Endocrine effects of a new histamine H 2-receptor antagonist, nizatidine (LY139037), in the male rat

Abstract

A new orally active histamine H 2-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 × ED50, or 10 × 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 H 2-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× the ED50 gastric acid secretion inhibitory values, and cimetidine (10× 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 (>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.