Differential Effects of Direct and Indirectly Acting Cholinergic Agonists on Growth Hormone Release in Man, and Lack of Effect on Cortisol Secretion

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Abstract
Acetylcholine plays a key role in the modulation of growth hormone secretion. In fact, growth hormone release after provocative stimuli is blocked by muscarinic cholinergic antagonists, and conversely, indirect cholinergic agonists potentiate growth hormone secretion. To further understand the mechanism by which cholinergic pathways exert their effects, we have compared the growth hormone and cortisol secretion elicited on normal volunteers by pyridostigmine and by RS-86 (2-ethyl-8-methyl-2,8-diazaspiro-((4,5))-decan-1,3-dion hydrobromide). The former acts by inhibiting acetylcholinesterase, thus being an indirect muscarinic agonist, while the latter is a muscarinic receptor agonist which binds directly to and stimulates cholinergic receptors. In six subjects, pyridostigmine (120 mg po) induced an increase of growth hormone of 11.0+/-2.4 mug/L at 90 min, significantly greater than following placebo administration (1.4 +/- 0.3 mug/L). In another group of five volunteers, RS-86 was administered in separate tests at a dose of 0.5, 1 and 2 mg po. Growth hormone levels were not altered by any RS-86 dose compared with placebo values. Neither pyridostigmine nor RS-86 altered cortisol values. These results suggest that the mechanism of action of the cholinergic agonists is of great importance for their growth hormone-releasing capabilities, and question the accepted view of a cholinergic regulation of cortisol secretion in man.

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