Skip to main content
SpringerLink
Log in

Effect of “high ceiling” diuretics on active salt transport in the cortical thick ascending limb of Henle's loop of rabbit kidney

Correlation of chemical structure and inhibitory potency

  • Transport Processes, Metabolism and Endocrinology; Kidney, Gastrointestinal Tract, and Exocrine Glands
  • Published:
Pflügers Archiv Aims and scope Submit manuscript

Abstract

The group of “high ceiling” diuretics consists of a variety of chemically different potent diuretic and saluretic substances. Appart from a few exemptions direct evidence for an action of these substances in the thick ascending limb of the loop of Henle (TAL) is still lacking. For furosemide, we have reported recently that it inhibits most likely the Naü-2Cl−-Kü cotransport system present in the lumen membrane of the TAL. The present study tests: 1. whether other “high ceiling” diuretics have a similar site and mode of action, and 2. how modifications of the furosemide molecule alter the inhibitory potency. Isolated cortical TAL (cTAL) segments (n=185) of rabbit kidneys were perfused in vitro. The equivalent short circuit current (Isc=transepithelial PD/transepithelial resistance), as a measure of active salt transport was correlated to the dose of 64 substances.

Several diuretics, such as 2-aminomethyl-4-(1,1-dimethylethyl)-6-iodophenol hydrochloride (MK 447), hydrochlorothiazide, muzolimine, etozoline, tizolimide, amiloride, and triamterene were ineffective both from the lumen and basolateral side at concentrations as high as 10−4–10−3 mol·l−1. The phenoxyacetic acids ethacrynic acid, indacrinone (MK 196), and to less an extend tienilic acid were inhibitory active. They differed from furosemide in one or more of the following criteria: delayed onset, incomplete reversibility, stronger action from the bath, different slope of the dose response curve. Similarly, l-ozolinone acted stronger from the bath. In contrast, the diuretics of the furosemide type and related compounds (bumetanide and piretanide) showed rapid onset and complete reversibility of inhibition. These substances acted stronger from the lumen. The individual positions in the benzyl ring of the diuretics were differently affected by substitutions, leading to parallel shifts in the dose response curves with halfmaximal inhibition at concentrations ranging between 8·10−8 to >10−4 mol·l−1. For these substances the calculated Hill coefficients were close to unity: 0.96±0.05. We conclude that the so called “high ceilling” or “loop” diuretics consist of at least 3 groups: 1. drugs that do not interfere with the active salt transport in the cTAL segment, 2. drugs that interfere by so far not characterised mechanisms, and 3. drugs of the furosemide type which inhibit the Naü−2Cl−−Kü cotransport system in the lumen membrane of the cTAL segment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Allen RC (1982) Sulfonamide diuretics. In: Cragoe EJ (ed) Diuretics, Wiley and Sons, chapter 3

  2. Brown DR, Feldman AM (1978) Pharmacology of hearing and ototoxicity. Ann Rev Pharmacol Toxicol 18:233–252

    Google Scholar 

  3. Burg MB (1976) Mechanisms of action of diuretic drugs. In: Brenner BM, Rector FC (eds) The kidney, vol 1, 19. Saunders Company, Philadelphia London Toronto, pp 737–762

    Google Scholar 

  4. Burg MB, Green N (1973) Effect of mersalyl on the thick ascending limb of Henle's loop. Kidney Int 4:245–251

    Google Scholar 

  5. Burg MB, Green N (1973) Effect of ethacrynic acid on the thick ascending limb of Henle's loop. Kidney Int 4:301–308

    Google Scholar 

  6. Burg MB, Green N (1973) Function of the thick ascending limb of Henle's loop. Am J Physiol 224(3):659–668

    Google Scholar 

  7. Burg MB, Stoner L (1976) Renal tubular chloride transport and the mode of action of some diuretics. Ann Rev Physiol 38:37–45

