Characterization of Hydronephrosis in Neonatal Rats from Dams Receiving Candesartan Cilexetil (TCV-116), an Angiotensin II Type 1 Receptor Antagonist

Abstract

The characteristics and mechanisms of hydronephrosis in neonatal rats induced by candesartan cilexetil (TCV-116), a potent angiotensin II (AngII) type 1 receptor antagonist, were examined. TCV-116 (300 mg/kg/day) was orally administered to dams for 4 weeks from gestation day 15 through lactation day 21. On lactation days 0, 4, 7, 14, and 22, the kidneys of the pups were examined. Hydronephrosis was observed starting on lactation day 14 accompanied by other histological changes, atrophy of the renal papillary tubules, dilatation of the renal tubules, and basophilic renal tubules in the cortex. These changes could also be observed at 10 weeks of age, 7 weeks after the last dose was administered. These renal structural abnormalities were consistent with that seen in other renin-angiotensin system antagonists. TCV-116 (300 mg/kg/day) was then administered to dams for four separate 1-week periods: gestation days 15 through 21, lactation days 0 to 6, lactation days 7 to 13, and lactation days 14 to 21. Pups were most susceptible to the induction of hydronephrosis when TCV-116 was administered from lactation days 0 to 6 and lactation days 7 to 13. The increased incidence of hydronephrosis and renal histological changes in the pups was prevented by administering mineralocorticoid, deoxycorticosterone acetate (10 mg/kg/day), subcutaneously to the pups from lactation days 7 to 13. Also, plasma aldosterone concentration in the pups was decreased after three daily treatments of TCV-116, accompanied by the increased plasma potassium concentration and urine Na/K ratio and the decreased urine osmolality. Therefore, we considered that the development of hydronephrosis in pups is closely related to the AngII blockade for the first 2 weeks after birth, and the reduction of aldosterone secretion by the inhibition of AngII leads to the disorder of the sodium and potassium homeostasis in neonates, and subsequent increase in urine volume may be involved in the mechanisms of hydronephrosis. We conclude that the hydronephrosis was caused by the sodium imbalance resulted from the pharmacological action of TCV-116 during the neonatal period.