Age-Related Modulatory Activity by a Cholinergic Agonist on the Growth Hormone Response to GH-Releasing Hormone in the Rat

Panzeri, G.; Torsello, Antonio; Cella, Silvano G.; Müller, Eugenio E.; Locatelli, Vittorio

doi:10.3181/00379727-193-43039

Cited by 14 publications

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“…However, accumulating evidence suggests that major alterations in ageing may be located at the hypothalamic and/or suprahypothalamic level. In fact, short-term GHRH treatment has been shown to re store the GH responsiveness to GHRH in elderly subjects [15,16]; a similar effect has been reported in old rats after passive immunization with antisomatostatin serum [12] or administration of pilocarpine [17], a muscarinic cho linergic agonist which inhibits hypothalamic somatostatin output [18], Moreover, studies performed in the dog have shown that in old animals short-term administration of clonidine (CLO), an cis-adrenoceptor agonist that trig gers GH release acting on the hypothalamus, restored the defective GH secretion [2], Although the mechanisms(s) underlying the GH-releasing effect of CLO is not yet completely clarified, the drug may stimulate GHRH [19][20][21][22] and/or inhibit somatostatin [11,23,24] release. In a recent study, acute administration of CLO strikingly potentiated in old dogs GHRH-stimulated GH release, implying that CLO was acting via inhibition of hypotha lamic release of somatostatin [11] and indicating, albeit inferentially, the existence of an age-related increase in hypothalamic somatostatinergic function.…”

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confidence: 74%

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

et al. 1993

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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.

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confidence: 74%

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

et al. 1993

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“…Pyridostigmine administration, for example, potentiates spontaneous diurnal GH secretion in short children (4) and counteracts the blunted GH response to GHRH in obese children and adults (5,6). Additionally, in rats, treatment with the direct cholinergic agonist, pilocarpine, can partially reverse some of the agerelated decline in the GH response to a GHRH bolus (7).…”

Section: Introductionmentioning

confidence: 99%

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

Friend

Iranmanesh²,

et al. 1997

European Journal of Endocrinology

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Growth hormone (GH) release from the anterior pituitary gland is predominantly regulated by the two antagonistic hypothalamic peptides, growth hormone-releasing hormone (GHRH) and somatostatin. Appraising endogenous GHRH action is thus made difficult by the confounding effects of (variable) hypothalamic somatostatin inhibitory tone. Accordingly, to evaluate endogenous GHRH actions, we used a clinical model of presumptively acute endogenous somatostatin withdrawal with concomitant GHRH release. To this end, we administered in randomized order placebo or the indirect cholinergic agonist, pyridostigmine, for 48 h to 13 healthy men of varying ages (29-77 years) and body mass indices (21-47 kg/m 2 ). We sampled blood at 10-min intervals for 48 h during both placebo and pyridostigmine (60 mg orally every 6 h) administration, and used an ultrasensitive GH chemiluminescence assay (sensitivity 0.002-0.005 mg/l) to capture GH pulse profiles. Multiparameter deconvolution analysis was applied to quantitate the number, amplitude, mass, and duration of significant underlying GH secretory bursts, and simultaneously estimate the GH half-life and concurrent basal GH secretion. Approximate entropy was utilized as a novel regularity statistic to quantify the relative orderliness of the hormone release process. All measures of GH secretion/half-life and orderliness were statistically invariant across the two consecutive 24-h placebo sessions. In contrast, pyridostigmine treatment significantly increased the mean serum GH concentration from 0.23 Ϯ 0.054 mg/l during placebo to 0.45 Ϯ 0.072 mg/l during the first day of treatment (P < 0.01). There was also a significant rise in the calculated 24-h pulsatile GH production rate from 8.9 Ϯ 1.7 mg/l/day on placebo to 27 Ϯ 5.6 mg/l/day during active drug treatment (P < 0.01). Pyridostigmine significantly and selectively amplified GH secretory burst mass to 1.5 Ϯ 0.35 mg/l compared with 0.74 Ϯ 0.19 mg/l on placebo (P < 0.01). This was attributable to stimulation of GH secretory burst amplitude (maximal rate of GH secretion attained within the release episode) with no prolongation of estimated burst duration. Basal GH secretion and approximate entropy were not altered by pyridostigmine. However, age was strongly related to more disorderly GH release during both days of pyridostigmine treatment (r = +0.79, P = 0.0013). During the second 24-h of continued pyridostigmine treatment, most GH secretory parameters decreased by 15-50%, but in several instances remained significantly elevated above placebo. Body mass index, but not age, was a significantly negative correlate of the pyridostigminestimulated increase in GH secretion (r = ¹0.65, P = 0.017).In summary, assuming that somatostatin is withdrawn and (rebound) GHRH release is stimulated via pyridostigmine administration, we infer that relatively unopposed GHRH action principally controls GH secretory burst mass and amplitude, rather than apparent GH secretory pulse duration, the basal GH secretion rate, or the serial regularity/orderli...

