Oral zeranol shortens the prolonged bleeding time of uremic rats

Intravenous conjugated estrogens reduce the prolonged bleeding time in uremic patients and in a rat model of uremia. However, estrogens have major side effects related to their hormonal activity. We investigated whether a beta-resorcylic acid lactone, zeranol (a compound with close spatial similarity to estrogens but with a weak estrogenic activity), improves primary hemostasis in uremic rats and whether the effect is mediated by estrogen receptors. The results showed that single oral administration of zeranol significantly (P less than 0.01) shortened the bleeding time of uremic rats, 20 mg/kg being the minimum effective dose. This effect was long-lasting (72 hours). The dose of 30 mg/kg zeranol reproduced the pattern observed after 20 mg/kg but bleeding time values were still significantly (P less than 0.01) shortened 96 hours after the administration. No changes in hematocrit, platelet and leukocyte count, and serum creatinine were detected after zeranol administration. When uremic rats were pre-treated orally with two estrogen receptor antagonists, tamoxifen and clomiphene (3 mg/kg), zeranol did not shorten the bleeding time, thus suggesting that the hemostatic effect of zeranol was due to an estrogen receptor-mediated mechanisms. These results might have important future implications for the management of uremic bleeding in humans.