Production of Hypertonic Urine in the Absence of Pituitary Antidiuretic Hormone Robert W. Berliner, Douglas G. Davidson J Clin Invest. 1957;36(10):1416-1427. https://doi.org/10.1172/JCI103541. Research Article Find the latest version: https://jci.me/103541/pdf PRODUCTION OF HYPERTONIC URINE IN THE ABSENCE OF PITUITARY ANTIDIURETIC HORMONE 1 BY ROBERT W. BERLINER AND DOUGLAS G. DAVIDSON 2 (From the Laboratory of Kidney and Electrolyte Metabolism, National Heart Institute, National Institutes of Health, Public Health Sertice, Department of Health, Education, and Welfare, Bethesda, Md.) (Submitted for publication May 1, 1957; accepted May 23, 1957) The mechanism by which pituitary antidiuretic permeability of the tubule membrane to water. hormone (ADH) produces its renal effect has The change to hypertonicity cannot be so readily not been clearly established. Under ordinary con- attributed to an effect on water permeability with- ditions, in the absence of ADH, urine of a con- out some assumptions as to the mechanism by centration considerably below that of plasma is which the hypertonicity is produced. However, produced in large volume. With increasing it is a reasonable hypothesis that the mechanism amounts of ADH, administered or secreted, the for the production of hypertonicity is not depen- osmotic pressure of the urine rises to and above dent upon ADH but that its effects are unmasked, that of plasma. With respect to total water bal- in the presence of ADH, by 1) changes in the vol- ance, the quantitatively more important contri- ume and concentration of urine delivered to it and, bution to water economy is the change between possibly, 2) changes in the permeability of the maximally dilute and isotonic urine, since this, in membranes separating the concentrating mecha- normal man, may involve a change in water ex- nism from the urine in the tubule lumen. cretion in excess of 10 ml. per minute. The fur- The most tenable view of the mechanism by ther saving of water effected by the elaboration of which the urine is diluted is that the process in- hypertonic urine is a relatively small one, amount- volves abstraction of solute in a segment of the ing, at usual rates of solute excretion, to not more tubule, -presumably the distal convoluted tubule, than an additional 1 or 2 ml. per minute. Thus, relatively impermeable to water (3); indeed, the although it is commonly stated that the function of results to be presented strongly support this as- ADH is to cause the excretion of a hypertonic sumption. The only solute available in quanti- urine, its more important function might be better ties adequate to account for the volume of water defined as preventing the excretion of a dilute freed of solute in the process of urine dilution is urine. sodium and its equivalent anions. Anything which Recent studies of the effects of posterior pitui- limits the amount of sodium salts reaching the tary extracts on frog skin have shown that these diluting segment or the capacity of that segment preparations markedly reduce the resistance of to remove sodium and anion should reduce the this membrane to the flow of water in response to capacity of the kidney to produce a dilute urine. gradients of osmotic pressure (1). Observations Thus, in the absence of ADH, if one were able to on frog bladder also suggest this mechanism of reduce the volume of renal tubule fluid delivered to action (2). It would seem reasonable to examine the diluting segment, it might be possible to limit the extent to which a similar mechanism of action the amount of water "freed" by the removal of could explain the effects of ADH on the concen- the remaining sodium salts. Under these condi- tration of the urine. Since the change from dilute tions the volume of fluid and particularly the vol- to isotonic urine is clearly in the direction of the ume of "free water" leaving the diluting segment dissipation of an osmotic gradient, this effect of and entering the final segment, believed to be the ADH could well be attributed to a change in the site of the production of hypertonicity, would be small. If the mechanism for rendering a urine 1 The material in this paper was presented in summary hypertonic functions in the absence of ADH, it form at the meeting of the American Society for Clinical Investigation, Atlantic City, May, 1956. might be possible, then, to obtain urine hypertonic 2Dr. Davidson's work was done under the tenure of an to plasma since removal of only a small amount of American Heart Association Fellowship. water would be required. 