SEROTONIN (5HT(1A)-RECEPTOR) AGONIST-INDUCED COLLECTING DUCT VACUOLATION AND RENAL PAPILLARY NECROSIS IN THE RAT

General anxiety in humans is treated with azaspirodecanedions, which a ct through a reduction of serotonin transmission. Ipsapirone also repr esents a serotonin (5-HT1A) receptor agonist and was under development as an anxiolytic drug. Histopathologic evaluation of animal experimen ts revealed cellular swelling and/or vacuolation of renal papillary an d medullary collecting duct (MCD) epithelium in rats but not in dogs o r mice. The changes ensued already after 1 wk of dosing and were first localized in the inner MCDs. Longer treatment periods showed that the se changes proceeded from proximal to distal, approaching the papillar y collecting ducts. The changes were most likely the result of altered hemodynamics in the papillary tip. Swelling resulted in partial or to tal papillary necrosis in some cases. Furthermore, rats treated with i psapirone showed a sharp and transient rise in urinary endothelin excr etion. Concomitantly, urinary PGE(2) levels were elevated. In contrast , no elevated levels of endothelin were detected in urine samples of p atients from a volunteer study, leading to the conclusion that the hum an kidney is not susceptible to the ipsapirone-induced alterations see n in the collecting ducts of rats.