    Google Scholar 

  8. Burg MB, Grantham J, Abramow M, Orloff J (1966) Preparation and study of fragments of single rabbit nephrons. Am J Physiol 210:1293–1298

    Google Scholar 

  9. Burg MB, Stoner L, Cardinal J, Green N (1973) Furosemide effect on isolated perfused tubules. Am J Physiol 225(1):119–124

    Google Scholar 

  10. Clapp JR, Robinson RR (1968) Distal sites of action of diuretic drugs in the dog nephron. Am J Physiol 215(1):228–235

    Google Scholar 

  11. Cragoe EJ (ed) (1978) Diuretic agents. ACS symposium series 83, Am Chem Soc, Washington

    Google Scholar 

  12. Dunham PB, Stewart GW, Ellory JC (1980) Chloride-activated passive potassium transport in human erythrocytes. Proc Nat Acad Sci USA 77(3):1711–1715

    Google Scholar 

  13. Forbush III B, Palfrey HC (1982) Bumetanide and benzmetanide binding to membranes from shark rectal gland and canine kidney. Biophys J 37:M-PM-Po 133

    Google Scholar 

  14. Friedman PA, Andreoli TE (1982) CO2-Stimulated NaCl absorption in the mouse renal cortical thick ascending limb of Henle. Evidence for synchronous Naü/Hü and Cl−/HCO −3 exchange in apical plasma membranes. J Gen Physiol 80:683–711

    Google Scholar 

  15. Frizzell RA, Welsh MJ, Smith PL (1980) Regulation of chloride secretion by canine tracheal epithelium. Nieren Hochdruckkrankheiten 9:208

    Google Scholar 

  16. Geck P, Heinz E, Pfeiffer B (1981) Influence of high ceiling diuretics on ion fluxes and cell volume of Ehrilich ascites tumour cells. Scand Audiol Suppl 14:25–37

    Google Scholar 

  17. Geck P, Pietrzyk C, Burckhardt BC, Pfeiffer B, Heinz E (1980) Electrically silent cotransport of Naü, Kü, and Cl− in Ehrlich cells. Biochim Biophys Acta 600:432–447

    Google Scholar 

  18. Goldberg M (1973) The renal physiology of diuretics. In: Handbook of physiology, Section 8: Ren Physiol 28:1003–1031

  19. Greger R (1981) Cation selectivity of the isolated perfused cortical thick ascending limb of Henle's loop of rabbit kidney. Pflügers Arch 390:30–37

    Google Scholar 

  20. Greger R (1981) Chloride reabsorption in the rabbit cortical thick ascending limb of the loop of Henle. A sodium dependent Process. Pflügers Arch 390:38–43

    Google Scholar 

  21. Greger R (1981) Coupled transport of Naü and Cl− in the thick ascending limb of Henle's loop of rabbit nephron. Scand Audiol Suppl 14:1–15

    Google Scholar 

  22. Greger R, Frömter E (1980) Time course of ouabain and furosemide on transepithelial potential difference in cortical thick ascending limbs of rabbit nephrons. In: Takacs L (ed) Kidney and body fluids. Adv Physiol Sci 11:375–379

  23. Greger R, Hampel W (1981) A modified system for in vitro perfusion of isolated renal tubules. Pflügers Arch 389:175–176

    Google Scholar 

  24. Greger R, Schlatter E (1983) Properties of the lumen membrane of the cortical thick ascending limb of Henle's loop of rabbit kidney. Pflügers Arch (in press)

  25. Greger R, Schlatter E (1983) Properties of the basolateral membrane of the cortical thick ascending limb of Henle's loop of rabbit kidney. A model for secondary active chloride transport. Pflügers Arch (in press)

  26. Greger R, Schlatter E, Lang F (1983) Evidence for electroneutral sodium chloride cotransport in the cortical thick ascending limb of Henle's loop in rabbit kidney. Pflügers Arch (in press)

