Serotonin (5-HT1A-receptor) agonist-induced collecting duct vacuolation and renal papillary necrosis in the rat.
General anxiety in humans is treated with azaspirodecanedions, which act through a reduction of serotonin transmission. Ipsapirone also represents a serotonin (5-HT1A) 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.
Rinke
M
M
Bayer AG, PH-PDT Toxicology, Pharma Research Center, Wuppertal, Germany.
Bomhard
E M
EM
Hildebrand
H
H
Leser
K H
KH
Loof
I
I
Ruehl-Fehlert
C
C
D000328:Adult; D000410:Alanine Transaminase / Q000378:metabolism; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D005021:Ethylamines / Q000494:pharmacology; D005260:Female; D006801:Humans; D007679:Kidney Medulla / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007681:Kidney Papillary Necrosis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D007685:Kidney Tubules, Collecting / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D011743:Pyrimidines / Q000633:toxicity*; D051381:Rats; D011910:Rats, Brattleboro; D017208:Rats, Wistar; D017366:Serotonin Receptor Agonists / Q000633:toxicity*; D013045:Species Specificity; D014617:Vacuoles / Q000187:drug effects / Q000473:pathology
D005021:Ethylamines; D011743:Pyrimidines; D017366:Serotonin Receptor Agonists; C004504:2-bromoethylamine; D001127:Arginine Vasopressin; C043077:ipsapirone; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase