Cimetidine (Tagamet) is a reproductive toxicant in male rats affecting peritubular cells

Cimetidine (Tagamet) is a potent histaminic H2-receptor antagonist, extensi vely prescribed for ulcers and now available without prescription. Cimetidi ne is a known testicular toxicant, but its mechanism of action remains unce rtain. Rats were treated i.p. with cimetidine either at 50 mg/kg or 250 mg/ kg body weight for 59 days. Accessory sex organ weights, but not testis wei ght, were significantly reduced in the high dose treated groups. FSH levels were significantly elevated in both treated groups, but testosterone level s were unchanged. A high degree of variability characterized testis histolo gy, with most tubules appearing normal and some tubules (15-17%) partially lacking or devoid of germ cells. Morphometry showed that although seminifer ous tubule volume was not significantly changed, the volume of peritubular tissue was reduced in the high dose group. There was extensive duplication of the basal lamina, lamina densa in both apparently normal spermatogenic t ubules and severely damaged tubules. Apoptotic peritubular myoid cells were also found. TUNEL labeling confirmed extensive apoptotic cell death in per itubular cells, but revealed apoptosis of vascular smooth muscle. Given tha t 1) peritubular myoid cell apoptosis occurs in apparently normal tubules, that 2) basal lamina disorders are found, and that 3) peritubular cells are lost from the testis, it is suggested that the primary event in cimetidine -related damage is targeted to testicular smooth muscle cells. This is the first in vivo-administered toxicant to be described that targets myoid cell s, resulting in abnormal spermatogenesis.