THE NATURE OF THE ACTION OF INTRAVENOUS ALDOSTERONE: EVIDENCE FOR A ROLE OF THE HORMONE IN URINARY DILUTION Edmund H. Sonnenblick, … , Paul J. Cannon, John H. Laragh J Clin Invest. 1961;40(6):903-913. https://doi.org/10.1172/JCI104329. Research Article Find the latest version: https://jci.me/104329/pdf THE NATURE OF THE ACTION OF INTRAVENOUS ALDOSTERONE: EVIDENCE FOR A ROLE OF THE HORMONE IN URINARY DILUTION* By EDMUND H. SONNENBLICK,t PAUL J. CANNON AND JOHN H. LARAGH (Fromi the Deparbiwitt of Medicine, College of Physicians and Surgeons, Columbia Unzivcrsitv, and the Presbyterian Hospital, New York, N. Y.) (Submitted for publication September 15, 1960; accepted January 13, 1961) Aldosterone increases the renal retention of so- This action takes place in the tubule at a locus dium chloride and promotes the excretion of po- distal to that of isosmotic reabsorption. Also, this tassium ions ( 1-11 ); but where and how the hor- effect of the hormone on sodium chloride reab- mone acts in the renal tubule is poorly understood. sorption appears to be dissociated from the effect The present study was designed to characterize on potassium excretion. further the mode and site of action of aldosterone in the nephron. EXPERIMENTAL Information can be obtained about the site of action of a compound by observing its effect on Seven studies were performed on 3 subj ects without evidence of renal or cardiovascular disease. Four of the free water formation (12). According to a cur- experiments were done with subj ects maintained on a rent concept of renal physiology (13), reabsorp- normal NaCl intake (4 to 6 g NaCl per day for 7 tion of solute (sodium chloride) is isosmotic in days), two with the subj ects on a higher intake of the proximal tubule (14), whereas, in the more salt for 7 days (8 to 20 g NaCl per day), and one after distal reabsorption may or may not be drastic salt deprivation (less than 250 mg per day for segments, 6 days). In two subjects on normal salt intake, con- isosmotic (15, 16). During water diuresis (ab- trol studies of similar protocol but without administra- sence of antidiuretic hormone) the distal reab- tion of aldosterone were performed. All experiments sorption of solute is selective, i.e., occurs without were conducted in the fasting state at the same early isosmotic amounts of water, leaving "solute-free" morning hour with the subjects in a recumbent position. Thus, by de- Water diuresis was induced by having the patient in- water behind for excretion (17). gest about 1,500 ml of water by mouth during the hour termining the effect of a compound on solute ex- before the experiment and was subsequently maintained cretion and on free water formation during main- by intravenous infusion of 5 per cent dextrose and water tained water diuresis, information may be ob- at a constant rate, at least 2 ml per minute greater than tained about its site of action (12). If aldosterone urinary output. Adequate control periods were obtained were to act to promote isosmotic reabsorption of until a steady state of maximum urine flow was demon- strated, so that any subsequent change in free water sodium, the consequent reduction in solute excre- clearance could not be attributed to an increasing water tion would be accompanied by a fall in urine flow diuresis. and no change or fall in free water excretion. When a steady state of maximum water diuresis had However, if aldosterone acts only at a more distal been achieved, 1 mg of d,l-aldosterone monoacetate in where is the reduced 10 ml of 10 per cent ethanol was administered intrave- site, reabsorption selective, nously.' This was followed by another 1 mg given in sodium excretion would be accompanied by no the dextrose and water infusion over the next hour. change in urine flow and hence, by a rise in free After the aldosterone administration was complete, the in- water excretion. fusion of dextrose and water was continued at a con- In the present study it has been shown that