Sibilia V, Muccioli G, Deghenghi R, Pagani F, De Luca V, Rapetti D, Locatelli V, Netti C
Department of Pharmacology, Chemotherapy and Medical Toxicology, University of Milano, Milano, Milan, Italy.
J Neuroendocrinol. 2006 Feb;18(2):122-8. doi: 10.1111/j.1365-2826.2005.01391.x.
Ghrelin, the endogenous ligand of the GH secretagogue receptor (GHS-R) has been previously shown to inhibit gastric acid secretion in pylorus-ligated rats. Two isoforms of GHS-R have been identified: GHS-R(1a) and GHS-R(1b). The present study aimed: (i) to characterise the type of GHS-R involved in the central gastric inhibitory activity of ghrelin by using des-octanoyl ghrelin, and synthetic GHS-R(1a) agonist (EP1572) and antagonist (D-Lys(3)-GHRP-6) and (ii) to investigate the relationship between ghrelin and cortistatin (CST) in the control of gastric acid secretion by using the natural neuropeptide CST-14 and the synthetic octapeptide CST-8. The specific interactions of all the compounds with GHS-R(1a) were determined by comparing their ability to displace labelled ghrelin or somatostatin from its receptors on rat hypothalamic membranes or on rat cardiomyocyte, respectively. Intracerebroventricular administration of 0.01 and 1 nmol/rat des-octanoyl ghrelin did not affect gastric acid secretion in pylorus-ligated rats, whereas EP1572 either i.c.v. (0.01-1 nmol/rat) or i.p. (10 and 20 nmol/kg) inhibited acid gastric secretion. Preteatment with D-Lys(3)GHRP-6 (3 nmol/rat, i.c.v.) was able to remove the inhibitory action of ghrelin (0.01 nmol/rat, i.c.v.) on gastric acid volume and acid output, thus indicating that the type 1a GHS-R likely mediates the gastric inhibitory action of ghrelin. This is supported by binding data showing that D-Lys(3)GHRP-6, but not des-octanoyl ghrelin, binds to hypothalamic GHS-R. CST-14 (1 nmol/rat, i.c.v.) did not affect either basal or ghrelin inhibition of gastric acid secretion. CST-8 (1 nmol/rat, i.c.v.) was able to counteract the gastric ghrelin response. The observation that CST-14 binds both GHR-S and somatostatin receptors, whereas CST-8 specifically displaces only ghrelin binding, indicates that CST-8 behaves as a GHS-R(1a) antagonist.
胃饥饿素是生长激素促分泌素受体（GHS-R）的内源性配体，此前已证明其可抑制幽门结扎大鼠的胃酸分泌。已鉴定出GHS-R的两种亚型：GHS-R(1a)和GHS-R(1b)。本研究旨在：（i）通过使用去辛酰基胃饥饿素、合成的GHS-R(1a)激动剂（EP1572）和拮抗剂（D-Lys(3)-GHRP-6）来确定参与胃饥饿素中枢性胃抑制活性的GHS-R类型；（ii）通过使用天然神经肽CST-14和合成八肽CST-8来研究胃饥饿素与可的肽（CST）在胃酸分泌控制中的关系。通过比较所有化合物分别从大鼠下丘脑膜或大鼠心肌细胞上的受体置换标记的胃饥饿素或生长抑素的能力，来确定所有化合物与GHS-R(1a)的特异性相互作用。脑室内注射0.01和1 nmol/大鼠的去辛酰基胃饥饿素对幽门结扎大鼠的胃酸分泌没有影响，而EP1572无论是脑室内注射（0.01 - 1 nmol/大鼠）还是腹腔注射（10和20 nmol/kg）均抑制胃酸分泌。用D-Lys(3)GHRP-6（3 nmol/大鼠，脑室内注射）预处理能够消除胃饥饿素（0.01 nmol/大鼠，脑室内注射）对胃酸量和酸排出量的抑制作用，因此表明1a型GHS-R可能介导胃饥饿素的胃抑制作用。结合数据支持了这一点，该数据表明D-Lys(3)GHRP-6而非去辛酰基胃饥饿素与下丘脑GHS-R结合。CST-14（1 nmol/大鼠，脑室内注射）对胃酸分泌的基础水平或胃饥饿素抑制作用均无影响。CST-8（1 nmol/大鼠，脑室内注射）能够抵消胃饥饿素对胃的反应。CST-14同时结合生长激素释放肽受体和生长抑素受体，而CST-8仅特异性置换胃饥饿素结合的观察结果表明，CST-8表现为一种GHS-R(1a)拮抗剂。
