EVIDENCE IN MAN THAT URINARY ELECTROLYTE LOSS INDUCED BY PITRESSIN IS A FUNCTION OF WATER RETENTION Alexander Leaf, … , Roberto F. Santos, Oliver Wrong J Clin Invest. 1953;32(9):868-878. https://doi.org/10.1172/JCI102805. Research Article Find the latest version: https://jci.me/102805/pdf EVIDENCE IN MAN THAT URINARY ELECTROLYTE LOSS IN- DUCED BY PITRESSIN IS A FUNCTION OF WATER RETENTION' By ALEXANDER LEAF,2 FREDERIC C. BARTTER,3 ROBERTO F. SANTOS,4 AND OLIVER WRONG (From the Department of Medicine, Massachusetts General Hospital and the Harvard Medical School, Boston, Mass., and the Clinic of General Medicine and Experimental Therapeutics, National Heart Institute, Baltimore, Md.) (Submitted for publication April 21, 1953; accepted May 15, 1953) INTRODUCTION larly as Pitressin Tannate in Oil,5 2.0 units initially, followed by 1.0 unit every 12 hours for two to four days. There are many conflicting reports on the acute This dose of pitressin was estimated to be within the effects of posterior pituitary extract on the renal physiological range of endogenous antidiuretic hormone excretion of sodium and chloride. This subject production (3, 4). Twenty separate periods of pitressin has been recently reviewed administration were studied. In all but one instance an (1). antidiuretic effect was maintained throughout the period The present study was made to' determine the of hormone administration. effects on electrolyte excretion in man of a long- Urine and serum were analyzed for sodium, chloride, acting posterior pituitary extract administered potassium, nitrogen, and total solutes. Two studies in- cluded calcium and phosphorus determinations and stool over a period of several days. The results suggest analyses. Analytical methods used have been described that the state of hydration determines the effect in a previous communication (5). Recently, however, the of pitressin on electrolyte excretion. The rela- saline standard solutions used in the measurement of tionship of the findings to the problem of volume total solute concentrations have -been corrected for ac- tivity coefficients calculated from data obtained in the regulation of the body fluids will be considered. Intemational Critical Tables (6). Thus, in the studies on R. S., N. W., and 0. W. i which the new standards METHODS were used, the normal level of total solute concentration of serum was found to be approximately 290 mOsm. per L. Metabolic studies were conducted at the Metabolism rather than the previously reported value of 310 mOsm. Ward of the Massachusetts General Hospital (2) and at per L. the U. S. Public Health Service Hospital, Baltimore, Inulin and para-aminohippurate clearances (7) were Maryland. Subjects studied included four normal adults, used as measures of glomerular filtration rate and renal two patients with anterior pituitary insufficiency, one with plasma flow in one subject, M. K. H. In two subjects, anterior and posterior pituitary insufficiency, one with R. S. and 0. W., 24 hour clearances of endogenous adrenal cortical insufficiency, and one with ovarian agene- creatinine were used as an estimate of glomerular filtra- sis. Subjects were maintained on a constant diet, and tion rate's (8). Acute changes in plasma volume were the fluid intake was controlled at various levels. No calculated in subjects R. S. and 0. W. from hematocrit restrictions were made on the activity or position of the and hemoglobin measurements (9). subjects. Dietary sodium intake was fixed in each study and ranged in different studies from 20 to 175 mEq. per RESULTS day. Following an initial control period of several days, A. The effects of pitressin on electrolyte excretion posterior pituitary extract was administered intramuscu- Figure 1 shows a typical response of a normal 1 Supported by grants from the Milton Fund of Har- subject to administration of pitressin over a period vard University, the American Heart Association, and 5Lots L888G or L654C were used. The Pitressin the Worcester Chapter of the Massachusetts Heart As- Tannate in Oil was generously supplied by Dr. A. C. sociation. Bratton, Jr., Parke, Davis and Co., Detroit 23, Michigan. 2Howard R. Hughes Fellow in Medicine. 6 Although not as valid a measure of glomerular filtra- B Senior Surgeon, United States Public Health Service. tion rate as is the clearance of inulin, the clearance of Present address: National Heart Institute, National In- endogenous creatinine is a useful estimate of the filtration stitutes of Health, United States Public Health Service, rate over the daily period of urine collection. This avoids Bethesda, Maryland. the fallacy of correlating the excretion of water and 4Kellogg Fellow of the American College of Physicians. solutes over twenty-four hours with the clearance of inulin Present address: Bahia, Brazil. over a few minutes. 