The pulsatile pattern of growth hormone secretion from the anterior pituitary gland reflects a changing balance in the output of two hypothalamic systems, the GH-releasing hormone (GHRH) neurones that stimulate GH secretion and the inhibitory somatostatin neurones. The GH secretagogues stimulate GH secretion by a direct pituitary action and also by a central mechanism that includes effects on the hypothalamic GHRH-somatostatin pulse generating system. In the 1980s CY. Bowers and colleagues identified the first member of a class of synthetic growth hormone (GH)-releasing compounds, GH-releasing peptide-6 (GHRP-6), whose actions were potent and selective for GH secretion. Direct GH-releasing activity at the pituitary level was observed in vitro, providing evidence for a direct pituitary action and the GH-releasing mechanism was clearly different to that of GHRH. That GHRP-6 may also affect the hypothalamic regulation of GH secretion was first suggested by Clark and Robinson.
They proposed that part of the GH-releasing mechanism of GHRP-6 is hkely to include increased GHRH release, since the GHRP-6-induced GH response was attenuated in rats passively immunized with GHRH antiserum. Furthermore they suggested that GHRP-6 may alter somatostatin secretion, since it disrupted the cyclic changes in GH release following regular injections of GHRH (a response which has been attributed to cyclic changes in somatostatin secretion). Certainly, it emerged that the GH-releasing actions of GH secretagogues could not be explained solely by a pituitary action since, when administered together, GHRP-6 and GHRH had merely additive effects on GH secretion in vitro (in pituitary perfusion experiments and in cell culture) but produced an enormous synergistic effect in vivo. Rather it was suggested that the central actions of GHRP-6 may include the release of an unknown hypothalamic-releasing factor (a "U-factor") into the portal blood; according to this hypothesis, the U-factor would act together with GHRH to stimulate GH secretion from the pituitary. The first direct evidence that the GH secretagogues are centrally active compounds was provided by studies demonstrating increased activity of a sub-population of cells in the hypothalamic arcuate nucleus. In this study and in subsequent studies, cells activated following systemic GH secretagogue injection were detected using two complementary approaches: by the immunocytochemical detection of Fos protein (the product of the immediate early gene, c-fos, which is expressed in many neuronal systems following activation) and by changes in electrical activity of arcuate neurones recorded in anaesthetised rats. Following systemic injection of GHRP-6, nuclear staining for Fos was detected in a subpopulation of ceUs in the arcuate nucleus; most Fos-positive nuclei were located in the most ventromedial aspects of this nucleus, although there were also a few scattered more ventrolaterally. No increase in Fos expression was detected in any other forebrain structure studied. The selectivity of the GH secretagogue response is quite remarkable, considering the distribution of the GH secretagogue receptor.
This receptor was cloned in 1997 by Howard and colleagues and subsequently shown to be present in a number of CNS structures. In addition to the arcuate nucleus, GH secretagogue receptor mRNA was detected in several other hypothalamic nuclei (including the ventromedial nucleus, preoptic nucleus, anterior hypothalamic area, suprachiasmatic nucleus) and in discrete regions of many non-hypothalamic structures (including the hippocampus, thalamus and brainstem). Thus, assuming that GH secretagogues have access to CNS regions other than the arcuate nucleus, it would appear that GH secretagogue action is not coupled with expression of Fos in these regions. Consistent with this hypothesis, no additional forebrain structures expressed Fos when GHRP-6 was administered directly into the brain ventricles; both the distribution and the number of cells activated was identical to that described for systemic injection of this compound. In a recent study, the effects of GH secretagogues on Fos expression within the CNS have been extended to include the brainstem. Interestingly, systemic GHRP-6 injection induced Fos expression in the area postrema and in the nucleus tractus solitarii. The physiological consequences of activation of these cells by GH secretagogues is not known.
The area postrema is a circumventricular organ, that is, an area of the CNS where the blood-brain barrier is incomplete and where information about circulating levels of peripheral factors is monitored. It is closely interconnected with the nucleus tractus sohtarii and together they form an important role in relaying such information to the hypothalamus, for the regulation of pituitary hormone secretion. It is possible that the GH secretagogueresponsive cells in the brainstem form part of a projection to the hypothalamus and that this plays some role in regulating hypothalamic activity. It is evident, however, that the GH secretagogues also have more direct actions within the hypothalamus. That the GH secretagogues act directly within the arcuate nucleus to activate cells has been demonstrated in electrophysiological vStudies in vitro\ GHRP-6 was shown to activate a sub-population of cells in a hypothalamic slice preparation in which all but closely adjacent inputs to the arcuate nucleus had been severed.
Our website is not responsible for the information contained by this article. Articleinput.com is a free articles resource thus practically any visitor can submit an article. However if you notice any copyrighted material, please contact us and we will remove the article(s) in discussion right away.
Note: This article was sent to us by: Harry S. at 12172009
1. Clinical evaluation in humans
© 2009 ArticleInput.com.