RESUMEN
A new orally active histamine H2-receptor antagonist, nizatidine (LY139037), was evaluated in male rats for effects on mechanisms regulating accessory sex organ growth and function. Cimetidine antagonized androgen binding to cytosolic receptors in vitro while nizatidine had no effect. Nizatidine and cimetidine were administered at the ED50, 5 X ED50, or 10 X ED50 doses for inhibition of gastric acid secretion previously determined using in vivo dog and rat models. The relative potencies of both agents to antagonize histamine H2-receptor-mediated gastric acid secretory responses have been confirmed in human clinical trials. Neither nizatidine nor cimetidine antagonized the in vivo uptake or nuclear translocation of radiolabeled androgen into the hypothalamic-preoptic-amygdala, pituitary, or ventral prostate. Nizatidine, given at doses equal to and 10 X the ED50 gastric acid secretion inhibitory values, and cimetidine (10 X ED50 value) had no effect on the response of male accessory sex organs to a submaximally stimulating dose of androgen in castrated rats. High doses of dietary nizatidine (greater than 500 mg/kg-day) administered for 6 months did not alter intact rat male accessory sex organ weights or circulating androgen levels relative to untreated controls. Acute administration of either nizatidine or cimetidine produced transient elevations in plasma prolactin (PRL) levels. Cimetidine was more potent and consistent than nizatidine in producing these increases in circulating PRL. The data described herein support the contention that unlike cimetidine, nizatidine is not a pharmacological antagonist of androgen action and has less of a stimulatory effect upon plasma prolactin. Taken together, these studies indicate that in the male rat, nizatidine exhibits a large therapeutic index between its gastric antisecretory activity and potential endocrinological effects.
Asunto(s)
Andrógenos/fisiología , Antagonistas de los Receptores H2 de la Histamina/farmacología , Tiazoles/farmacología , Animales , Cimetidina/farmacología , Ácido Gástrico/metabolismo , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Masculino , Metribolona/metabolismo , Estructura Molecular , Nizatidina , Orquiectomía , Tamaño de los Órganos/efectos de los fármacos , Hipófisis/efectos de los fármacos , Hipófisis/metabolismo , Área Preóptica/efectos de los fármacos , Área Preóptica/metabolismo , Prolactina/sangre , Próstata/anatomía & histología , Próstata/efectos de los fármacos , Próstata/metabolismo , Ratas , Ratas Endogámicas , Receptores Androgénicos/efectos de los fármacos , Receptores Androgénicos/metabolismo , Vesículas Seminales/anatomía & histología , Testículo/análisisRESUMEN
Fenarimol (alpha-(2-chlorophenyl)-alpha(4-chlorophenyl)-5-pyrimidine-methanol), a pyrimidine carbinol agricultural fungicide, was previously reported to cause a dose-related decrease in fertility in rats (K. S. Hirsch, E. R. Adams, D. G. Hoffman, J. K. Markham, and N. V. Owen (1986), Toxicol. Appl. Pharmacol. 86, 391-399). Based on the results of a number of reproduction studies (K. S. Hirsch, E. R. Adams, D. G. Hoffman, J. K. Markham, and N. V. Owen (1986), Toxicol. Appl. Pharmacol. 86, 391-399), the infertility appeared to be associated with an impairment of male sexual behavior. When [14C]fenarimol was administered to the dam, high concentrations of radioactivity were observed in the neonatal hypothalamus, which functions in the development and subsequent expression of male sexual behavior. In the present studies fenarimol exhibited neither antiandrogenic nor antiestrogenic activities. The compound did, however, prevent the increase in nuclear estrogen receptors in the brain which normally occurs in the male during the early postnatal period. These results suggested that fenarimol might be acting to inhibit estrogen biosynthesis (via the aromatase enzyme complex) within the central nervous system. [3H]Testosterone was administered to neonatal rats, and the tritiated metabolites were isolated. Testosterone and dihydrotestosterone (17 beta-hydroxy-5 alpha-androstan-3-one) concentrations were similar in all treatment groups. Tritiated estrogens were detected in the brain cell nuclei from control neonates but not in neonates exposed to fenarimol. Fenarimol was also observed to inhibit rat ovarian aromatase activity in vitro. These data indicate that the decrease in male sexual behavior and the infertility associated with exposure to fenarimol were, most likely, due to inhibition of aromatase activity within the central nervous system.