Argente J, García-Segura L M, Pozo J, Chowen J A
Department of Pediatrics, Universidad Autónoma, Madrid, Spain.
Horm Res. 1996;46(4-5):155-9. doi: 10.1159/000185015.
Growth hormone (GH)-releasing peptides (GHRPs), a family of synthetic oligopeptides which stimulate GH release, were identified more than a decade ago. The effects of these peptides on GH release have been described in vivo and in vitro, in both animals and humans, using various doses and administration routes. It is generally accepted that GHRPs stimulate the release of GH by acting at the level of the pituitary through a receptor different to that for the endogenous GH-releasing hormone (GHRH). In addition, it has been reported that there are specific binding sites for these peptides in the hypothalamus and that systemic administration of GHRPs increases the expression of the immediate early gene c-fos in a subpopulation of hypothalamic neurons. However, the identity of these hypothalamic neurons and the mechanism of action of GHRPs at both the hypothalamic and pituitary levels remain unknown. One interesting aspect of GHRPs is that they are orally active and this phenomenon has been demonstrated in both animals and humans. Furthermore, these drugs stimulate GH secretion in humans dose-dependently with the magnitude and duration of this response being comparable to that seen with an intravenous peptide bolus. We have studied the oral activity of GHRP-2 on GH release in normal children. In addition, we have analyzed the response to GHRP-2 of obese adolescents, as well as the effects of an intravenous bolus of GHRH alone and GHRH plus GHRP-2. Orally administered GHRP-2 stimulates GH secretion in normal children and, although it seems that this drug is more potent in girls, there were no statistical differences between the groups. Characteristically, GH levels started to increase by 15 min, peaked at 60 min and returned to basal concentrations by 180 min. The effect of GHRP-2 was synergistic with GHRH 1-29 NH2. In addition, obese subjects appeared to have a greater response to this peptide than did normal controls. To study the effects of GHRPs on hypothalamic GHRH and somatostatin neurons, female dwarf rats (dw/dw) were treated continuously with GHRP-6 (1 mg/kg per 24 h) for 14 days. In situ hybridization for GHRH and SS was performed. We found that GHRP-6 stimulated GHRH mRNA levels in the posterior arcuate nucleus (ARC), with no significant effect in the anterior ARC or ventromedial hypothalamic neurons. SS mRNA levels in the posterior periventricular nucleus (PeN) were decreased after GHRP-6 treatment, while no effect was seen in the anterior PeN, ARC, or lateral paraventricular nucleus. These results suggest that GHRP-6 treatment modulates hypothalamic neurons controlling GH secretion; however, whether this effect is direct or mediated through another factor remains to be elucidated.
生长激素（GH）释放肽（GHRPs）是一类能刺激GH释放的合成寡肽家族，十多年前就已被发现。这些肽对GH释放的影响已在体内和体外、动物和人类中进行了描述，使用了各种剂量和给药途径。人们普遍认为，GHRPs通过作用于垂体水平，通过与内源性生长激素释放激素（GHRH）不同的受体来刺激GH释放。此外，据报道，这些肽在下丘脑中存在特异性结合位点，并且全身给予GHRPs会增加下丘脑神经元亚群中即早基因c-fos的表达。然而，这些下丘脑神经元的身份以及GHRPs在下丘脑和垂体水平的作用机制仍然未知。GHRPs的一个有趣方面是它们具有口服活性，这一现象已在动物和人类中得到证实。此外，这些药物在人类中剂量依赖性地刺激GH分泌，这种反应的幅度和持续时间与静脉注射肽推注所见相当。我们研究了GHRP-2对正常儿童GH释放的口服活性。此外，我们分析了肥胖青少年对GHRP-2的反应，以及单独静脉注射GHRH和GHRH加GHRP-2的效果。口服GHRP-2可刺激正常儿童的GH分泌，尽管似乎这种药物在女孩中更有效，但两组之间没有统计学差异。典型的是，GH水平在15分钟时开始升高，在60分钟时达到峰值，并在180分钟时恢复到基础浓度。GHRP-2的作用与GHRH 1-29 NH2具有协同性。此外，肥胖受试者对这种肽的反应似乎比正常对照组更大。为了研究GHRPs对下丘脑GHRH和生长抑素神经元的影响，雌性侏儒大鼠（dw/dw）连续14天接受GHRP-6（每24小时1 mg/kg）治疗。进行了GHRH和SS的原位杂交。我们发现GHRP-6刺激了后弓状核（ARC）中GHRH mRNA水平，而在前ARC或下丘脑腹内侧神经元中没有显著影响。GHRP-6治疗后，室旁后核（PeN）中的SS mRNA水平降低，而在前PeN、ARC或外侧室旁核中未观察到影响。这些结果表明，GHRP-6治疗可调节控制GH分泌的下丘脑神经元；然而，这种作用是直接的还是通过另一种因素介导的，仍有待阐明。
