Advertisement

Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Prostaglandins and renal NaCl excretion in healthy human subjects: Effects of prostaglandin synthesis inhibition with indomethacin

Die Rolle von Prostaglandinen bei der Regulation der renalen NaCl Ausscheidung: Untersuchungen an gesunden Versuchspersonen während Hemmung der Prostaglandinsynthese mit Indometacin

Summary

The effect of a single oral dose of 75 mg of indomethacin on renal function and urinary excretion of prostaglandin (PG) E2 was investigated in six healthy volunteers. In the absence of changes in GFR, indomethacin significantly reduced urinary excretion of sodium and chloride for 12 h with a return to control values afterwards. This effect on the renal excretory function was closely paralleled by a decrease in urinary excretion of PGE|12|0 which also returned to control values after 12 h. In a second series of experiments, inhibition of PG synthesis was performed in healthy volunteers during sustained water diuresis to determine the tubular site of altered NaCl absorption using clearance methods. Again, indomethacin induced a significant suppression of urinary excretion of sodium, chloride and potassium without changes in GFR or urinary excretion of phosphate. Indomethacin treatment had no effect on the delivery of chloride beyond the proximal tubule to the distal tubules (distal delivery) but significantly increased the distal fractional absorption of chloride (DFACl). In a third series of experiments, the effect of furosemide on GFR and tubular NaCl absorption was studied without and with concomitant administration of indomethacin. Furosemide induced an almost twelvefold increase in the urinary excretion of sodium and chloride, an approximately threefold increase in urinary excretion of potassium and a significant increase in urinary phosphate excretion. Furosemide also increased distal delivery and decreased DFACl and also increased urinary excretion of PGE2. Concomitant indomethacin treatment significantly suppressed urinary excretion of PGE2 but did not affect any of the furosemide induced changes in renal function. Our results support the concept that PG participate in the regulation of renal NaCl excretion and suggest that the diluting segments of the nephron may be the site of action of renal PG. Furthermore, furosemide stimulates renal synthesis of PGE2 but the tubular effects of this diuretic appear not to be mediated by the renal PG system.

Zusammenfassung

An sechs gesunden Versuchspersonen wurde die Wirkung einer oral verabreichten Einzeldosis von 75 mg Indometacin auf die Nierenfunktion und die Urinausscheidung von Prostaglandin (PG) E2 untersucht. Indometacin bewirkte eine signifikante Reduktion der NaCl Ausscheidung über einen Zeitraum von 12 h ohne gleichzeitige Wirkung auf die GFR. Diese Wirkung auf die exkretorische Nierenfunktion war von einer gleichzeitigen Abnahme der Urinausscheidung von PGE2 begleitet, welche ebenfalls nach 12 h wieder auf Kontrollwerte anstieg. In einer zweiten Versuchsserie wurde die Wirkung einer Indometacingabe auf proximale und distale Tubulusfunktion während Wasserdiurese mittels Clearance-Methoden ermittelt. Dabei kam es nach Indometacingabe wiederum zu einer signifikanten Reduktion der Urinausscheidung von Chlorid, Natrium und Kalium ohne Änderungen der GFR oder der Urinausscheidung von Phosphat. Die Indometacingabe hatte keinen Effekt auf die Chloridmenge, die den distalen Tubulus erreicht (distal delivery), führte jedoch zu einem signifikanten Anstieg der distalen fraktionellen Absorption von Chlorid (DFACl). In einer dritten Versuchsserie wurde die Wirkung von Furosemid auf die GFR und die tubuläre NaCl Absorption ohne und mit gleichzeitiger Gabe von Indometacin untersucht. Nach Gabe von Furosemid kam es zu einem fast zwölffachen Anstieg der Urinausscheidung von Natrium und Chlorid, einem etwa dreifachen Anstieg der Urinausscheidung von Kalium und einem signifikanten Anstieg der Urinausscheidung von Phosphat. Weiterhin kam es nach Furosemidgabe zu einem signifikanten Anstieg der “distal delivery”, einer Abnahme der DFACl und einem Anstieg der Urinausscheidung von PGE2. Unter gleichzeitiger Gabe von Indometacin kam es zu einer signifikanten Abnahme der Urinausscheidung von PGE2 ohne daß die Furosemid-induzierten Änderungen der exkretorischen Nierenfunktion dadurch verändert wurden. Unsere Ergebnisse legen eine Rolle des endogenen PG-Systems bei der Regulation der renalen NaCl Ausscheidung nahe und lokalisieren eine solche Wirkung in das Verdünnungssegment des distalen Tubulus. Furosemide vermag die renale Synthese von PGE2 zu stimulieren aber die tubuläre Wirkung dieses Diuretikums scheint nicht über das renale PG System vermittelt zu werden.

