Muccioli G, Broglio F, Valetto M R, Ghè C, Catapano F, Graziani A, Papotti M, Bisi G, Deghenghi R, Ghigo E
Departments of Pharmacology, Via P. Giuria, 13, 10125 Turin, Italy.
Ann Endocrinol (Paris). 2000 Feb;61(1):27-31.
Growth Hormone (GH)-releasing peptides (GHRPs) and their non peptidyl analogues are synthetic molecules which exhibit strong, dosedependent and reproducible GH-releasing activity but also significant PRL- and ACTH/cortisol-releasing effects. An influence of these compounds on food intake and sleep pattern has been also shown. The neuroendocrine activities of GHRPs are mediated by specific receptors subtypes that have been identified in the pituitary gland, hypothalamus and various extra-hypothalamic brain regions with (125)I-Tyr-Ala-hexarelin, an octapeptide of the GHRP family. In addition, GHRP receptors were also present in different peripheral tissues such as heart, adrenal, ovary, testis, lung and skeletal muscle, with a density significantly higher than that found in the hypothalamo-pituitary -system. A remarkable specific (125)I-Tyr-Ala-hexarelin binding was observed in the human cardiovascular system where the highest binding levels were detected in ventricles, followed by atria, aorta, coronaries, carotid, endocardium and vena cava. The binding of the radioligand to cardiac membranes was inhibited by unlabeled Tyr Ala hexare lin and hexarelin as well as by GHRP-6, GHRP-1 and GHRP-2 but not by MK-677, a non peptidyl GHRP analog. In other experiments on H9c2 myocytes, a fetal cardiomyocytes-derived cell line, specific GHRP binding was found and hexarelin showed an anti-apoptotic activity. On the other hand, in vivo studies in animals and in humans showed that GHRPs possess direct cardiotropic actions. In fact, hexarelin protects from ischemia-induced myocardial damage in aged and GH deficient rats while hexarelin shows a positive inotropic effect in normal subjects as well as in patients with GH deficiency. In conclusion, GHRPs possess extra--neuroendocrine biological activity and, particularly, show direct GH-independent cardiotropic effects.
生长激素（GH）释放肽（GHRPs）及其非肽类类似物是合成分子，它们具有强大的、剂量依赖性且可重复的GH释放活性，同时还具有显著的催乳素（PRL）和促肾上腺皮质激素/皮质醇释放作用。这些化合物对食物摄入和睡眠模式也有影响。GHRPs的神经内分泌活性由特定的受体亚型介导，这些受体亚型已通过GHRP家族的八肽（125）I-Tyr-Ala-六肽瑞林在垂体、下丘脑和各种下丘脑外脑区中被鉴定出来。此外，GHRP受体也存在于不同的外周组织中，如心脏、肾上腺、卵巢、睾丸、肺和骨骼肌，其密度明显高于下丘脑 - 垂体系统中的密度。在人类心血管系统中观察到显著的特异性（125）I-Tyr-Ala-六肽瑞林结合，其中在心室中检测到的结合水平最高，其次是心房、主动脉、冠状动脉、颈动脉、心内膜和腔静脉。放射性配体与心肌膜的结合受到未标记的Tyr Ala六肽瑞林和六肽瑞林以及GHRP-6、GHRP-1和GHRP-2的抑制，但不受非肽类GHRP类似物MK-677的抑制。在其他关于H9c2心肌细胞（一种源自胎儿心肌细胞的细胞系）的实验中，发现了特异性GHRP结合，并且六肽瑞林显示出抗凋亡活性。另一方面，在动物和人类中的体内研究表明，GHRPs具有直接的心脏otropic作用。事实上，六肽瑞林可保护老年和GH缺乏大鼠免受缺血诱导的心肌损伤，而六肽瑞林在正常受试者以及GH缺乏患者中均显示出正性变力作用。总之，GHRPs具有额外的神经内分泌生物活性，特别是显示出直接的不依赖GH的心脏otropic作用。
