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Renal Tubular Effects of Ethacrynic Acid

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Renal Tubular Effects of Ethacrynic Acid Renal Tubular Effects of Ethacrynic Acid Laurence E. Earley, Robert M. Friedler J Clin Invest. 1964;43(7):1495-1506. https://doi.org/10.1172/JCI105026. Research Article Find the latest version: https://jci.me/105026/pdf Journal of Clinical Investigation Vol. 43, No. 7, 1964 Renal Tubular Effects of Ethacrynic Acid * LAURENCE E. EARLEY t AND ROBERT M. FRIEDLER (From the Thorndike Memorial Laboratory and the Second and Fourth [Harvard] Medical Services, Boston City Hospital, and the Department of Medicine, Harvard Medical School, Boston, Mass.) Ethacrynic acid,1 2,3-dichloro-4- (2 methylene- intravenous infusion of isotonic saline, at 0.30 ml per butyryl) -phenoxyacetic acid, is a recently intro- minute, which contained inulin and p-aminohippurate is (PAH) in amounts to deliver 10 mg and 3 mg per min- duced, orally effective natriuretic agent that ute, respectively. This infusion was begun at least 1 structurally unrelated to thiazides (1) and has hour before experimental collections were started. Urine proven useful in clinical disorders associated with was collected into graduated cylinders through an indwell- edema (2-5). The present studies were under- ing Foley catheter, and suprapubic pressure was em- taken to determine the natriuretic potency of ployed at the end of each collection period. Blood sam- ples were collected at the mid-point of experimental pe- this agent, its effect on the excretion of electro- riods by free flow from an indwelling venous catheter lytes other than sodium, and whether 'a specific into heparinized tubes. Studies in individual animals site of action within the renal tubule is demon- were conducted at intervals of no less than 7 days. strable. Current knowledge of the anatomical In samples of urine and plasma, inulin was determined areas within the nephron where sodium transport by the method of Walser, Davidson, and Orloff (13), PAH by a modification of the method of Smith and his leads to urinary concentration and dilution has colleagues (14), chloride by amperometric titration (15), been employed frequently for the purpose of lo- sodium and potassium by internal standard flame photom- calizing the tubular sites where natriuretic agents etry, and osmolality by the freezing point depression, exert their effect (6-12). In the present stud- using the Fiske osmometer. ies, ethacrynic acid was given intravenously to Maximal hydropenia. Animals were deprived of wa- ter for 48 hours, and of food for 24 hours, before the dogs during water diuresis and during the elabora- experimental procedure. Sixteen to 18 hours before ex- tion of concentrated urine. The unique combina- periments, the animals received 5 U of vasopressin in tion of changes in urinary dilution and concen- oil 2 intramuscularly, and in all except one experiment tration associated with the natriuretic effect of (Table I), the animals also received 10 mg of desoxy- this agent is consistent with the concept that a corticosterone acetate (DOCA) intramuscularly. The maintenance infusion contained vasopressin 3 and in four major part of the natriuresis is due to interference experiments (Figure 1), desoxycorticosterone,4 in amounts with the transport of sodium by the ascending to deliver 50 mU per kg per hour and 20 lsg per minute, limb of Henle's loop. In addition, two drug- respectively.5 Maintenance solutions containing vaso- sensitive sites of urinary dilution are apparent, pressin were acidified to pH 5.0 to 5.5 by the addition of one affected by chlorothiazide and the other by acetic acid. In each animal, TCHo was determined dur- ing the infusion of 15% mannitol in 50 mM NaCl. After ethacrynic acid. collection of control periods, infusion of the mannitol solution was begun and increased in a stepwise fashion Methods until a urinary flow rate of approximately 20 ml per min- These studies served as controls for were carried out in four unanesthetized fe- ute was achieved. Studies on the effect of acid. trained to stand quietly with the subsequent observations ethacrynic male mongrel dogs similar preparatory condi- support of loose slings. Each animal received a constant In two experiments (under tions), ethacrynic acid was administered intravenously * Submitted for publication February 5, 1964; accepted at a dose of 1 mg per kg acutely, and 1 mg per kg per April 1, 1964. :Aided in part by grant AM-5401-02 from the National 2Pitressin Tannate, Parke, Davis, Detroit, Mich. Institutes of Health. 