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

References

  1. 1.

    Düsing R, Kramer HJ (1978) Prostaglandins and renal sodium excretion. In: Annual Research Reviews. The Renal Prostaglandins. Lee JB (ed). Eden Press, Montreal, pp 92–107

  2. 2.

    Düsing R, Kramer HJ (1980) A possible role for prostaglandins in the regulation of renal sodium chloride excretion. In: Lichardus B, Schrier RW, Ponec J (eds) Regulation of Renal Sodium Excretion by Hormones. Elsevier/North-Holland, Amsterdam, pp 205–212

  3. 3.

    Dunn MJ, Hood VL (1977) Prostaglandins and the kidney. Am J Physiol 233:F169-F184

  4. 4.

    Stokes JB (1981) Prostaglandins and the regulation of NaCl transport across renal epithelia. Mineral Electrolyte Metab 6:35–45

  5. 5.

    Düsing R, Opitz WD, Kramer HJ (1977) The role of prostaglandins in the natriuresis of acutely salt loaded rats. Nephron 18:212–219

  6. 6.

    Düsing R, Melder B, Kramer HJ (1976) Prostaglandins and renal function in acute extracellular volume expansion. Prostaglandins 12:3–10

  7. 7.

    Higashihara E, Stokes JB, Kokko JP, Campbell WB, DuBose TD Jr (1979) Cortical and papillary micropuncture examination of chloride transport in segments of the rat kidney during inhibition of prostaglandin production. Possible role for prostaglandins in the chloruresis of acute volume expansion. J clin Invest 64:1277–1287

  8. 8.

    Frölich JC, Hollifield JW, Dormois JC, Frölich BL, Seyberth H, Michelakis AM, Oates JA (1976) Suppression of plasma renin activity by indomethacin in man. Circ Res 39:447–452

  9. 9.

    Attallah AA, Lee JB (1973) Radioimmunoassay of prostaglandin A. Intrarenal PGA2 as a factor mediating saline induced natriuresis. Circ Res 33:696–703

  10. 10.

    Williamson HE, Bourland WA, Marchand GR, Farley DB, van Orden DE (1975) Furosemide induced release of prostaglandin E to increase renal blood flow. Proc Soc Exp Biol Med 150:104–106

  11. 11.

    Abe K, Yasujima M, Chiba S, Irokawa N, Ito T, Yoshinaga K (1977) Effect of furosemide on urinary excretion of prostaglandin E in normal volunteers and patients with essential hypertension. Prostaglandins 14:513–521

  12. 12.

    Brater DC, Beck JM, Adams BV, Campbell WB (1980) Effects of indomethacin on furosemide stimulated urinary PGE2 excretion in man. Europ J Pharmacol 65:213–219

  13. 13.

    Patak RV, Fadem SZ, Rosenblatt SG, Lifschitz MD, Stein JH (1975) Diuretic induced increase in renal blood flow. Proc Soc Exp Biol Med 148:1173–1176

  14. 14.

    Düsing R, Nicolas V, Glänzer K, Kipnowski J, Kramer HJ (1982) Prostaglandins participate in the regulation of NaCl absorption in the diluting segments of the nephron in vivo: Effects of furosemide. Renal Physiol 5:115–123

  15. 15.

