Hirotani Chiharu, Oki Yutaka, Ukai Kiyoharu, Okuno Tadashi, Kurasaki Shigeru, Ohyama Tadashi, Doi Naomi, Sasaki Ken, Ase Katsuhiko
Central Research Laboratories, Kaken Pharmaceutical Co. Ltd., 14 Shinomiya Minamikawara-cho, Yamashinaku, Kyoto, 607-8042, Japan.
Naunyn Schmiedebergs Arch Pharmacol. 2005 Jan;371(1):54-60. doi: 10.1007/s00210-004-1009-3. Epub 2005 Jan 12.
KP-102 (GHRP-2: pralmorelin) is a synthetic growth hormone releasing peptide (GHRP) that powerfully stimulates the release of GH by acting (i.v.) at both hypothalamic and pituitary sites. Intravenous (i.v.) administration of KP-102 also elicits slight but significant release of adrenocorticotropic hormone (ACTH) in both animals and humans, as is seen with other GHRPs. GHRPs are thought to stimulate the hypothalamic-pituitary-adrenal axis by releasing endogenous ACTH secretagogues such as arginine vasopressin (AVP) and/or corticotropin releasing factor (CRF), though neither AVP nor CRF has been shown clearly to be involved significantly in GHRP-evoked ACTH release. In the present study, we investigated the effects of KP-102 on ACTH release in conscious rats under improved experimental conditions that minimized the influence of stress. Administration of KP-102 i.v. increased plasma ACTH significantly, but did not stimulate ACTH release from rat primary pituitary cells. Administration of KP-102 together with either AVP or CRF elicited significantly greater increases in plasma ACTH levels than any of the agonists alone. Notably, the combination of KP-102 and AVP produced a much greater increase in ACTH than KP-102 plus CRF, indicating that KP-102 augments the effect of exogenous CRF only weakly. Conversely, a CRF antagonist markedly inhibited KP-102-induced ACTH release in conscious rats, whereas an AVP antagonist or anti-AVP antiserum did not. Taken together, these findings suggest that KP-102 acts via the hypothalamus to stimulate ACTH release in rats, and that these effects are mediated mainly by the release of CRF.
KP - 102（生长激素释放肽 - 2：普拉莫瑞林）是一种合成的生长激素释放肽（GHRP），通过静脉注射作用于下丘脑和垂体部位，有力地刺激生长激素（GH）的释放。与其他生长激素释放肽一样，静脉注射KP - 102在动物和人类中也会引起促肾上腺皮质激素（ACTH）轻微但显著的释放。生长激素释放肽被认为通过释放内源性促肾上腺皮质激素释放因子如精氨酸加压素（AVP）和/或促肾上腺皮质激素释放因子（CRF）来刺激下丘脑 - 垂体 - 肾上腺轴，尽管尚未明确显示AVP和CRF在生长激素释放肽诱发的促肾上腺皮质激素释放中起显著作用。在本研究中，我们在尽量减少应激影响的改进实验条件下，研究了KP - 102对清醒大鼠促肾上腺皮质激素释放的影响。静脉注射KP - 102可显著提高血浆促肾上腺皮质激素水平，但不刺激大鼠原代垂体细胞释放促肾上腺皮质激素。将KP - 102与AVP或CRF一起给药，血浆促肾上腺皮质激素水平的升高显著大于单独使用任何一种激动剂。值得注意的是，KP - 102与AVP的组合比KP - 102加CRF产生的促肾上腺皮质激素增加幅度大得多，表明KP - 102对外源性CRF的作用增强较弱。相反，CRF拮抗剂可显著抑制清醒大鼠中KP - 102诱导的促肾上腺皮质激素释放，而AVP拮抗剂或抗AVP抗血清则无此作用。综上所述，这些发现表明KP - 102通过下丘脑作用于大鼠刺激促肾上腺皮质激素释放，且这些作用主要由CRF的释放介导。
