODSThe subjects were three normal men and seven adult male patients, of whom four had neurodermEititis, one psoriasis, one bronchial asthma, and one rheumatoid ar-1A preliminary report (1) thritis. All were free of renal or cardiovascular disease. Dietary intake was controlled only with regard to its sodium content. The regimens employed were: 1) "saltfree" diet providing approximately 15 mEq. of sodium daily; 2) "salt-poor" diet providing 35-70 mEq. of sodium daily; 3) "regular" diet of unrestricted salt content containing approximately 170-250 mEq. of sodium; 4) "high-salt" diet consisting of the "regular" diet with 170 mEq. of added sodium chloride. The same regimen was employed for a minimum of three days before each experiment, except that the "high-salt" diet was given for only one day prior to an experiment in subjects who had previously been taking the regular diet. Repeated studies were performed on the same subjects at intervals which ranged from one week to 10 months. Hence weight changes unrelated to dietary salt intake occurred.The subjects came to the laboratory one to two hours after breakfast, voided, and were weighed on a scale sensitive to + 10 gm. Arterialized venous blood (12) was then obtained and a water load established by the ingestion of tap water at room temperature. In most experiments, 1500 ml. were drunk during a period of 10 to 40 minutes. The subject was again weighed and the water load was maintained throughout the experiment by oral administration ...