  27. Greven J, Heidenreich O (1978) Effects of ozolinone, a diuretic active metabolite of etozoline, on renal function. I. Clearance studies in dogs. Naunyn-Schmiedeberg's Arch Pharmacol 304:283–287

    Google Scholar 

  28. Greven J, Klein H, Heidenreich O (1978) Effects of ozolinone, a diuretic active metabolite of etozoline, on renal function. II. Localization of tubular site of diuretic action by micropuncture in the rat. Naunyn-Schmiedeberg's Arch Pharmacol 304:289–296

    Google Scholar 

  29. Greven J, Defrain W, Glaser K, Meywald K, Heidenreich O (1980) Studies with the optically active isomers of the new diuretic drug ozolinone. Pflügers Arch 384:57–60

    Google Scholar 

  30. Hebert SC, Culpepper RM, Andreoli TE (1981) NaCl transport in mouse medullary thick ascending limbs. I. Functional nephron heterogeneity and ADH-stimulated NaCl cotransport. Am J Physiol 241:F412-F431

    Google Scholar 

  31. Heintze K, Petersen KU (1980) Specific inhibition of colonic chloride secretion by loop diuretics. Fed Proc 39(3):2484

    Google Scholar 

  32. Imai M (1977) Effect of bumetanide and furosemide on the thick ascending limb of Henle's loop of rabbits and rats perfused in vitro. Eur J Pharmacol 41:409–416

    Google Scholar 

  33. Jacobson HR, Kokko JP (1976) Diuretics: sites and mechanisms of action. Ann Rev Pharmacol 38:201–214

    Google Scholar 

  34. Kinne R, Kinne-Saffran E, Koenig B, Bayerdoerffer E, Eveloff J (1981) Control mechanisms in active chloride transport. Scand Audiol Suppl 14:17–24

    Google Scholar 

  35. Kinsella JL, Aronson PS (1981) Amiloride inhibition of the Naü−Hü exchanger in renal microvillus membrane vesicles. Am J Physiol 241:F374-F379

    Google Scholar 

  36. Koechel DA (1981) Ethacrynic acid and related diuretics: Relationship of structure to beneficial and detrimental actions. Ann Rev Pharmacol Toxicol 21:265–293

    Google Scholar 

  37. Koenig B, Kinne R (1982) Sodium transport by plasma membranes isolated from cells of the thick ascending limb of Henle's loop. Fed Proc 41(4):4310

    Google Scholar 

  38. Kunau RT, Weller DR, Webb HL (1975) Clarification of the site of action of chlorothiazide in the rat nephron. J Clin Invest 56:401–407

    Google Scholar 

  39. Lang HJ, Knabe B, Muschaweck R, Hropot M, Lindner E (1978) 4-(3-Sulf-amoylphenyl)thiazolidin-4-ols. A novel class of sulfonamide compounds with salidiuretic activity. In: Cragoe Jr EJ (ed) Diuretic agents. ACS Symposium series 83:24–37

  40. Loew D, Meng K (1977) The renal mechanism of Bay g 2821. Pharmatherapeutica 1(6):333–340

    Google Scholar 

  41. Maass AR, Snow IB, Erickson R (1978) Ticrynafen: an antihypertensive, diuretic, uricosuric agent. In: Cragoe Jr EJ (ed) Diuretic agents. ACS Symposium series 83:84–92

  42. Merkel W, Bormann D, Mania D, Muschaweck R, Hropot M (1976) Piretanide (HOE 118) a new high ceiling salidiuretic. Eur J Med Chem Chimica Therap 11:399–406

    Google Scholar 

  43. Musch MW, Orellana SA, Kimberg LS, Field M, Halm DR, Krasny Jr. EJ, Frizzell RA (1982) Naü−Kü−Cl− co-transport in the intestine of a marine teleost. Nature 300:351–353

