Combined Administration of Growth-Hormone-Releasing Hormone and Clonidine Restores Defective Growth Hormone Secretion in Old Dogs

Abstract

We have studied in old dogs the effects of short-term administration of growth hormone (GH)-releasing hormone (GHRH) alone or co-administered with clonidine (CLO), an ct2-adrenergic agonist, on the GH secretory pattern (cluster analysis), and GH responsiveness to an acute GHRH or GHRH + CLO challenge and plasma somatomedin C (SMC) levels. Dogs were given either GHRH alone twice daily for 10 days (treatment 1) or combined GHRH + CLO both given twice daily (treatment 2) or GHRH + CLO given once daily (treatment 3). Animals were sampled from 09.00 to 15.00 h, at 10-min intervals, both before and 14 h after treatments. At the end of the 6-hour sampling period, dogs were challenged with simultaneous administration of GHRH and CLO, while they were tested with GHRH alone on the morning of the following day. In dogs undergoing treatment 1, acute administration of GHRH or GHRH + CLO elicited mean GH peak responses higher than before treatment, but none of the GH secretory indices were modified during the 6-hour sampling period, except for the increase in mean GH peak amplitude. In dogs undergoing treatment 2, acute administration of GHRH elicited a mean GH peak response higher than that before treatment, whereas administration of GHRH + CLO induced a mean GH peak response not different from that elicited by GHRH + CLO before treatment or by GHRH alone after treatment. However, this treatment significantly augmented the frequency of spontaneous bursts of GH secretion, the mean GH peak amplitude and the total peak area. In dogs undergoing treatment 3, acute administration of GHRH alone or GHRH + CLO elicited a mean GH peak response higher than that elicited by the same drugs before treatment. Moreover, there was an increase of GH peak frequency, mean GH peak amplitude and total peak area, even higher than after treatment 2. Plasma SMC levels rose significantly after all treatments, treatment 3 being the most effective in this instance. These data demonstrate that: (1) both a hypothalamic and a pituitary component play a role in the defective GH secretion in old dogs; (2) GH hypofunction is not an irreversible event, since GH secretion may be restored by pharmacological means acting at both the pituitary and the hypothalamic level, and (3) CLO given only once daily was more effective than CLO given twice daily, perhaps due to the property of this drug to down-regulate at high doses hypothalamic α₂-adrenoceptors.

The Effects of Xylazine on Plasma Concentrations of Growth Hormone, Insulin-like Growth Factor-I, Glucose and Insulin in Calves.

“…In dogs, an increase in plasma IGF-I level was observed after an administration of the drug, clonidine [25]. The present results, however, were consistent with reports that infusion of clonidine resulted in a decrease of IGF-I in sheep [Namu et al, unpublished data].…”

Effects of growth hormone secretagogues on the release of adenohypophyseal hormones in young and old healthy dogs

“…GHRH, despite the availability of a remarkable GHreleasable pool (Giustina and Veldhuis, 1998;Ghigo et al, 1999;Muccioli et al, 2002). These observations support the idea that the somatopause is driven primarily by the hypothalamus and that the pituitary somatotropes retain their capacity to synthesise and secrete adequate levels of GH (Cella et al, 1993;Corpas et al, 1992;Franchimont et al, 1989;Muccioli et al, 2002;Muller et al, 1999;Walker et al, 1990).…”

“…It seems that an impairment of pituitary function does not play a major role . Indeed, repeated GHRH injections in elderly subjects, combined administration of GHRH and clonidine in old dogs, or GHRH + GHRP-6 injection in aged rats (Walker et al, 1991) significantly increases circulating GH levels (Cella et al, 1993;Nicolas et al, 1994). Additionally, the age-related decrease of the GH response to ghrelin and synthetic GHSs agrees with the well-known in vitro hyporesponsiveness of the aged somatotroph cells to the majority of provocative stimuli, including Ghrelin GHRH NaCl GHRP-6 Ghrelin GHRH NaCl GHRP-6 Ghrelin GHRH NaCl GHRP-6 Ghrelin GHRH NaCl GHRP-6 Ghrelin GHRH NaCl GHRP-6 Ghrelin GHRH NaCl GH (µg/L) .…”

Pyridostigmine treatment selectively amplifies the mass of GH secreted per burst without altering GH burst frequency, half-life, basal GH secretion or the orderliness of GH release

“…This probably reflects the deliberately diverse composition of the cohort of men studied here, spanning a wide range of ages (29-77 years) and body mass indices (21-47 kg/square meters), since both factors are known to influence pulsatile GH release (1,3,20,23,25,(36)(37)(38)(39)(40)(41)(42). Because our study included only healthy otherwise unmedicated men, previously described differences in GH release due to gender or underlying illness were not variables in this investigation.…”