Arvat E, Di Vito L, Gianotti L, Ramunni J, Boghen M F, Deghenghi R, Camanni F, Ghigo E
Department of Internal Medicine, University of Turin, Italy.
Metabolism. 1997 Jan;46(1):83-8. doi: 10.1016/s0026-0495(97)90173-6.
The growth hormone (GH) response to GH-releasing hormone (GHRH) is strongly inhibited by previous administration of recombinant human GH (rhGH), likely as a consequence of a somatostatin-mediated GH negative autofeedback. Hexarelin (HEX), a synthetic hexapeptide belonging to the GH-releasing peptide (GHRP) family, possesses a GH-releasing activity greater than that of GHRH both in animals and in man. The mechanism of action of GHRPs is yet to be completely clarified, although concomitant actions at the pituitary and hypothalamic level have been hypothesized. To further clarify the mechanisms of action underlying the GH-releasing activity of HEX, in six normal young volunteers we studied the effects of rhGH (2 U intravenously [IV]) on the GH response either to GHRH (2 microg/kg IV) or to HEX (2 microg/kg IV) alone or combined with GHRH and/or pyridostigmine ([PD], 120 mg orally). The GH-releasing effect of HEX was higher than that of GHRH (area under the curve [AUC], 2,200.8 +/- 256.9 v 792.2 +/- 117.6 microg/L/h, P < .001), whereas combined administration of the two substances induced a true synergistic effect, with GH release after HEX plus GHRH (4,259.2 +/- 308.0 microg/L/h) being higher (P < .02) than the arithmetic sum of the GH increases induced by each compound separately administered. After rhGH administration, the GH-releasing effect of HEX was blunted (1,468.9 +/- 193.7 microg/L/h, P < .04; inhibition of 32.1%), whereas that of GHRH was nearly abolished (102.0 +/- 7.8 microg/L/h, P < .02; inhibition of 86.1%). The GH response to combined administration of HEX and GHRH was also blunted by the previous rhGH bolus (3,070.6 +/- 481.8 microg/L/h, P < .02; inhibition of 26.7%). PD did not modify the GH-releasing effect of HEX either alone (2,456.8 +/- 317.5 microg/L/h) or combined with GHRH (4,009.1 +/- 360.8 microg/L/h). rhGH was again able to blunt the GH response to HEX combined with PD (1,619.3 +/- 237.9 microg/L/h, P < .02), but failed to modify the GH response to HEX combined with GHRH and PD (4,548.4 +/- 698.0 microg/L/h). In conclusion, these results demonstrate that rhGH administration only blunts the GH-releasing activity of HEX, but abolishes that of GHRH. The blunting effect of rhGH on the GH response to HEX is probably mediated by a concomitant reduction in the activity of GHRH-secreting neurons and an increase of somatostatinergic tone.
生长激素（GH）对生长激素释放激素（GHRH）的反应会受到先前给予重组人生长激素（rhGH）的强烈抑制，这可能是生长抑素介导的GH负反馈自身调节的结果。六肽生长激素释放肽（HEX）是一种属于生长激素释放肽（GHRP）家族的合成六肽，在动物和人类中均具有比GHRH更强的生长激素释放活性。尽管已经推测GHRP在垂体和下丘脑水平存在协同作用，但其作用机制尚未完全阐明。为了进一步明确HEX的生长激素释放活性的潜在作用机制，我们对6名正常年轻志愿者进行了研究，观察rhGH（静脉注射2 U）对GH单独对GHRH（静脉注射2 μg/kg）、HEX（静脉注射2 μg/kg）或与GHRH和/或吡啶斯的明（[PD]，口服120 mg）联合使用时的反应的影响。HEX的生长激素释放作用高于GHRH（曲线下面积[AUC]，2200.8±256.9对792.2±117.6 μg/L/h，P<.001），而两种物质联合给药可产生真正的协同作用，HEX加GHRH后的GH释放量（4259.2±308.0 μg/L/h）高于（P<.02）每种化合物单独给药诱导的GH增加量的算术和。给予rhGH后，HEX的生长激素释放作用减弱（1468.9±193.7 μg/L/h，P<.04；抑制32.1%），而GHRH的作用几乎完全消失（102.0±7.8 μg/L/h，P<.02；抑制86.1%）。先前的rhGH推注也使HEX和GHRH联合给药的GH反应减弱（3070.6±481.8 μg/L/h，P<.02；抑制26.7%）。PD单独（2456.8±317.5 μg/L/h）或与GHRH联合（4009.1±360.8 μg/L/h）时均未改变HEX的生长激素释放作用。rhGH再次使HEX与PD联合的GH反应减弱（1619.3±237.9 μg/L/h，P<.02），但未能改变HEX与GHRH和PD联合的GH反应（4548.4±698.0 μg/L/h）。总之，这些结果表明，给予rhGH仅使HEX的生长激素释放活性减弱，但使GHRH的活性消失。rhGH对GH对HEX反应的减弱作用可能是由于分泌GHRH的神经元活性同时降低以及生长抑素能张力增加所致。
