Mediation by the central nervous system is critical to the in vivo activity of the GH secretagogue L-692,585.
Mediation by the central nervous system is critical to the in vivo activity of the GH secretagogue L-692,585.
复制标题
中枢神经系统的调节对于 GH 促分泌剂 L-692,585 的体内活性至关重要。
作者：
G. Hickey;J. Drisko;T. Faidley;C. Chang;L. Anderson;S. Nicolich;L. McGuire;E. Rickes;D. Krupa;William P. Feeney;B. Friscino;P. Cunningham;E. Frazier;Howard Y. Chen;P. Laroque;Roy G. Smith
为探讨切断垂体对清醒猪生长激素促分泌剂L-692,585促生长激素分泌活性的影响，将雄性去势猪随机分为垂体柄切断组(n=3)和假手术对照组(SOC；n=3)。术前-7~-3天和术后+3~+8天分别给予L-692,585(100微克/公斤)、人生长激素释放因子(1-29)氨基转移酶(GRF；20微克/公斤)或L-692,585(100微克/公斤)+GRF(20微克/公斤)。为了评估脑下垂体的完整性，动物在手术前后都接受促肾上腺皮质激素释放激素(CRH；150微克)或GnRH(150 ng/kg)的刺激。治疗后-60~+180分钟采血，测定GH、皮质醇和黄体生成素。术前，L-692,585(101+/-12比71+/-9)或L-692,585+GRF(171+/-21比174+/-21)组的生长激素峰值(ng/ml)在两组(SOC和HST)之间无显著差异(P&gT；0.05)。只有2/3的SOC猪和3/3的HST猪对GRF有反应(13+/-2比25+/-3)，导致两组之间的显着差异。术后，L-692,585后SOC组和HST组的峰值生长激素反应(ng/ml)有显著差异(79+/-6比13.8+/-1.0)，而对L-692,585+GRF的反应相似(115+/-8比94+/-7)。所有动物都对GRF有反应；然而，由于反应的大小，不同组之间存在显著差异。而SOC组和HST组术前对L-692,585的皮质醇反应(ng/ml)相似，术后差异有统计学意义(44.4+/-6.4vs14.6+/-2.1)。HST组和SOC组在手术前后对CRH或GnRH的反应均无显著差异。这些结果表明，L-692,585在完整动物中诱导了立即的GH反应，而GRF的GH释放是可变的。L-692,585也刺激皮质醇水平立即上升。切断垂体柄显著减少，但不能消融生长激素或皮质醇对L-692,585的反应。联合应用L-692,585+生长激素释放因子，在正常动物和高热休克动物均可立即产生类似幅度的生长激素反应。我们的结论是，L-692,585在垂体水平具有直接但有限的作用，需要完整的垂体柄才能产生最大的GH和皮质醇反应。L-692,585与GRF在垂体水平作用，诱导最大的GH反应。这些结果提示，L-692,585通过与生长激素释放因子联合作用，阻断生长抑素对生长激素的抑制作用，从而刺激生长激素的分泌。
To investigate the effect of hypophyseal transection (HST) on GH secretagogue activity of the non-peptidyl GH secretagogue L-692,585 in the conscious pig, male castrated swine were randomly assigned to either a hypophyseal stalk transection group (HST; n = 3) or to a sham-operated control group (SOC; n = 3). Treatments administered were L-692,585 (100 micrograms/kg), human GH-releasing factor(1-29)NH2 (GRF; 20 micrograms/kg) or L-692,585 (100 micrograms/kg) + GRF (20 micrograms/kg) on days -7 to -3 before surgery and days +3 to +8 after surgery. To evaluate the integrity of the pituitary gland, the animals were challenged with corticotropin-releasing hormone (CRH; 150 micrograms) or GnRH (150 ng/kg) both before and after surgery. Blood was collected from -60 to +180 min post treatment and assayed for GH, cortisol and LH. Before surgery, no significant difference (P > 0.05) in peak GH response (ng/ml) was present between the two groups (SOC vs HST) in response to L-692,585 (101 +/- 12 vs 71 +/- 9) or L-692,585 + GRF (171 +/- 21 vs 174 +/- 21). Only two out of three SOC vs three out of three HST pigs responded to GRF (13 +/- 2 vs 25 +/- 3) resulting in a significant difference between groups. Following surgery, significant differences were present in peak GH response (ng/ml) between SOC and HST groups following L-692,585 (79 +/- 6 vs 13.8 +/- 1.0); however, the response to L-692,585 + GRF was similar (115 +/- 8 vs 94 +/- 7). All animals responded to GRF; however, a significant difference was present between groups due to the magnitude of the responses. Whereas the cortisol responses (ng/ml) to L-692,585 in the SOC and HST groups were similar before surgery, a significant difference was present after surgery (44.4 +/- 6.4 vs 14.6 +/- 2.1). No significant difference was noted between the HST and SOC groups in response to CRH or GnRH either before or after surgery. These results indicated that L-692,585 induced an immediate GH response in the intact animal in contrast to GRF where the GH release was variable. L-692,585 also stimulated an immediate increase in cortisol levels. Transection of the hypophyseal stalk dramatically decreased but did not ablate the GH or cortisol response to L-692,585. Co-administration of L-692,585 + GRF induced an immediate GH response of similar magnitude in the intact and HST animal. We conclude that L-692,585 has a direct but limited action at the level of the pituitary and that an intact hypophyseal stalk is required for a maximal GH and cortisol response. L-692,585 acts with GRF at the level of the pituitary to induce a maximal GH response. These findings suggest that L-692,585 stimulates GH secretion by acting in combination with GRF and interrupting the inhibitory tone of somatostatin on the somatotroph.