Interactions of growth hormone secretagogues and growth hormone-releasing hormone/somatostatin

The class of novel synthetic compounds termed growth hormone secretagogues (GHSs) act in the hypothalamus through, as yet, unknown pathways. We perfor med physiologic and histochemical studies to further understand how the GHS system interacts with the well-established somatostatin (SRIF)/growth horm one-releasing hormone (GHRH) neuroendocrine system for regulating pulsatile GH secretion. Comparison of the GH-releasing activities of the hexapeptide growth hormone-releasing peptide-6 (GHRP-6) and GHRH administered intraven ously to conscious adult male rats showed that the pattern of GH responsive ness to GHRP-6 was markedly time-dependent, similar to that observed with G HRH, Immunoneutralization of endogenous SRIF reversed the blunted GH respon se to GHRP-6 at trough times, suggesting that GHRP-6 neither disrupts nor i nhibits the cyclical release of endogenous hypothalamic SRIF, By striking c ontrast, passive immunization with anti-GHRH serum virtually obliterated th e GH responses to GHRP-6, irrespective of the time of administration. These findings suggest that the GHSs do not act by altering SRIF release but, ra ther, stimulate GH release via GHRH-dependent pathways. Our dual chromogeni c and autoradiographic in situ hyhridization experiments revealed that a su bpopulation of GHRH mRNA-containing neurons in the arcuate (Arc) nucleus an d ventromedial nucleus (VMN) of the hypothalamus expressed the GHS receptor (GHS-R) gene. These results provide strong anatomic evidence that GHSs may directly stimulate GHRH release into hypophyseal portal blood, and thereby influence GH secretion, through interaction with the GHS-R on GHRH- contai ning neurons. Altogether, these findings support the notion that an additio nal neuroendocrine pathway may exist to regulate pulsatile GH secretion, po ssibly through the influence of the newly discovered GHS natural peptide, g hrelin.