    Google Scholar 

  44. Oberleithner H, Guggino W, Giebisch G (1982) Mechanism of distal tubular chloride transport in Amphiuma kidney. Am J Physiol 242:F331-F339

    Google Scholar 

  45. Palfrey HC, Feit PW, Greengard P (1982) cAMP-stimulated cation cotransport in avian erythrocytes: inhibition by “loop” diuretics. Am J Physiol 238:C139-C148

    Google Scholar 

  46. Palfrey HC, Silva P, Epstein JA, Eveloff J, Kinne R, Epstein FH (1979) Inhibition of cyclic AMP-stimulated chloride transport in the rectal gland of Squalus acanthias by a related series of “loop” diuretics. Bull Mount Desert Island Biol Lab 19:58–60

    Google Scholar 

  47. Petersen KU, Heintze K, Busch LC, Heidenreich O (1979) Effects of ethacrynic acid on electrolyte and fluid transport by the guinea pig gallbladder. Naunyn-Schmiedeberg's Arch Pharmacol 309:287–294

    Google Scholar 

  48. Rocha AS, Kokko JP (1973) Sodium chloride and water transport in the medullary thick ascending limb of Henle. J Clin Invest 52:612–623

    Google Scholar 

  49. Saito Y, Itoi K, Horiuchi K, Watanabe T (1980) Mode of action of furosemide on the chloride-dependent short-circuit current across the ciliary body epithelium of toad eyes. J Membr Biol 53:85–93

    Google Scholar 

  50. Seely JF, Dirks JH (1977) Site of action of diuretic drugs. Kidney Int 11:1–8

    Google Scholar 

  51. Smith RL, Schultz EM, Stokker GE, Cragoe EJ (1978) 2-Aminomethylphenols: A new class of saluretic agents. In: Cragoe Jr EJ (ed) Diuretic agents. ACS Symposium series 83:93–124

  52. Stokes JB (1981) Effect of elevated [K] on ion transport by the medullary thick ascending limb of Henle's loop (MTALH). Am Soc Nephrol 162A

  53. Stoner LC (1981) Isolated nephron segments as pharmacological tools. Trends in Pharmacological Sciences 3-5

  54. Suki WN, Eknoyan G, Martinez-Maldonado M (1973) Tubular sites and mechanisms of diuretic action. Ann Rev Pharmacol 13:91–106

    Google Scholar 

  55. Ullrich KJ, Greger R (1983) Approaches to study tubular transport functions. In: Seldin DW, Giebisch G (eds) Physiology and pathology of electrolyte metabolism. (in press)

  56. Woltersdorf Jr OW, de Solms SJ, Cragoe Jr EJ (1979) The evolution of the (aryloxy)acetic acid diuretics. In: Cragoe Jr EJ (ed) Diuretic agents. ACS Symposium series 83:190–230

  57. Widdicombe JH, Highland E, Nathanson IT (1982) Effects of “loop” diuretics on ion transport by dog tracheal epithelium. Fed Proc 41:5781

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Max-Planck-Institut für Biophysik, Kennedyallee 70, D-6000, Frankfurt/Main, Germany

    E. Schlatter, R. Greger & C. Weidtke

Authors
  1. E. Schlatter
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R. Greger
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C. Weidtke
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

This study was supported by the Deutsche Forschungsgemeinschaft, Gr 480/5-7. Parts of this study have been presented at the 56th meeting Deutsche Physiol. Ges. 1982, at the 16th meeting Europ. Soc. Clin. Invest. 1982, at the 66th meeting Federation Soc. Exper. Biol. 1982, and at the 4th Eur. Coll. Renal Physiol. 1982

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schlatter, E., Greger, R. & Weidtke, C. Effect of “high ceiling” diuretics on active salt transport in the cortical thick ascending limb of Henle's loop of rabbit kidney. Pflugers Arch. 396, 210–217 (1983). https://doi.org/10.1007/BF00587857

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00587857

Key words

Search

Navigation