Klinische Wochenschrift

, Volume 60, Issue 19, pp 1258–1263 | Cite as

Molecular actions of diuretics

  • O. Heidenreich
  • J. Greven
  • K. Heintze
Article

Summary

The criteria upon which diuretics are classified is based upon their site of action within the nephron. Carboanhydrase inhibitors act in the proximal tubule, high-ceiling diuretics in the ascending loop of Henle, the thiazides in the early distal tubule and the potassium-sparing diuretics in the late distal tubule and in the collecting duct. On the molecular level diuretics do not inhibit Na+-K+-ATPase but interfere with the permeability of the tubule membranes or transport systems for certain ions and thus also influence the potential differences in the different parts of the nephron. Since carboanhydrase is located in the proximal tubule cells, not only in the cytosol but also in the brushborders and in the peritubular membranes, acetazolamide and other carboanhydrase inhibitors act on three different sites in these cells. The loop diuretics inhibit the secondary active chloride reabsorption. The receptors in this part of the nephron are stereospecific. Only the levorotatory isomere of ozolinone has active diuretic properties whereas the dextrorotatory isomere does not. Perfusion experiments of the loop of Henle with different lectins give evidence that glycoproteins containing α-1-fucose are involved in the reabsorption of Na+ and Cl. Experiments on the isolated stripped rabbit colon under the condition of chloride secretion reveal striking similarities between the receptors for chloride reabsorption in the luminal cell membranes of the ascending loop of Henle and in the serosal cell membranes of the colon. The potassium-sparing diuretics amiloride and triamterene act by blocking sodium channels in the dista parts of the nephron. Thus the lumen negative potential difference decreases and (passive) potassium secretion is diminished.

Key words

Carboanhydrase inhibitors Loop diuretics Potassium-sparing diuretics Mammalian kidney Mammalian colon 

Molekulare Wirkungsmechanismen von Diuretika

Zusammenfassung

Die Einteilung von Diuretika in verschiedene Klassen erfolgt am besten aufgrund ihres Wirkungsortes im Nephron. Carboanhydrase-Hemmstoffe wirken im proximalen Tubulus, stark wirksame Diuretika im aufsteigenden Ast der Henleschen Schleife, die Benzothiadiazin-Derivate im frühen distalen Tubulus und die kaliumsparenden Diuretika im distalen Teil des distalen Tubulus und im Sammelrohr. Auf dem molekularen Niveau hemmen Diuretika nicht die Na+-K+-ATPase, sondern verändern die Permeabilität der Tubulus-Membranen oder Transport-Systeme für gewisse Ionen und beeinflussen so auch die Potentialdifferenzen in den verschiedenen Abschnitten des Nephrons. Da das Enzym Carboanhydrase nicht nur im Zytosol der proximalen Tubuluszellen, sondern auch in den Bürstensäumen und in den peritubulären Membranen vorkommt, wirken Acetazolamid und andere Carboanhydrase-Hemmstoffe an drei verschiedenen Stellen in den proximalen Tubuluszellen. Die Schleifendiuretika hemmen die sekundär aktive Chloridresorption. Die Rezeptoren in diesem Abschnitt des Nephrons sind stereospezifisch. Nur das linksdrehende Isomere von Ozolinon hat diuretische Wirkungen, das rechtsdrehende dagegen nicht. Perfusionsversuche der Henleschen Schleife mit verschiedenen Lectinen haben Hinweise dafür erbracht, daß Glykoproteine, die α-1-Fucose enthalten, an der Resorption von Na+ und Cl beteiligt sind. Versuche am isolierten Kaninchenkolon unter Bedingungen, in denen eine Chlorid-Sekretion abläuft, lassen erhebliche Ähnlichkeiten zwischen den Rezeptoren für die Chloridresorption in den luminalen Zellmembranen des aufsteigenden Astes der Henleschen Schleife und in den serosalen Zellmembranen des Kolons erkennen. Die kaliumsparenden Diuretika Amilorid und Triamteren wirken, indem sie Natriumkanäle in den distalen Abschnitten des Nephrons blockieren. Auf diese Weise nimmt die lumen-negative Potentialdifferenz ab, und die (passive) Kaliumsekretion wird vermindert.