stant rate. of Blood samples were taken via an indwelling hepari- aldosterone can promote abstraction sodium nized needle and urine collections were made with an in- chloride exclusive of water from the tubular urine. dwelling catheter except in Subjects S.H. and M.U., young males in whom adequate voluntary bladder empty- * This work was supported by the 'United States Public ing was possible at high rates of urine flow. Health Service (Grant H-1275) and by Mrs. R. C. duPont. I d,l-Aldosterone monoacetate, 1,000 ltg equivalent to t Present address: National Heart Institute, Bethesda, 500 pig active d-aldosterone supplied by Ciba Pharma- Md. ceutical Products, Summit, N. J. 903 904 EDMUND H. SONNENBLICK, PAUL J. CANNON AND JOHN H. LARAGH I 00 V~ U) ' 0% a, C\ 0% 0% el; 00 t. t- N Cd E (0 et a) -4 :L 00 - 00 00 N0 0. V 0% Cl 00 00 0 0 Cl4 CN Cl4 E d 0 U) 0 U) 4- V 00 t U) U0 U) Cl30 U) U) U) U) U) ._ U) U)\- 0t 0) at U) m4 0- U-) 0)00 Cl- 00 00 Nb 0 o o0 tor U) 0) * 0 o4 of *0.i q1) 0) 0 00 UI) t- t- Cl %0 111 d i. z 0-%U) 0 0) r-0-o -o V '0 0 %00 0w -o 4- U) 0 6 *2- Nb Cl U) -j4 t- Cl 0) ?8t 0 en U) > t-U); LI; 0 "0 - ho 4- m co ¢.1 w U) V Vt \0 U) -4 0. 10 a o 0 m oo V - 0 0 0 0 00 z .2 4-i V U) 0 0. u 0 00 V -- 0 '0 0 OOC) ud C 00M N *-0) o ovou 0) o 0) U1) -et ._ ._ 0 - U) V 0 U) V -6 0 (3 *.0 01) 0 0. ¢ 0. 0)00 Cl 0V .- to U) S 0% C 0 - CCl 01) 0 0. .0 blo 0 - _U U)1 o U) Ul) 0 0) I-. 0 o6o6 Y %0OV Vo o6 o o6 o6 o6 c~ 01) Cn .5 0i r.z 04- "0 0) a 0% . 00.. V V 0 U) V 0 V 0 u 10 0--ClC 0 0. 00 o- as a M '" 00U)'00+V 0%4 0 -I U) t- -0 U -4 000 0u 0 0- _oo 0) 0. 0 U) L4 00 000~nS UE 0 0UV 0) b* 4-0 00- x U) U) 0'm-CC\0-0C (L 120, to +++++++. r- 0 )-- -0C z CN -Cl 0- - 0 0 U,)VnU) U)~ Cl Vo 00k- U) (n N Cl U U) o4otoUV Cl00 -4 U-) 4/) 0 00000 0 0 0 0 44 Cl CN Cl 0- Cl 0- t- - 000 - +++C++00- - 0-Cl 0) 00 Cl t ItUl I+ +++++++ ALDOSTERONE AND URINARY DILUTION 905 Plasma and urine samples were analyzed for inulin or creatinine, para-aminohippuric acid, and sodium, po- tassium and chloride, by methods previously described -1'0 "20to (0)'14 O m '-.0 0 2 - "t (12). The urinary pH was measured by a Beckman pH 1r "1 rz -4-- eqaN m -)en meter on freshly voided samples and the urine and 'i 0 plasma urea concentrations were determined by a modi- -0 fication of the urease method of Van Slyke and Cullen (18). The urine and plasma total solute concentration le01 -l Nt % m ,4 C,4 ° ON 000 -t was measured with a Fiske osmometer. 0 l 4 L Calculations. As indicated by Smith (13) and by . 61 ci_ lici4 i4 ci- 4-J .0>W Anslow urine can be divided into two o.oo 00N 00 Uto 0oNo00- Wesson and (17), t t f;4. .- - N II 1 _" tn K _ moieties: the osmolar clearance (C0,,), the volume of 7 -- _q-. V l M M ' 't d1. m ; water necessary to contain the urinary solutes in a solu- tion isosmotic with the plasma (Cosm = UVosm/Posm); 0) water net excess or a IC (1 (Ds o Xo 10 mUo00 ON CWo-C) -I and the free clearance (CH20), the - 3 rto U SC-14 00(0) m U.)"1t deficit of water beyond the osmolar clearance. During C) water water is a positive value diuresis the free clearance 0> and is calculated as CE220 = V - Uo.mV/Posm, where V 00 0 0o -0 -oC r 0000 t-00 *) "I 0N K 00 I- 00r- 011) is the urine flow in milliliters per minute and Uo.m and 00 eo 1.u0 02 Posm are the solute concentrations of urine and of plasma 4-)a in milliosmoles per kilogram of water. OU) 00 Co CD 00(0 u) oo m -t -! 0e Il 6 \0 \ RESULTS Q The results of these experiments are summa- _Cd 00 - t 4-. rized in Tables I, II and III and in Figures 1 > *o in (en% 00 00 U00 '- el; Cl) F r- r- en oo00 00 to , -c c to_4r 4 t through 4. In Table III, a typical control proto- 0b - 0)En ( col is given. In Table I the complete protocol of 0) com- one experiment is given, and in Figure 1 the .0 *o > ttU) Onme0 °C ~t I-.. X- U-) 0 'IO00 00 -~ t- %0 .. >o._ Subject M.U.- Normal Diet *0); w Img d.l. aldosterone L.V. + 0 XU = lmg in 5% D/W infusion r0 in E oe d I-- tJ4%0 M %0ut I- I T--- I -- I - !-- U) U) -.