1416 PRODUCTION OF HYPERTONIC URINE IN THE ABSENCE OF ADH 1417 The experimental investigation of this possibility requires reduction of the rate of glomerular filtra- tion in the absence of antidiuretic hormone. The use of animals or patients with diabetes insipidus is subject to some uncertainty of interpretation since it is not possible ever to exclude with com- plete certainty some residual capacity to secrete ADH. Indeed, subject to this reservation, a num- ber of observations made-in diabetes insipidus have been wholly in accord with the premises set forth FIG. 1. INFLATABLE CUFF USED FOR COMPRESSION OF THE above (4-7).3 It appeared probable that the most RIGHT RENAL ARTERY certain demonstration of the absence of ADH would be afforded by the presence of a normal (O.D., 1.27 mm.) brought out through a separate stab kidney continuing to produce a urine of maximum wound in the flank.4 dilution during the necessary manipulations upon Either before or after the surgical procedure the dogs the other kidney. This has been the design used were trained to stand quietly, partially supported by a in the experiments to sling under the chest and around each hind quarter. be described. They were also trained to accept a stomach tube and veni- puncture without interruption of a water diuresis. All MATERIAL AND experiments were performed on such trained animals with- METHODS out anesthesia. Experiments were performed on 12 female mongrel Water diuresis was induced by the administration by dogs, weighing approximately 20 kilos. The animals stomach tube of approximately 30 ml. of water per kilo were prepared by a bladder-splitting procedure devised of body weight. The water load was then maintained by Desautel (9). In this operation the bladder is sepa- by the continuous intravenous administration of an in- rated from the urethra and divided longitudinally into fusion at a rate estimated to approximate the expected two halves, each containing one ureteral orifice. Each urine flow and containing in addition to creatinine and/or half is then formed into a pouch and connected to the inulin, p-aminohippurate (PAH) in amounts expected to insure outside a complete extraction, mannitol at a concentra- through nylon funnel protruding through the tion of to 2 skin of the abdomen through separate 1 per cent in many of the experiments, small wounds. Urine amounts of NaCl to replace anticipated losses in most of from each kidney thus drains separately and continuously the to the outside. The length of the studies, and sufficient glucose or fructose to bring the nylon tube protruding concentration of the solution to a non-hemolytic level. through the abdominal wall was sufficient to prevent Equality of renal function on the two sides was estab- drainage directly onto the skin and to permit the con- lished by the collection of urine from each kidney during nection of a short length of rubber catheter during urine several periods before inflation of the renal artery cuff. collections. Between experiments the dogs were kept In satisfactory surgical preparations, the filtration rates in metabolism cages so that the continuous drainage of of the two kidneys were within 10 per cent of each other urine left them relatively dry. and in most instances within 5 per cent. The urine flow At the same time as the bladder-splitting operation, and concentration and the rates of excretion of sodium, the right renal artery was approached through a sepa- potassium and chloride from the two kidneys were also rate incision in the flank. The artery was freed and any very close to equal. branches other than those to the kidney were ligated and After collection of the control periods, the polyethylene severed. A small inflatable cuff of silicone rubber (si- tube communicating with the cuff was connected to a lastic, Dow Corning) enclosed in a tantalum clip (Fig- mercury manometer and the cuff inflated with air until ure 1) was placed around the right renal artery and, in the urine flow from the right kidney had been reduced order to prevent extrusion of the artery upon inflation of to the desired level. This frequently required repeated the cuff, the ends of the tantalum clip were brought to- adjustment of the pressure level since there was almost gether with a loop of stainless steel wire. The silicone uniformly a greater depression of the urine flow during rubber cuff was then connected permanently to the ex- the first few minutes of compression than was apparent terior of the animal by a length of polyethylene tubing subsequently (10). When the desired level of urine flow had been obtained and maintained long enough to indicate 8 In addition, since completion of these studies del Greco and de Wardener (8) have reported the production 'We are greatly indebted to Dr. Robert L. Bowman of hypertonic urine upon reduction of glomerular filtra- for devising and constructing the inflatable cuff, and to tion rate under conditions in which the action of ADH Drs. Jerome Kay and Edward Sharp for performing the was believed to be excluded.