Schlüsselwörter

Carboanhydrase-Hemmer Schleifendiuretika Kaliumsparende Diuretika Säuger-Niere Säuger-Colon 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Brenner BM, Berliner RW (1973) Transport of potassium. In: Orloff J, Berlinger RW (eds) Handbook of physiology, Sct. 8: Renal physiology. Washington DC: Am Physiol Soc, pp 497–520Google Scholar
  2. Burg M, Green N (1973a) Function of the thick ascending limb of Henle's loop. Am J Physiol 224:659–668Google Scholar
  3. Burg M, Green N (1973b) Effect of ethacrynic acid on the thick ascending limb of Henle's loop. Kidney Int 4:301–308Google Scholar
  4. Burg M, Green N (1973c) Effect of mersalyl on the thick ascending limb of Henle's loop. Kidney Int 4:245–251Google Scholar
  5. Burg M, Stoner L, Cardinal J, Green N (1973) Furosemide effect on isolated perfused tubules. Am J Physiol 225:119–124Google Scholar
  6. Cuthbert AW (1973) An upper limit to the number of sodium channels in frog skin epithelium. J Physiol 228:681–692Google Scholar
  7. Cuthbert AW, Edwardson JM (1981) Attemps to define the amiloride receptor in kidney tissue. In: Macknight ADC, Leader JP (eds) Epithelial ion and water transport. Raven Press, New York, pp 35–42Google Scholar
  8. Dirks JH, Cirksena WJ, Berliner RW (1966) Micropuncture study of the effect of various diuretics on sodium reabsorption by the proximal tubules of the dog. J Clin Invest 45:1875–1885Google Scholar
  9. Duarte CG, Chométy F, Giebisch G (1971) Effect of amiloride, ouabain and furosemide on distal tubular function in the rat. Am J Physiol 221:632–639Google Scholar
  10. Frizzell RA, Field M, Schultz SG (1979) Sodium coupled chloride transport by epithelial tissues. Am J Physiol 236:F1-F8Google Scholar
  11. Frizzell RA, Heintze K, Stewart CP (1980) Mechanism of intestinal chloride secretion. In: Field M, Fordtran JS, Schultz SG (eds) Secretory Diarrhea. Amer Physiol Soc, Bethesda, Maryland, pp 11–19Google Scholar
  12. Frömter E (1980) Significance of carbonic anhydrase for HCO3-absorption and H+ secretion in renal tubules. In: Bauer C, Gros G, Bartels H (eds) Biophysics and physiology of carbondioxide. Springer, Berlin Heidelberg New York, pp 419–425Google Scholar
  13. Giebisch G (1977) Effects of diuretics on renal transport of potassium. In: Methods in pharmacology, Vol 4A. Plenum Press, New York, pp 121–164Google Scholar
  14. Giebisch G (1979) Renal tubular control of potassium transport. Klin Wochenschr 57:1001–1008Google Scholar
  15. Good DW, Wright FS (1979) Luminal influences on potassium secretion: sodium concentration and fluid flow rate. Am J Physiol 236:F192Google Scholar
  16. Greger R (1981) Chloride reabsorption in the rabbit cortical thick ascending limb of the loop of Henle. Pflügers Arch 390:38–43Google Scholar
  17. Greger R, Frömter E (1980) Time course of ouabain and furosemide effects on transepithelial potential difference in cortical thick ascending limbs of rabbit nephrons. 28. International Congress of Physiological Sciences. Hung Physiol Soc, Budapest, p 445Google Scholar
  18. Greven J, Beckers M, Defrain W, Meywald K, Heidenreich O (1980b) Studies with optically active isomers of the new diuretic drug ozolinone. II. Inhibition by d--ozolinone of furosemide-induced diuresis. Pflügers Arch 384:61–64Google Scholar
