Defining the susceptible period of developmental toxicity for the AT1‐selective angiotensin II receptor antagonist Losartan in rats

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Abstract
Previous developmental and reproductive toxicity studies conducted in rats with Losartan, a potent AT1 subtype selective angiotensin ll receptor antagonist, noted treatment-related effects on the pups of dams treated beyond the second trimester through lactation, as demonstrated by increases in pre- and postweaning pup deaths and decreased pup body weight [Spence et al. (1995) Teratology51: 000–000]. The studies presented here were designed to define the critical period for the induction of neonatal toxicity and to examine the effects of Losartan on Kidney development when the drug is administered to the dam beyond the second trimester through lactation. In a developmental toxicity study with postweaning evalution, pregnant rats were administered 5, 20, and 100, mg Losartan/kg/day on gestation days 6 through 15 (GD 6–15). There were no adverse effects on the F1 generation as assessed by mortality, clinical signs, weight gain, external examinations, developmental signs, behavioral tests, and gross or microscopic examination of the kidney. In a fostering/cross-fostering study, pregnant rats were administered 100 mg Losartan/kg/day on GD 15 through lactation day 20 (LD 20)Following delivery, pups from dams treated with Losartan were fostered to control dams, pups from control dams were fostered to Losartan-treated dams, and pups were also fostered to dams within the same group. Maternal exposure to Losartan during lactation increased the incidence of pup deaths on postnatal days 1–3 (PND 1–3), caused decreased pup weights on PND 7, and decreased performance in the auditory startle test in females and increased performance on the second swim maze test in males, relative to controls. Maternal exposure to Losartan during gestation was associated with decreased pup weight on PND 21 and effects observed on male performance in the swim maze test. Treatment during gestation was also associated with decreased pup cardiac weight as well as drug-induced histopathological changes of the kidneys from F1 pups, including medial hypertrophy of intracortical arterioles and dilatation of the renal pelvis. While the cardiac and renal vascular effects disappeared with time, significant renal lesions were still evident by PND 90. In a late-gestation/lactation study with renal evaluation, pregnant rats were administered 0. 5, 1. 0, 5. 0, 20, and 100 mg Losartan/kg/day on GD 15-LD 20. maternal toxicity was evident as decreased body weight gain in the 100 mg Losartan/kg/day group. Developmental toxicity was also evident in the 100 mg/kg/day group as decreased pup weights and histopathological kidney changes (dilatation of the renal pelvis, edema of the renal papilla, medial hypertrophy of intracortical arterioles, and chronic renal inflammation and irregular scarring of the renal parenchyma). Combined, these studies demonstrated that the critical period for Losartan-induced development toxicity (decreased pup weights and increased pup mortality) is GD 15-LD 20, while the critical period for Losartan-induced kidney lesions is GD 15-20. The relevance of these findings to the development of the renin/angiotensin system in rats is discussed.