868 WATER RETENTION AND ELECTROLYTE LOSS 869 E.L ME 35 UNITS/24fR NORMAAL FEMALE 3505 1/27/5I 160 Ii 1 3E 155s'l144t8 330 150 126 3201148112~~~~~~~~~~~~~~~~1 3o0J3.13013514 S"9Lt - -] Z 290 130 64 CONCEN\/TR_ 290 125 46 120 32 , EQ4H KE9. A 123MLEQJL126 li61112 0 96 16 ---'@''- N.EO/KDYL~~~~~~~~~~~~~0 SERUM It48 asOI5.01 1264 ..... I FIG.in1.6lt0964STHE EFFECTS OF PSERNONK SERUM ELECTROLYTE CONCEN- 468 KEQ. 32 93mOsm/L320C 5FLEQ[./4R 4 2400 alyi1200 a 4.0 ____-____t_r. lsoo9~ ~ ~ ......4 .LJ24HR intravenously4.0NETO,ADCoCrRctOYWEGTOthe e....Te#7/SUAVJNRMPAL SUBECT 56.0KG. 55.01 ACTUAAL WEIGHT 53.0 1 2 3 ~4 . 7 S 9 10 pAYS t r b n-DIET REFUSALs *1300CC. 3% SALINE LV. FIG. 1. THE EFFECTS OF PITRESSIN ON SERUm ELECTROLYTE CONCENTRA- TIONS, URiNARY ELECTROLYTE EXCRETION, URINARY VOLUME AND TOTAL SOLUTE CONCENTRATION, ANqD BoDY WEIGHT OF A N'ORMAL SuBjECTr The hatched columns represent total 24 hour excretions and the broken lines urinary concentrations. Note the prompt antidiuret.ic effect of pitressin but the delay in the excretion of sodium and chloride. Sodium intake was 60 mEq. per day by analysis. Because of anorexia and nausea, part of the diet and fluid intake was refused on the last two- days of pitressin administration. The day after pitressin was stopped 300 ml. of 'three per cent saline were administered intravenously to correct the extracellular fluid hypotonicity. The abnortmally high serum potassium on Day 10 was twice repeated but remains unexplained; no comparable result was seen in any other experiment. 870 A. LEAF, F. C. BARTTER, R. F. SANTOS, AND 0. WRONG toc 500 2 300 3000 200o 20001 URtAR,0/M 0o 54'.0 52.0 WEIGHT 52.0 6 0 2 4 a 10 12 14 26 a 3 32 34 0 a *REFUSD P ET FIG. 2. THE EFFECTS OF PITRESSIN ON SERUM ELECTROLYTE AND TOTAL SOLUTE CONCENTRATIONS, URINARY ELECTROLYTE EXCRETION, URINARY VOLUME AND TorAL SOLUTE CONCENTRATION, AND BODY WEIGHT IN A SUBJECT WITH ANTERIOR AND POSTERIOR PITUrrARY INSUFFICIENCY The concentrations of serum sodium, chloride and total solute were abnormally high during the control period. In the left-hand section of this figure the effects of pitressin alone are presented. In the right-hand section the effects of pitressin following seven days of continuous cortisone therapy are presented. On cortisone the antidiuretic effect of pitressin was increased, as indicated by the higher urinary total solute concentration. The sodium and chloride loss and symptoms of water intoxication were also increased with cortisone. Sodium iptake was 49 mEq. per day by analysis. WATER RETENTION AND ELECTROLYTE LOSS 871 of three days. The antidiuretic effect of pitressin is seen in the abrupt decrease in urine volume and 5/IZiSI 540626 increase in urine total solute concentration that occurred on the first day of hormone administra- tion. The water retention produced by this anti- diuretic effect resulted in an increase in body weight and dilution of serum sodium, chloride and total solutes. On the third day of pitressin ad- ministration a large increase in urinary sodium and chloride excretion occurred. The large water diuresis following the pitressin period represented excretion of water retained during pitressin ad- ministration, and returned the weight to the con- trol level. The urinary sodium excretion fell to low levels in the post-pitressin period. These after-effects have been constant sequelae of pitres- sin administration when the latter has caused fluid retention and sodium loss. The left-hand section of Figure 2 shows similar data obtained from a patient with anterior and posterior pituitary insufficiency. Again pitressin had a prompt antidiuretic effect. Only after the first 24 hours was there an increased excretion of sodium and chloride, which progressed stepwise throughout the remainder of the pitressin period. Similar, though less striking, results were ob- tained in a subject with adrenal cortical insuf- ficiency (Figure 3) treated with 25 mgs. of corti- sone acetate orally every eight hours throughout the study. The delay in the appearance of the increases in electrolyte excretion suggested that they could be dissociated from the prompt antidiuretic action of pitressin. The increased sodium excretion during O * 2 3 4 5 6 7 S 9 10 11 12 13 14 IS W~ ~wrs ~ aaama administration of pitressin was associated with *fUWa. oF OCT progressive retention of water. This suggested FIG. 3. THE EFFECTS OF PITRESSIN ON SERuM ELEC- that the effects on electrolyte excretion could re- TROLYTE AND TOTAL SOLUTE CONCENTRATIONS, URINARY sult from the overhydration produced by pitressin ELECTROLYTE AND NITROGEN EXCRETION, URINARY VOL- UME AND ToTAL SOLUTE CONCENTRATION, AND BODY rather than from a primary action of pitressin. WEIGHT IN A SUBJECT WITH ADRENAL CORTICAL INSUF- FICIENCY B. Prevention of the effects of pitressin on elec- The subject was maintained on 25 mg. of cortisone trolyte excretion by dehydration acetate orally every eight hours throughout the study. To test this hypothesis pitressin was given to Urinary calcium and phosphorus excretion and salivary electrolyte concentrations are also shown.