Hickey G, Jacks T, Judith F, Taylor J, Schoen W R, Krupa D, Cunningham P, Clark J, Smith R G
Department of Basic Animal Science Research, Merck Research Laboratories, Rahway, New Jersey 07065.
Endocrinology. 1994 Feb;134(2):695-701. doi: 10.1210/endo.134.2.8299565.
L-692,429 is a substituted benzolactam that has recently been shown to stimulate GH secretion from rat pituitary cells in vitro with an ED50 of 60 nM. In the current studies, we evaluated the efficacy and specificity of L-692,429 as a GH secretagogue in beagles. L-692,429 at 0.1, 0.25, or 1.0 mg/kg or saline vehicle was administered iv to four male and four female beagles in a balanced cross-over design. Blood samples were collected up to 75 min posttreatment, and serum was assayed for GH, cortisol, PRL, and LH. Mean peak serum GH levels were significantly increased (P < 0.05) by L-692,429 to 13 +/- 2 (mean +/- SEM) ng/ml (0.1 mg/kg), 39 +/- 6 ng/ml (0.25 mg/kg), or 71 +/- 11 ng/ml (1.0 mg/kg) over the saline control value of 3.6 +/- 0.6 ng/ml. Mean peak GH levels occurred at 15 min and had returned to near-baseline levels by 75 min. There was no difference in response between sexes. Mean peak cortisol levels were significantly increased (P < 0.05) by 2.2-, 2.7-, and 3.1-fold above control levels (3.0 +/- 0.2 micrograms/dl) at 25-35 min and returned to near-baseline levels by 75 min. PRL was slightly decreased after L-692,429 treatment, whereas LH was not affected. In a second study, three groups of three male beagles each were administered 5.0 mg/kg L-692,429, iv; iv saline, or 2.2 U/kg ACTH, im. Blood was collected for 8 h posttreatment and assayed for GH, cortisol, ACTH, aldosterone, PRL, insulin, T3, and T4. L-692,429 administration significantly increased (P < 0.05) GH over the control level (6.0 +/- 3.6 ng/ml) to 133 +/- 14 ng/ml by 15 min, with a return to pretreatment levels by 120 min. Cortisol levels were significantly increased (P < 0.05) by 2.0-fold (L-692,429) or 2.9-fold (ACTH) over the saline control peak concentration of 5.6 +/- 1.6 micrograms/dl and were associated with concurrent increases in ACTH levels of 1.2-fold (L-692,429) or 2.1-fold (ACTH) over the saline control peak concentration of 67 +/- 20 pmol/L. Aldosterone, PRL, T3, and T4 were not significantly affected after L-692,429 administration; however, ACTH treatment significantly increased aldosterone (P < 0.05). These data demonstrate that L-692,429 is a novel nonpeptidyl secretagogue that stimulates a marked, but transient, increase in serum GH levels in the dog.(ABSTRACT TRUNCATED AT 400 WORDS)
L-692,429是一种取代苯并内酰胺，最近的研究表明，它在体外能刺激大鼠垂体细胞分泌生长激素（GH），半数有效剂量（ED50）为60 nM。在当前研究中，我们评估了L-692,429作为一种GH促分泌素在比格犬体内的疗效和特异性。采用平衡交叉设计，给4只雄性和4只雌性比格犬静脉注射0.1、0.25或1.0 mg/kg的L-692,429或生理盐水。在给药后75分钟内采集血样，检测血清中的GH、皮质醇、催乳素（PRL）和促黄体生成素（LH）。与生理盐水对照组3.6±0.6 ng/ml的水平相比，L-692,429使血清GH平均峰值水平显著升高（P<0.05），分别达到13±2（均值±标准误）ng/ml（0.1 mg/kg）、39±6 ng/ml（0.25 mg/kg）或71±11 ng/ml（1.0 mg/kg）。GH平均峰值出现在15分钟，到75分钟时已恢复至接近基线水平。两性之间的反应无差异。皮质醇平均峰值水平在25 - 35分钟时比对照水平（3.0±0.2微克/分升）显著升高（P<0.05）2.2倍、2.7倍和3.1倍，到75分钟时恢复至接近基线水平。L-692,429治疗后PRL略有下降，而LH未受影响。在第二项研究中，每组3只雄性比格犬，分别静脉注射5.0 mg/kg的L-692,429、静脉注射生理盐水或肌肉注射2.2 U/kg促肾上腺皮质激素（ACTH）。给药后8小时采集血样，检测GH、皮质醇、ACTH、醛固酮、PRL、胰岛素、三碘甲状腺原氨酸（T3）和甲状腺素（T4）。静脉注射L-692,429使GH在15分钟时显著高于对照水平（6.0±3.6 ng/ml），达到133±14 ng/ml，到120分钟时恢复至治疗前水平。与生理盐水对照组峰值浓度5.6±1.6微克/分升相比，皮质醇水平显著升高（P<0.05）2.0倍（L-692,429）或2.9倍（ACTH），同时ACTH水平分别比生理盐水对照组峰值浓度67±20 pmol/L升高1.2倍（L-692,429）或2.1倍（ACTH）。L-692,429给药后醛固酮、PRL、T3和T4未受显著影响；然而，ACTH治疗使醛固酮显著升高（P<0.05）。这些数据表明，L-692,429是一种新型非肽类促分泌素，能使犬血清GH水平显著但短暂升高。（摘要截短至400字）
