Hormonal Effects of Z-350, Possessing Steroid 5 a-Reductase Inhibitory and a ι-Adrenoceptor Antagonistic Actions, in the Rat

Abstract

ABSTRACT-We examined the hormonal effects of Z-350, (S)-4-[3-(4-{1-(4-methylphenyl)-3-[4-(2-methoxyphenyl)piperazine-1-yl]propoxy}benzoyl)indole-1-yl]butyric acid hydrochloride, which has both a1-adrenoceptor blocking activity and steroid 5a-reductase inhibitory activity, in male and female rats. Z-350 administered orally for 14 days at a dose of 30 mg/ kg to normal male rats significantly reduced the weight of the prostate and seminal vesicles without affecting the weight of the testis, epididymis, adrenals, kidney or liver. Prostatic levels of dihydrotestosterone decreased dose-dependently, with a slight increase in the level of testosterone at a Z-350 dose of 100 mg/ kg. We observed no effects on the weight of the prostate in castrated rats or on the weight of the uterus in normal or 17b-estradiol-treated female rats. These results suggest that Z-350 inhibits prostatic growth via inhibition of steroid 5-reductase without other hormonal effects.Keywords: Z-350, Steroid 5a-reductase, Benign prostatic hyperplasia, Testosterone, Dihydrotestosterone Benign prostatic hyperplasia (BPH), which is a common disorder in aging men, is associated with growth of prostatic glandular and stromal elements. BPH causes symptoms in the lower urinary tract and reduces quality of life.The lower urinary tract symptoms caused by BPH are attributed to two main components: a dynamic component involving excessive contraction of prostatic smooth muscle mediated by a 1-adrenoceptors (1 -4) and a static component involving obstruction of the urethra by the enlarged prostate (5). a1-Adrenoceptor blockers (6 -10) represent a palliative approach to therapy for lower urinary tract symptoms caused by BPH and are effective in alleviating dynamic obstruction. On the other hand, anti-androgens can improve static obstruction by reducing prostatic mass, although they have adverse effects on sexual function, including impotence and decreased libido, which is caused by plasma testosterone deprivation (5).Steroid 5a-reductase (EC 1.3.1.22; 5a-R), a rate-limiting enzyme that converts testosterone to the potent androgen dihydrotestosterone, plays a critical role in prostatic growth (11). Finasteride is a specific 5a-R inhibitor that can reduce prostate volume with fewer adverse effects on sexual function than anti-androgens (12 -15), and it has already been approved for clinical use in the US and Europe.On the basis of the concept that combined activity (i.e., a 1-adrenoceptor blocking and 5a-R inhibition) may be more beneficial for the treatment of BPH than each activity alone, we recently reported the pharmacological profile of Z-350, which possesses a1-adrenoceptor blocking and 5a-R inhibitory activity, in vitro (16) and in vivo (17). Z-350 inhibited rat prostatic 5a-R in a non-competitive manner and prevented testosterone-induced re-growth of the prostate in castrated rats.In the present study, we investigated the effects of Z-350 on the weight of the testis, epididymis, adrenal gland and other organs in normal male rats to evaluate the hormonal eff...