This Article Full Text (PDF) References Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to Saved Citations Download to citation manager Add to My Marked Citations Citing Articles Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Ishimura, Y. Articles by Sato, S. Search for Related Content PubMed Articles by Ishimura, Y. Articles by Sato, S. Social Bookmarking                         What's this?

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

Hikari Branch, Drug Safety Research Laboratories, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Yamaguchi, Japan

Fumio Chatani

Drug Safety Research Laboratories, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan

Shuzo Sato

Drug Safety Research Laboratories, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan

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.

Key Words: Angiotensin II Type 1 Receptor Antagonist • Candesartan Cilexetil • Hydronephrosis • Neonates • Rat • Renin-angiotensin-aldosterone System • TCV-116

International Journal of Toxicology, Vol. 18, No. 6, 369-378 (1999)
DOI: 10.1080/109158199225071


CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?