The first study was performed in 1988. Also, at this same time Ilson of SmithKline Beecham performed a clinical study with GHRP-6. Recorded is the comparative GH releasing activity of GHRH and 3 synthetic GHRPs, GHRP-6, GHRP-1 and GHRP-2 after i.v. bolus administration of 1 micro g/kg to normal young men. The results demonstrate that all the GHRPs released more GH than GHRH. Also, they demonstrate that any endogenous GHRH possibly released by a GHRP hypothalamic action would not, by itself, fully explain the mechanism of how GHRP releases more GH than GHRH. Results in men and women again support the independent and complementary action of GHRP and GHRH on GH release, because in normal younger and older men and women, i.v. bolus 1 Mg/kg GHRP-2 administered together with 1 fig/kg GHRH, released GH synergistically in all of the subjects.
Also, the GH response to GHRP, GHRH and the 2 peptides together in the older subjects, compared to the younger subjects, was decreased. Several different, important and somewhat surprising results evolved from 2 studies performed by Craig Jaffe and Ariel Barkan as well as Michael Thorner's group in which GHRP-6 was continuously administered i.v. over 36 or 24 hours to normal young men. Since the amplitude but not the frequency of pulsatile GH secretion was increased in both studies, the results demonstrate that continuous infusion of GHRP augments the physiological pattern of pulsatile GH release. There was essentially no rise of the interpulse GH level indicating lack of an attenuation effect on the release or action of SRIF but there was an increase in the serum IGF-I level of about 40%.
These overall results were somewhat surprising because in earlier studies in rats repeated hourly injections of GHRP and continuous infusion of GHRP-6 during perifusion of the rat pituitary in vitro markedly desensitized the GH release induced by GHRP. Also, as recorded in the study by Jaffe and Barkan, the individual acute GH responses to i.v. bolus TRH, GHRH and GHRP were determined at the end of the GHRP infusion period. These results reveal that TRH had no effect on GH release; the GH response to the first two of the three sequential boluses of GHRH were increased while the third was decreased and, as predicted, the GH response to i.v. bolus GHRP was markedly decreased. To explain these results it is postulated that both sensitization and desensitization of the GHRP GH releasing action was induced by continuous GHRP infusion. The i.v. bolus GHRH GH response was sensitized while the i.v. bolus GHRP GH response was desensitized. The sustained sensitization of the GHRP action on the spontaneous pulsatile release of GH during the entire infusion period shows that the desensitization effect of GHRP is only partial. Also, the results reveal that continuous GHRP administration does not inhibit or interfere with the timing of the normal pulsatile secretion of endogenous GHRH from the hypothalamus or appear to enhance the pulsatile secretion of GH by interfering with the hypothalamic release or pituitary action of SRIF. The normal pulsatile GH secretion supports that the negative feedback effect of serum GH and IGF-I on GHRH and SRIF release are still operative. These intact feedback actions help to promote physiological pulsatile secretion of GH and to minimize the superphysiological secretion of GH.
The effects of continuous infusion of GHRP in vivo are envisioned to enhance the pituitary GH response to exogenous GHRH and endogenous GHRH and, in this study, may be the reason the GH response to GHRH as well as the spontaneous GH pulses are increased. A somewhat confusing issue is that this GHRH sensitization effect is hypothesized to be mediated via a hypothalamic action rather than a direct pituitary action of GHRP presumably via the hypothalamic putative U-factor. Because of the excess GHRH administered i.v. at the end of the GHRP infusion period, it is apparent that the sensitization or augmentation of the GHRH GH response induced by GHRP does not result from any effect it may have on the release of endogenous GHRH. Furthermore, GHRP seems unUkely to augment the GHRH action by inhibiting the release of SRIF from the hypothalamus or the action of SRIF on the pituitary. During the normal physiological secretion of GH, enhanced SRIF tone is the usual reason proposed for a lower interpulse level of GH; however, GHRP at dosages which increase the amplitude of the spontaneous GH pulse has essentially Uttle to no effect on interpulse GH levels. Pertinent is that the GH response to GHRP is increased when SRIF release or action is decreased experimentally by pentobarbital, opiates, SRIF antiserum or pyridostigmine. If GHRP released GH by interfering with the release or action of SRIF, these agents would not be expected to further increase the GH response to GHRP. However, the SRIF inhibitory pituitary action may possibly be attenuated by a high dose of 10 fig/kg GHRP as well as 1 micro g/kgGHRP+GHRH.
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1. Clinical evaluation in humans
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