2 Pitressin, Parke, Davis, Detroit, Mich. tFellow of the Boston Medical Foundation, Inc. 4 Steraloids, Inc., Queens, N. Y. 1 MK 595, Merck Sharp & Dohme. Kindly supplied 5 Under the described conditions, TcH2o was found to for use in these studies by Dr. William H. Wilkinson of remain stable through a greater range of solute excre- Merck Sharp & Dohme Research Laboratories, West tion than has been observed in similar studies (12) with- Point, Pa. out the use of DOCA. 1495 1496 LAURENCE E. EARLEY AND ROBERT M. FRIEDLER TABLE I The effects of iv ethacrynic acid on the renal concentrating mechanism* Urine Time vol GFR Uosm Cosm TCH20 POSm minutes ml/minute mI/ mOsm/kg ml/minute ml/minute mOsm/kg minute Dog B -90 0.8% saline, 0.3 ml/minute; inulin, 10 mg/minute; PAH, 3 mg/minute; vasopressin, 50 mU/kg/hour -68--31 0.20 1,920 1.30 1.1 296 -31 15% mannitol in 50 mM NaCl, 5 ml/minute 0-13 6.58 67 452 9.65 3.1 308 13-38 8.32 60 404 10.70 2.4 314 15% mannitol in 50 mM NaCI, 12 ml/minute 38-55 11.7 65 399 14.6 2.9 329 55-68 14.5 57 388 16.8 2.3 335 68-79 17.3 63 389 19.5 2.2 345 79-89 17.6 56 393 19.8 2.2 351 Infusion of mannitol discontinued 89-102 15.4 51 401 17.6 2.2 351 142-152 6.35 47 487 8.91 2.6 347 Ethacrynic acid, 1 mg/kg at once, and 1 mg/kg/hour 152-164 11.0 42 380 12.1 1.1 344 164-176 11.3 30 344 11.1 -0.2 350 160 mEq/L Na, 4.0 mEq/L K, 20 mEq/L HCO3, 144 mEq/L Cl, 30 ml/minute 176-187 13.9 36 341 13.8 -0.1 344 187-195 21.0 49 339 20.8 -0.2 342 Hypertonic electrolyte solution slowed to 10 ml/minute 195-204 22.7 49 338 22.2 -0.5 345 * GFR = glomerular filtration rate; Uosm = urine osmolality; Cosm = osmolar clearance; TCH20 = renal concentrat- ing capacity; Posm = plasma osmolality; PAH = p-aminohippurate. hour, after the collection of control periods. In two ex- Each animal was given 50 ml per kg of tap water by periments, the drug was administered, during an inter- stomach tube. Two and one-half per cent dextrose was mediate rate of infusion of hypertonic mannitol, and then infused at a rate approximately 1 ml per minute then the infusion of mannitol was discontinued. In one in excess of the rate of urine flow. When the rate of experiment, the drug was administered at the height of urine flow had been relatively constant for a minimum of a hypertonic mannitol infusion (which was then dis- 30 minutes and urine osmolality was below 60 mOsm, continued), and in one experiment the agent was given ethacrynic acid was administered intravenously in a dose when the flow of urine had receded after an infusion of of 1 mg per kg acutely, and 1 mg per kg per hour. hypertonic mannitol. In four experiments, the rate of hypotonic dextrose In five of the six drug experiments described above, infusion was adjusted to partially match the increased after the peak drug effect was observed, a hypertonic rate of, urine flow that followed administration of the electrolyte solution (Na, 160; K, 4.0; Cl, 144; and HCO3, drug. In five experiments, the infusion of hypotonic 20 mEq per L) was infused at a rate of 30 to 35 ml per dextrose was discontinued at the time ethacrynic acid minute, until a desired rate of urine flow was achieved. was administered, and an infusion of hypotonic electro- The purpose of this infusion was to restore the electro- lyte solution (Na, 110; K, 4.0; HCO3, 15; Cl, 99 mEq lyte losses induced by ethacrynic acid. Through ex- per L) was begun and maintained at a rate approximately perience we learned that the electrolyte losses produced 1 ml per minute less than the rate of urine flow. In by the drug were associated with decreases in the clear- four of the five latter experiments, chlorothiazide was ances of inulin and PAH. Restoration of the electro- administered at a dose of 5 mg per kg acutely, and 5 lyte losses increased these measurements of renal hemo- mg per kg per hour, at a time when the flow of urine dynamics and allowed a comparison of concentrating ca- was relatively constant during the administration of pacity at various rates of solute excretion and glomerular ethacrynic acid and the hypotonic electrolyte solution. filtration. In three experiments during the height of water diu- Water diuresis. Animals were not fed on the day of resis, chlorothiazide was administered at the above de- study, but otherwise no special preparation was employed. scribed dose. When collection periods had been made TUBULAR EFFECTS OF ETHACRYNIC ACID 1497 O3Pr[-hnsioF1 * /5*A Mnnuto/F ° chacrynicAcid IDog e .In 6 * 0 0 0 M. 0 0 4 0 : .--0* 0 0 .I 2 -% To2 0 I ° ' 0Or Lt' twr X . IrobI r ,, (mL/min) _** * _~O~,I Dog R.
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