Nakagawa T, Ukai K, Ohyama T, Koida M, Okamura H
Central Research Institute, Kaken Pharmaceutical Co. Ltd., Kyoto, Japan.
Life Sci. 1996;59(9):705-12. doi: 10.1016/0024-3205(96)00356-6.
KP-102 (D-Ala-D-beta-Nal-Ala-Trp-D-Phe-Lys-NH2), a new second generation hexapeptide, has a potent growth hormone (GH)-releasing action in vivo and in vitro. Here, we evaluated the GH-releasing action of KP-102 under pentobarbital (PB) anesthesia in neonatally sodium-glutamate-monohydrate-treated low growth (NMSG-LG) rats. The plasma GH level in NMSG-LG rats after i.v. administration of KP-102 at 100 micrograms/kg was 1/6.7 (95% C.L. 1/14.7 - 1/3.0) of that in normal rats given the same dose (p < 0.01). However, the increase was significant compared with that in normal rats after saline administration (p < 0.01). The plasma GH releasing action of KP-102 at 100 micrograms/kg i.v. in rats with lesions in the bilateral hypothalamic arcuate nuclei (ARC), was about 1/6.3 (95% C.L. 1/12.4 - 1/3.2) of that in normal rats under PB anesthesia (p < 0.01). When KP-102 was injected into the ARC at doses of 0.0002, 0.02 and 2 micrograms/rat, GH release was dose-related (p < 0.01) under PB anesthesia. KP-102 at 2 micrograms i.c.v. also increased the plasma GH levels (p < 0.01) to about 1/8.3 (95% C.L. 1/22.7 - 1/3.1) of that by systematic administration, at the same potency as the ARC injection (1/13.7 and 95% C.L. 1/37.2 - 1/5.0). These findings suggest that KP-102 potently stimulates the GH release by a direct or indirect antagonism of somatostatin (SRIF) and growth hormone releasing hormone (GHRH) release in the hypothalamus and by a direct action on the pituitary. Furthermore, the GH-releasing action of KP-102 was similar and additive upon both regions in vivo at the maximum effective dose. Moreover, since the GH-release in response to KP-102 administration differed between NMSG-LG and normal rats, and since KP-102 increased the GH release even in NMSG-LG rats, it should be evaluated in the hypophysial GH secretion tests, and may be used to treat the hypophysial GH secretion insufficiency.
KP-102（D-丙氨酸-D-β-萘丙氨酸-丙氨酸-色氨酸-D-苯丙氨酸-赖氨酸-NH2），一种新型第二代六肽，在体内和体外均具有强大的生长激素（GH）释放作用。在此，我们评估了在戊巴比妥（PB）麻醉下，KP-102对新生期经谷氨酸钠一水合物处理的低生长（NMSG-LG）大鼠的GH释放作用。静脉注射100微克/千克的KP-102后，NMSG-LG大鼠的血浆GH水平是给予相同剂量的正常大鼠的1/6.7（95%置信区间1/14.7 - 1/3.0）（p < 0.01）。然而，与给予生理盐水后的正常大鼠相比，该增加具有显著性（p < 0.01）。静脉注射100微克/千克的KP-102对双侧下丘脑弓状核（ARC）有损伤的大鼠的血浆GH释放作用，约为PB麻醉下正常大鼠的1/6.3（95%置信区间1/12.4 - 1/3.2）（p < 0.01）。当以0.0002、0.02和2微克/只的剂量将KP-102注入ARC时，在PB麻醉下GH释放呈剂量相关（p < 0.01）。脑室内注射2微克的KP-102也使血浆GH水平升高（p < 0.01），达到系统给药时的约1/8.3（95%置信区间1/22.7 - 1/3.1），与注入ARC时的效力相同（1/13.7和95%置信区间1/37.2 - 1/5.0）。这些发现表明，KP-102通过对下丘脑生长抑素（SRIF）和生长激素释放激素（GHRH）释放的直接或间接拮抗作用以及对垂体的直接作用，有力地刺激了GH释放。此外，在最大有效剂量下，KP-102在体内对这两个区域的GH释放作用相似且具有叠加性。而且，由于给予KP-102后NMSG-LG大鼠和正常大鼠的GH释放情况不同，并且KP-102即使在NMSG-LG大鼠中也增加了GH释放，因此应在垂体GH分泌试验中对其进行评估，并且它可能用于治疗垂体GH分泌不足。
