Serotonin (5-HT1 A -Receptor) Agonist-Induced Collecting Duct Vacuolation and Renal Papillary Necrosis in the Rat

Abstract

General anxiety in humans is treated with azaspirodecanedions, which act through a reduction of serotonin transmission. Ipsapirone also represents a serotonin (5-HT1_A) receptor agonist and was under development as an anxiolytic drug. Histopathologic evaluation of animal experiments revealed cellular swelling and/or vacuolation of renal papillary and medullary collecting duct (MCD) epithelium in rats but not in dogs or mice. The changes ensued already after 1 wk of dosing and were first localized in the inner MCDs. Longer treatment periods showed that these changes proceeded from proximal to distal, approaching the papillary collecting ducts. The changes were most likely the result of altered hemodynamics in the papillary tip. Swelling resulted in partial or total papillary necrosis in some cases. Furthermore, rats treated with ipsapirone showed a sharp and transient rise in urinary endothelin excretion. Concomitantly, urinary PGE₂ levels were elevated. In contrast, no elevated levels of endothelin were detected in urine samples of patients from a volunteer study, leading to the conclusion that the human kidney is not susceptible to the ipsapirone-induced alterations seen in the collecting ducts of rats.

Keywords

Kidney renal medulla vacuolar swelling azaspirodecanedions Wistar rat Brattleboro rat species specific

References

1. Bach PH and Bridges JW (1985). Chemical induced renal papillary necrosis and upper urothelial carcinoma. Crit. Rev. Toxicol. 15: 217–411.

2. Bach PH and Kwizera EN (1988). Nephrotoxicity: A rational approach to target cell injury in vitro in the kidney. Xenobiotica 18: 685–698.

3. Boyce JT , DiBartola SP , Chew DJ , and Gasper PW (1984). Familial renal amyloidosis in Abyssinian cats. Vet. Pathol. 21: 33–38.

4. Burry A (1978). Pathology of analgesic nephropathy: Australian experience. Kidney Int. 13: 34–40.

5. Carlton WW and Engelhardt JA (1989). Experimental renal papillary necrosis in the Syrian hamster. Food Chem. Toxicol. 27: 331–340.

6. Eknoyan G , Qunibi WY , Grissom RT , and Ayus JC (1982). Renal papillary necrosis: An update. Medicine 61: 55–73.

7. Elliott GA (1986). Papillary necrosis, rat. In: Monographs on Pathology of Laboratory Animals, Urinary System. TC Jones , U Mohr , and RD Hunt (eds). Springer-Verlag, Berlin, pp. 184–189.

8. Evan AP and Gardner KD (1976). Comparison of human polycystic and medullary cystic kidney disease with diphenylamine-induced cystic disease. Lab. Invest. 35: 93–101.

9. Fuwa M and Waugh D (1968). Experimental papillary necrosis: Effects of diuresis and antidiuresis. Arch. Pathol. 85: 404–409.

10.

10. Goldberg HL (1984). Benzodiazepine and nonbenzodiazepine anxiolytics. Psychopathology 17: 45–55.

11.

11. Gunson DE (1983). Papillary necrosis in horses. J. Am. Vet. Med. Assoc. 182: 263–266.

12.

12. Hansen GP , Tisher CC , and Robinson RR (1980). Response of the collecting duct to disturbances of acid-base and potassium balance. Kidney Int. 17: 326–337.

13.

13. Hardy TL and Bach PH (1984): The effect of N-phenyanthranilic acid-induced renal papillary necrosis on urinary acidification and renal electrolyte handling. Toxicol. Appl. Pharmacol. 75: 265–277.

14.

14. Hildebrand H , Bomhard EM , Leser KH , Rinke M , Schoellnhammer G , Sundaresan P , and Schlueter G (1993). Ipsapirone induces increased urinary excretion of endothelin in rat but not in man–-Correlation with renal alterations. European Science Foundation Meeting, Sitges, Spain (poster).

15.

15. Koe BK (1979). Biochemical effects of antianxiety drugs on brain monamines. In: Anxiolytics, S Fielding and H Lal (eds). Futura Publishing Company, Mount Kisco, New York, pp. 173–195.

16.

16. Kriz W (1967). Architectural and functional structure of the rat kidney. Z Zellforsch. Mikrosk. Anat. 82: 495–535 (in German).

17.

17. Lenz SD and Carlton WW (1990). Diphenylamine-induced renal papillary necrosis and necrosis of pars recta in laboratory rodents. Vet. Pathol. 27: 171–178.

18.

18. Leser KH , Bomhard EM , Luckhaus G , Rinke M , Schmidt B , and Schlueter G (1993). Renal alterations induced by 5HT1A-receptor agonists. 32nd Annual Meeting Society of Toxicology, New Orleans (abstract no. 744). Toxicologist 13: 203.

19.

19. Molland EA (1978). Experimental renal papillary necrosis. Kidney Int. 13: 5–14.

20.

20. Muehrcke RC and Rosen S (1954). Hypokalemic nephropathy in rat and man: A light and electron-microscopic study. Lab. Invest. 13: 1359–1373.

21.

21. Oliver J , MacDowell M , Welt LG , Holliday MA , Hollander W Jr , Winters RW , Williams TF , and Segar WE (1957). The renal lesions of electrolyte imbalance. I. The structural alterations in potassium-depleted rats. J. Exp. Med. 106: 563–574.

22.

22. Peroutka S (1965). Selective interaction of novel anxiolytics with 5-hydroxytryptamine 1A receptors. Biol. Psychiatry 20: 971–979.

23.

23. Powell CJ , Adams T , Hall DE , Bach PH , and Bridges JW (1985). The comparative subacute nephrotoxicity of diphenlyamine and N-phenyanthranilic acid. In: Renal Heterogenity and Target Cell Toxicity. John Wiley & Sons, Chichester, UK, pp. 199–202.

24.

24. Rosenbaum JF (1982). The drug treatment of anxiety. N. Engl. J. Med. 306: 401–404.

25.

25. Strange K (1991). Volume regulatory CI– loss after Na+ pump inhibition in CCT principle cells. Am. J. Physiol. 260: F225–F234.

26.

26. Toback FG , Ordonez NG , Bortz SL , and Spargo BH (1976). Zonal changes in renal structure and phospholipid metabolism in potassium-deficient rats. Lab. Invest. 34: 115–124.

27.

27. Wanke R (1986): Toxic tubular necrosis with papillary necrosis in dogs. Tierarzll. Umsch. 41: 460–467.

28.

28. Wolf DC , Lenz SD , and Carlton WW (1991). Renal papillary necrosis in two domestic cats and a tiger. Vet. Pathol. 28: 84–87.

29.

29. Zeidel ML , Brady HR , Kone BC , Gullans SR , and Brenner BM (1989). Endothelin, a peptide inhibitor of Na+-K+-ATPase in intact renal tubular epithelial cells. Am J. Physiol. 257: C1101–C1107.

30.

30. Zwicker GM , Gosselin SJ , Solomon JL , and Hurst GH (1996). Effects found in a one-year oral toxicity study in Sprague-Dawley rats of a novel 5-HT1A receptor partial agonist for the treatment of anxiety in humans. Toxicol. Pathol. 24: 207–213.