Effects of losulazine on rat reproduction and development.
Losulazine, a hypotensive agent, was given orally by gastric intubation to Sprague-Dawley rats in doses of 0, 2, 4, or 8 mg/kg/day in a study of fertility and general reproductive performance. Eighteen males per group were treated for 67 days before cohabitation, then daily until killed. Thirty-six females per group were treated for only 14 days because estrous cycles had been disrupted. Females remained untreated for 7 days before cohabitation; treatment was resumed after insemination was confirmed or when the cohabitation period ended. Males were cohabited on a 1:2 basis with females from the same treatment group for up to 14 days, then for 14 days with untreated females. The conception rate of both treated and untreated females was statistically significantly decreased as the dose increased. Mean body weights were statistically significantly greater and mean gestation periods were statistically significantly longer in losulazine-treated females than in females of the vehicle control group. Throughout the preweaning period mean body weights were significantly less in offspring from treated dams than in offspring of dams in the vehicle control group. This adverse effect on weight gain continued in male offspring until at least postpartum day 79. Functional development was significantly delayed in the offspring of losulazine-treated dams tested for pinna detachment, auditory startle, negative geotaxis, eye opening, and learning (swimming M-maze). Delays in development were generally greater in offspring of dams and sires treated with higher doses of losulazine. Fertility of male offspring from dams and sires treated with losulazine at 4 and 8 mg/kg/day was also affected adversely.
Morris
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DF
Reproductive and Developmental Toxicology Research, Upjohn Company, Kalamazoo, Michigan 49001.
Marks
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Mesfin
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GM
D000818:Animals; D000959:Antihypertensive Agents / Q000633:toxicity*; D001522:Behavior, Animal / Q000187:drug effects; D001763:Blepharoptosis / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004971:Estrus / Q000187:drug effects; D005260:Female; D006128:Growth / Q000187:drug effects*; D008297:Male; D010879:Piperazines / Q000633:toxicity*; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains; D012098:Reproduction / Q000187:drug effects*; D013737:Testis / Q000187:drug effects / Q000473:pathology
D000959:Antihypertensive Agents; D010879:Piperazines; C036654:losulazine hydrochloride