Testicular Lesions in Rats Treated with a Sympatholytic Hypotensive Agent (Losulazine)

Abstract

Groups of 25 male Sprague-Dawley rats were treated orally with losulazine at 0 (vehicle control), 4, 8, 16, or 32 mg/kg/day for 1 year. Daily clinical signs, weekly food consumption and body weight changes, and terminal hematologic and blood chemistry values were evaluated. Terminal urinalysis in 10 randomly selected rats from all groups and levels of serum luetinizing hormone, prolactin, and testosterone from control, low-, and high-dose groups were also evaluated. Fertility was determined in eight randomly selected rats from each group at 35–49 weeks. Reversibility of breeding performance was evaluated in 10 rats treated for 30 weeks and allowed to recover for 17 weeks. Selected organs were weighed and the testes and epididymides were microscopically evaluated in all rats that survived through the 1 year treatment period.

Rats treated with losulazine showed dosage-dependent ptosis, somnolence, fecal softening, and decreased food consumption with a corresponding retarded body weight gain. There were no biologically significant changes in hematologic, blood chemistry, or urinalysis values between treated and control rats. Relative spleen, heart, adrenal, and brain weights were increased in treated rats. There was a reversible dosage and time-dependent decreased fertility in rats treated with losulazine for 6–12 months. The incidence of testicular tubular atrophy/degeneration, usually confined to the subcapsular areas of the testes, and concentration of degenerate ge.minal cells in the epididymides, were increased in treated compared to vehicle control rats. Testicular lesions were not dosage related, were minimal to mild after 1 year of treatment, and were not attended by a decrease in relative testicular weights. Decreased fertility was not correlated with the apparently treatment-related testicular lesions. It could not be determined whether the minor testicular lesions seen in rats treated with losulazine were related to stressful conditions the rats were apparently under or to the effects of the drug on the hypothalamus-pituitary-gonadal axis or the sympathetic nervous system.

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