  19. Greven J, Defrain W, Glaser K, Meywald K, Heidenreich O (1980a) Studies with the optically activ isomers of the new diuretic drug ozolinone. I. Differences in stereoselectivity of the renal target structures of ozolinone. Pflügers Arch 384:57–60Google Scholar
  20. Greven J, Heidenreich O (1977) Effect of etozolin on whole kidney function and fluid and electrolyte reabsorption in rat proximal convoluted tubules and loops of Henle. Arzneimittel-Forsch 27:1755–1757Google Scholar
  21. 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 304:289–296Google Scholar
  22. Greven J, Schreibmüller F (1981) Effect of carbohydrate binding lectins on sodium and chloride transport in the loop of Henle. Pflügers Arch, Suppl to Vol 389:R41Google Scholar
  23. Heidenreich O, Baumeister L, Fülgraff G, Hahnege V, Laaff H (1967) Vergleichende Untersuchungen über die diuretische Wirkung und die akute Toxizität von g-Strophanthin, Scillaren A und Proscillaridin an Hunden. Arch Int Pharmacodyn 166:1–10Google Scholar
  24. Heidenreich O, Gharemani G, Keller P, Kook Y, Schmiz K (1964) Die Wirkungen von 2-Carbäthoxymethylen-3-methyl-5-N-piperidinothiazolidon-4 auf die Nierenfunktion von Ratten und Hunden. Arzneimittel Forsch 14:1242–1248Google Scholar
  25. Heintze K, Petersen K-U (1980) Specific inhibition of colonic chloride secretion by loop diuretics. Fed Proc 39:738Google Scholar
  26. Heintze K, Petersen K-U, Heidenreich O (1982) Stereospecific inhibition by ozolinone of stimulated chloride secretion in rabbit colon descendens. Naunyn-Schmiedeberg's Arch Pharmacol 318:363–367Google Scholar
  27. Hook JB, Williamson HE (1965) Influence of probenecid and alterations in acidbase balance on the saluretic activity of furosemide. J Pharmac Exp Ther 149:404–408Google Scholar
  28. Hoyer JR, Seiler MW (1979) Pathophysiology of Tamm-Horsfall protein. Kidney Int 16:279–289Google Scholar
  29. Khuri RN, Wiederholt M, Strieder N, Giebisch G (1975) Effects of flow rate and potassium intake on distal tubular potassium transfer. Am J Physiol 228:1249–1261Google Scholar
  30. Kunau RT, Webb HC, Borman SC (1974) Characteristics of the relationship between the flow rate of tubular fluid and potassium transport in the distal tubule of the rat. J Clin Invest 54:1488–1495Google Scholar
  31. Pitts RF (1968) The Physiology of the kidney and body fluids. Year Book Med Publ, ChicagoGoogle Scholar
  32. Pitts RF, Alexander RS (1945) The nature of the renal tubular mechanism for acidifying the urine. Amer J Physiol 144:239–254Google Scholar
  33. Stokes JB (1981) Potassium secretion by cortical collecting tubule: relation to sodium absorption, luminal sodium concentration, and transepithelial voltage. Am J Physiol 241:F395–402Google Scholar
  34. Ullrich KJ, Frömter E, Murer H (1979) Prinzipien des epithelialen Transportes in Niere und Darm. Klin Wochenschr 57:977–991Google Scholar
  35. Wistrand PJ, Kinne R (1977) Carbonic anhydrase activity of isolated brush border and basal-lateral membranes of renal tubular cells. Pflügers Arch 370:121–126Google Scholar

Copyright information

© Springer-Verlag 1982

Authors and Affiliations

  • O. Heidenreich
    • 1
  • J. Greven
    • 1
  • K. Heintze
    • 1
  1. 1.Abteilung Pharmakologie der Medizinischen Fakultät der Rhein.-Westf. Technischen Hochschule AachenAachenGermany

Personalised recommendations