Studies of Growth Hormone Secretion in Calorically Restricted Dogs: Effect of Cholinergic Agonists and Antagonists, Glucose and Thyrotropin-Releasing Hormone

Abstract

The effect of caloric restriction (CR) on the growth hormone (GH) response to compounds reportedly capable of acting via somatostatinergic influences, i.e. cholinergic agonist or antagonist drug, glucose or thyrotropin-releasing hormone (TRH), administered alone or combined with GH-releasing hormone (GHRH), was evaluated in dogs. Eight beagle dogs, aged 4–5 years, underwent a 26-day period of increasing CR; they were evaluated either under basal conditions or starting from day 13 of CR, according to a schedule which allowed the mean length of CR to be similar among individual tests. CR resulted in a significant increase in basal GH levels, and starting from day 13 in a significant decrease in plasma somatomedin C levels; plasma glucose levels were significantly diminished on day 13 of CR and then remained unaltered. Administration of GHRH (GHRH1–44, 2 µg/kg, i.v.) induced a rise in plasma GH levels strikingly higher during CR than under basal conditions. Pyridostigmine (2 mg/kg orally), a muscarinic cholinergic agonist reportedly capable of restraining hypothalamic release of somatostatin (SS), enhanced the GH response to GHRH under basal conditions, but failed to do so during CR. Conversely, pirenzepine (0.6 mg/kg, i.v.), a muscarinic cholinergic antagonist, abolished the GHRH-induced GH rise under basal conditions, but only reduced it during CR. Only by doubling the dose of pirenzepine was complete inhibition of the GHRH-induced GH rise effected. Glucose alone (2 g/kg, p.o.) failed to modify basal GH secretion either before or during CR, but significantly inhibited the GHRH-induced GH rise either before or during CR. TRH (5 µg/kg, i.v.) did not modify plasma GH levels under basal conditions, but partially counteracted the rise in plasma GH occurring during CR. Like glucose, TRH significantly inhibited the GHRH-induced GH rise either before or during CR. Neither glucose nor TRH alone induced a ‘paradoxical’ rise in plasma GH during CR. In summary, (1) the data obtained with drugs affecting cholinergic transmission suggest that the latter is increased in dogs during CR and this likely results in a reduced hypothalamic SS tone, and (2) the data obtained with glucose and TRH suggest that these compounds may be effective to trigger not only hypothalamic SS release but also synthesis or, alternatively, they may act via inhibitory influences other than SS.

Somatostatin Withdrawal as Generator of Pulsatile GH Release in the Dog: A Possible Tool to Evaluate the Endogenous GHRH Tone?

“…16, 34-37] and data in humans favor the idea that this occurs via changes in GHRH synthesis and/or release [37] secondary to alterations in neurotrans mitter function [38]. This interpretation, however, is compounded by the progressive decline of plasma IGF-I titers with fasting [ 15,34,[39][40][41][42][43], and the possibility that this event, via a lack of IGF-I negative feedback, may be responsible forGH hypersecretion [44].…”

“…We performed our studies under different conditions of endogenous GHRH function, in the dog, a species with aspects of GH regulation resembling those in humans [13,14], First, we evaluated the ability of withdrawal of SS infusion to induce a GH secretory burst during a situation of en hanced GHRH function, i.e. young dogs under sustained caloric restriction (CR) [15] or short-term fasting [16]. Secondly, we performed experiments in aged dogs, in which hypothalamic GHRH secretion is thought to be reduced [ 17], Old dogs were evaluated under basal condi tions, and, then, following fasting or short-term adminis tration of GHRH alone or followed by fasting.…”

Neuronal M 3 muscarinic acetylcholine receptors are essential for somatotroph proliferation and normal somatic growth

“…Pharmacological studies suggest that central muscarinic cholinergic pathways play a role in stimulating GH release in experimental animals and humans (1)(2)(3)(4)(5)(6)(7)(8)(9). The identification of the molecular pathways and the specific muscarinic ACh receptor (mAChR) subtypes involved in mediating these responses should be of considerable potential therapeutic interest.…”

Effect of intra-hippocampal injection of human recombinant growth hormone on synaptic plasticity in the nucleus basalis magnocellularis-lesioned aged rats

“…The evidence suggests that a functional link may exist between the cholinergic system and growth hormone (GH) secretion. For example, the secretion of GH from the pituitary is enhanced by acetylcholinesterase inhibitor (pyridostigmine) 7 and a primary mediator of growth hormone/insulin-like growth factor-1 (IGF-1) or GH-releasing hormone, which can stimulate secretion of acetylcholine from rat cortical slices and the hippocampus respectively 8,9 . It has recently been shown that age-related reductions in plasma GH, known as somatopause, is associated with increased incidence of cognitive impairment and AD, and can be compensated through GH treatment 10,11 .…”