Inhibition of pituitary gonadotropin secretion by 4-aminopyrazolo(3,4-d) pyrimidine.
Inhibition of pituitary gonadotropin secretion by 4-aminopyrazolo(3,4-d) pyrimidine.
复制标题
4-氨基吡唑并(3,4-d)嘧啶抑制垂体促性腺激素分泌。
作者：
M. Blank;E. Loumaye;D. Sgoutas;K. Catt;M. Dufau
最近研究表明，用4-氨基吡唑并（3，4-d）嘧啶（4-APP）处理的雄性大鼠血浆睾酮（T）降低与血浆LH下降有关，似乎是继发于促性腺激素分泌受损，而不是腺嘌呤类似物引起的脂蛋白胆固醇降低。用5、10、25和50 mg 4-APP/kg BW ip处理成年雄性大鼠3天，分析4-APP对垂体功能的影响和促性腺激素分泌下降的机制。24小时后，5 mg 4-APP/kg BW给药动物的血清胆固醇水平降低68 +/- 5%（平均值+/- SE），更高剂量给药后降低高达84 +/- 1%。5 mg/kg APP对血清T基础水平无影响，但较高剂量显著降低（P <0.05）。在APP治疗的大鼠中，血清T对人CG（100 IU）刺激的反应在绝对幅度上降低，但在高于基线的百分比增加方面增强。3个最高剂量的4-APP降低了LH（51-79%）和FSH（21-39%）的血清水平。然而，4-APP治疗后，血清促性腺激素对GnRH刺激的反应，LH增加了32 +/- 9%，FSH增加了27 +/- 12%。25和50 mg/kg的4-APP显著降低血清TSH水平（P <0.05），仅高剂量的4-APP降低血清PRL。5 mg/kg的4-APP可降低血清GH水平，升高ACTH水平，垂体LH、FSH和TSH含量无明显变化，PRL和GH含量略有升高，但差异显著（P <0.05）。在体内用25和50 mg/kg 4-APP处理后，GnRH的垂体受体（88 +/- 14 fmol/mg蛋白质）减少到52 +/- 5和57 +/- 7 fmol/mg，但10 mg/kg 4-APP没有减少。在体外用10（-7）或10（-5）M 4-APP暴露48小时后，没有观察到垂体GnRH受体含量的变化。4-APP处理后，内侧下丘脑GnRH含量无变化。4-APP对血清胆固醇和T水平的分离作用，以及对人CG的T应答的维持，提供了进一步的证据，证明睾丸雄激素生物合成不仅仅依赖于循环胆固醇。垂体促性腺激素对4-APP抑制的更大敏感性是该药物对体内垂体激素释放的选择性作用的证据。虽然4-APP处理未改变下丘脑GnRH含量，但体内观察到垂体GnRH受体减少，以及循环LH和FSH下降和促性腺激素对GnRH刺激的反应保留，表明4-APP的主要作用是抑制下丘脑GnRH合成和/或释放。
The reduction of plasma testosterone (T) in male rats treated with 4-aminopyrazolo(3,4-d)pyrimidine (4-APP) has been recently shown to be associated with a fall in plasma LH, and appears to be secondary to this impairment of gonadotropin secretion rather than to the decrease in lipoprotein cholesterol caused by the adenine analog. The effects of 4-APP on pituitary function and the mechanism of the fall in gonadotropin secretion were analyzed in adult male rats treated ip with 5, 10, 25, and 50 mg 4-APP/kg BW for 3 days. Twenty four hours later, serum cholesterol levels were reduced by 68 +/- 5% (mean +/- SE) in animals treated with 5 mg 4-APP/kg BW and by up to 84 +/- 1% after higher doses. Basal levels of serum T were not affected by 5 mg/kg APP but were significantly reduced by higher doses (P less than 0.05). Serum T responses to human CG (100 IU) stimulation in APP-treated rats were reduced in absolute magnitude, but were enhanced in terms of percentage increase above baseline. The three highest doses of 4-APP reduced serum levels of LH (51-79%) and FSH (21-39%). However, serum gonadotropin responses to GnRH stimulation were augmented by 32 +/- 9% for LH and 27 +/- 12% for FSH after 4-APP treatment. Serum levels of TSH were significantly (P less than 0.05) reduced by 25 and 50 mg/kg 4-APP and serum PRL was lowered by only the higher dose. Serum GH was lowered and ACTH increased by 5 mg/kg 4-APP. The pituitary contents of LH, FSH, and TSH were unchanged after 4-APP treatment, but PRL and GH contents were slightly but significantly increased (P less than 0.05). Pituitary receptors for GnRH (88 +/- 14 fmol/mg protein) were reduced by in vivo treatment with 25 and 50 mg/kg 4-APP to 52 +/- 5 and 57 +/- 7 fmol/mg, but not by 10 mg/kg 4-APP. No change in pituitary GnRH receptor content was observed after 48-h exposure to 10(-7) or to 10(-5) M 4-APP in vitro. The medial hypothalamic GnRH content was unchanged by 4-APP treatment. The dissociated effects of 4-APP on serum cholesterol and T levels, and the maintenance of T responses to human CG, provide further evidence that testicular androgen biosynthesis is not solely dependent on circulating cholesterol. The greater sensitivity of pituitary gonadotropins to 4-APP inhibition is evidence for a selective action of this drug on pituitary hormone release in vivo. Although the hypothalamic content of GnRH was unaltered by 4-APP treatment, the decrease in pituitary GnRH receptors observed in vivo, together with the fall in circulating LH and FSH and retention of gonadotropin responses to GnRH stimulation, suggest that the primary effect of 4-APP is to inhibit GnRH synthesis and/or release from the hypothalamus.
黄体酮的负反馈效应与下丘脑去甲肾上腺素和多巴胺周转率、中位黄体生成素释放激素和外周血浆促性腺激素的变化相关。
影响因子：
4.8
作者：
Rance,N;Wise,PM;Barraclough,CA
通讯作者：
Barraclough,CA
新生儿谷氨酸钠治疗改变正中隆起黄体生成素释放激素神经末梢对钾和前列腺素 E2 的反应。
影响因子：
4.8
作者：
DePaolo,LV;Negro-Vilar,A
通讯作者：
Negro-Vilar,A