Kovács M, Halmos G, Groot K, Izdebski J, Schally A V
Endocrine, Polypeptide and Cancer Institute, Veterans Administration Medical Center, New Orleans, LA 70146, USA.
Neuroendocrinology. 1996 Sep;64(3):169-76. doi: 10.1159/000127115.
To assess the efficacy of a potent agonist analog of GH-releasing hormone (GH-RH), [Dat1,Gln8,Orn12,21,Abu15,Nle27,Asp28,A gm29]hGH-RH(1-29) (JI-38), we investigated the effects of its chronic administration on growth responses in monosodium glutamate (MSG)-lesioned and normal young rats. Body weight (BW), body length (BL), tibia length (TIL), and tail length (TAL) were monitored. Basal serum GH concentrations, GH responses to bolus injections of GH-RH, pituitary GH and serum IGF-I concentrations were measured by RIA. Pituitary GH-RH receptor concentration and binding affinity was also evaluated after the treatment. Neonatal treatment with MSG resulted, as expected, in blunted growth and a decrease in serum and pituitary GH concentration and serum IGF-I levels. A reduction in GH-RH receptor concentration, associated with increased binding affinity of the GH-RH receptor was also found. Chronic administration of GH-RH agonist JI-38 in doses of 2 micrograms at 12-hour intervals for 2 weeks markedly increased the GH responsiveness to GH-RH and stimulated growth, with MSG-treated animals achieving the growth rate of normal controls. Acceleration of growth was associated with stimulated GH synthesis and IGF-I secretion, although basal serum GH levels did not change. Pituitary GH-RH receptor concentration and binding affinity were not significantly modified by the treatment. Treatment of normal young growing rats with agonist JI-38 did not further increase the normal growth acceleration in these rats, but stimulated the GH synthesis and augmented the GH secretory responsiveness. The treatment of MSG-lesioned rats with GH-RH agonist was generally more effective in female than in male animals, and in some cases masked the sex differences in growth rate. Our findings provide the first evidence that the blunted growth rate of the MSG-lesioned rats is associated with a decreased pituitary GH-RH receptor concentration. Our work demonstrates that administration of GH-RH agonist JI-38 is able to restore the normal growth rate of the GH-deficient rats by stimulating GH synthesis and IGF-I secretion.
为评估生长激素释放激素（GH-RH）的一种强效激动剂类似物[Dat1，Gln8，Orn12，21，Abu15，Nle27，Asp28，A gm29]hGH-RH(1-29)（JI-38）的疗效，我们研究了其长期给药对谷氨酸单钠（MSG）损伤的幼鼠和正常幼鼠生长反应的影响。监测了体重（BW）、体长（BL）、胫骨长度（TIL）和尾长（TAL）。通过放射免疫分析法（RIA）测定基础血清GH浓度、对GH-RH推注的GH反应、垂体GH和血清IGF-I浓度。治疗后还评估了垂体GH-RH受体浓度和结合亲和力。如预期的那样，新生期用MSG治疗导致生长迟缓，血清和垂体GH浓度以及血清IGF-I水平降低。还发现GH-RH受体浓度降低，同时GH-RH受体的结合亲和力增加。以2微克的剂量、每隔12小时一次、连续2周长期给予GH-RH激动剂JI-38，显著增加了GH对GH-RH的反应性并刺激了生长，MSG处理的动物达到了正常对照的生长速率。生长加速与GH合成和IGF-I分泌增加有关，尽管基础血清GH水平没有变化。垂体GH-RH受体浓度和结合亲和力未因治疗而发生显著改变。用激动剂JI-38治疗正常生长的幼鼠并没有进一步增加这些大鼠正常的生长加速，但刺激了GH合成并增强了GH分泌反应性。用GH-RH激动剂治疗MSG损伤的大鼠，雌性动物通常比雄性动物更有效，在某些情况下掩盖了生长速率的性别差异。我们的研究结果首次证明，MSG损伤大鼠生长速率降低与垂体GH-RH受体浓度降低有关。我们的工作表明，给予GH-RH激动剂JI-38能够通过刺激GH合成和IGF-I分泌来恢复GH缺乏大鼠的正常生长速率。