    Kramer HJ, Düsing R, Stinnesbeck B, Prior W, Bäcker A, Eden J, Kipnowski J, Glänzer K, Krück F (1980) Interaction of conventional and antikaliuretic diuretics with the renal prostaglandin system. Clin Sci 59:67–70

  16. 16.

    Patak RV, Mookerjee BK, Bentzel CJ, Hysert PE, Babej M, Lee JB (1975) Antagonism of the effects of furosemide by indomethacin in normal and hypertensive man. Prostaglandins 10:649–659

  17. 17.

    Oliw E, Kover G, Larsson C, Anggard E (1978) Reduction by indomethacin of furosemide effects in the rabbit. Eur J Pharmacol 38:95–100

  18. 18.

    Wahlefeld AW, Holz G, Bergmeyer HU (1974) In: Bergmeyer HU (ed) Methoden der enzymatischen Analyse. Verlag Chemie, Weinheim, vol 2, pp 1834–1838

  19. 19.

    Jaffe BM, Behrmann HR, Parker CW (1973) Radioimmunoassay measurement of prostaglandin E, A, and F in human plasma. J Clin Invest 52:398–405

  20. 20.

    Snedecor GW (1956) Statistical Methods. Iowa State University Press, Ames, Iowa, 5th edition

  21. 21.

    Danovitch GM, Bricker NS (1976) Influence of volume expansion on NaCl absorption in the diluting segments of the nephron: A study using clearance methods. Kidney Int 10:229–238

  22. 22.

    Gill JR Jr, Bartter FC (1978) Evidence for a prostaglandin-independent defect in chloride absorption in the loop of Henle as a proximal cause of Bartter's syndrome. Am J Med 65:766–772

  23. 23.

    Newcombe DS, Thanassi NM, Ciosek CP Jr (1974) Cartilage cyclic nucleotide phosphodiesterase: Inhibition by anti-inflammatory agents. Life Sci 14:505–519

  24. 24.

    Gaut ZN, Solomon HM (1971) Inhibition of nicotinate phosphoribosyl transferase by nonsteroidal anti-inflammatory drugs: a possible mechanism of action. J Pharm Sci 60:1887–1888

  25. 25.

    Leyssac PP, Christensen P, Hill R, Skinner SL (1975) Indomethacin blockade of renal PGE-synthesis: effect on total renal and tubular function and plasma renin concentration in hydropenic rats and on their response to isotonic saline. Acta Physiol Scand 94:484–496

  26. 26.

    Foman RJ, Kauker ML (1978) Renal effects of prostaglandin synthetase inhibition in rats: micropuncture studies. Am J Physiol 235:F111-F118

  27. 27.

    Stokes JB, Kokko JP (1977) Inhibition of sodium transport by prostaglandin E across the isolated perfused rabbit collecting tubule. J Clin Invest 49:1099–1104

  28. 28.

    Stokes JB (1979) Effect of prostaglandin E on chloride transport across the thick ascending limb of Henle. Selective inhibition of the medullary portion. J Clin Invest 64:495–502

  29. 29.

    Frölich JC, Wilson TW, Sweetman BJ, Smigel M, Nies AS, Carr K, Watson JT, Oates JA (1975) Urinary prostaglandins: Identification and origin. J Clin Invest 55:763–770

Download references

Author information

Correspondence to Dr. R. Düsing.

Additional information

Dedicated to Professor F. Krück on the occasion of his 60th birthday

This study was supported by research grant No. FA-8476, Ministerium für Wissenschaft und Forschung NRW, FRG

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Düsing, R., Kipnowski, J. & Kramer, H.J. Prostaglandins and renal NaCl excretion in healthy human subjects: Effects of prostaglandin synthesis inhibition with indomethacin. Klin Wochenschr 60, 1229–1233 (1982). https://doi.org/10.1007/BF01716728

Download citation

Key words

  • Prostaglandins
  • NaCl excretion
  • Excretory renal function
  • Tubular function

Schlüsselwörter

  • Prostaglandine
  • NaCl Ausscheidung
  • Exkretorische Nierenfunktion
  • Tubuläre Funktion