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“…In rats of different ages (10 days to 29 months), pilocarpine, an agonist at muscarinic cho linergic receptors, potentiates the GH response to GHRH during the entire life span of the rat [45]. Interestingly, the only exception are the 10-day-old rats, in which an imma turity of the somatostatin system can be envisaged [46].…”

Section: Neuroactive Drugs Alone or With Ghrh And Gh Secretionmentioning

confidence: 99%

Somatotropic Dysregulation in Old Mammals

Müller

Cella²,

Parenti³

et al. 1995

Horm Res

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In old mammals, including humans, the spontaneous growth hormone (GH) secretory pattern is markedly reduced resulting in lower amounts of GH released over 24 h, and the GH response to administration of GH-releasing hormone (GHRH) is reduced. In agreement with these in vivo findings, an impaired responsiveness to GHRH is evident in the pituitary of old male and female rats in vitro, and this is linked with a diminished stimulation of adenylate cyclase by GHRH. The poor GH responsiveness to GHRH in old mammals, which in the rat is coupled to a defective number of GHRH receptors in the somatotrophs, is likely due to a primary deficiency of GHRH availability, as implied by the diminished GHRH immunoreactivity and gene expression in and GHRH release from the hypothalamus of old rats. Attempts have been made to stimulate the sluggish somatotrophic function in elderly humans and dogs using GHRH; in either species positive results were obtained though, overall, it would seem that the GHRH hypofunction does not entirely account for the GH hyposecretory state during ageing. Concerning somatostatin, although the expression of this peptide decreases with age in the rat hypothalamus, secretion and activity of this hormone is increased, resulting in an altered relationship between GHRH and somatostatin gene expression and secretion. It is likely that defects, especially in catecholaminergic and cholinergic neurons, are instrumental in altering specific peptidergic neurons. Reportedly, catecholamines induce GH release by stimulating GHRH neurons and inhibiting somatostatin-releasing neurons; acetylcholine stimulates GH release via muscarinic receptors, in this way inhibiting the action of somatostatin neurons. In old beagle dogs short-term administration of the α₂-adrenoceptor clonidine strikingly potentiated GHRH-stimulated GH release, thus implying that clonidine was acting via inhibition of hypothalamic release of somatostatin, and the combination GHRH plus clonidine was highly effective in restoring the pulsatile release of GH and plasma IGF-1 levels. The possibility is envisaged that GHRH or other GH-releasing peptides, e.g. GH-releasing hexapeptide (GHRP-6) and hexarelin, given in conjunction with compounds allegedly capable of reducing somatostatinergic function (clonidine, arginine) may be potent pharmacologic tools to reinstate in old humans GH secretion in a physiologic, pulsatile manner.

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Age-Related Modulatory Activity by a Cholinergic Agonist on the Growth Hormone Response to GH-Releasing Hormone in the Rat

Cited by 14 publications

References 0 publications

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

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

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

Somatotropic Dysregulation in Old Mammals

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