Pyridostigmine (PD), a cholinesterase inhibitor, has been shown to elicit GH release when given alone and to potentiate the GH response to GH-releasing hormone (GHRH) in man. Numerous experiments have indirectly indicated that somatostatin (SS) inhibition is its likely mechanism of action. This study sought to establish the ability of PD to induce GH release in the rat, determine the dose-response relationship, and test the hypothesis that SS inhibition is the method of action. Three experiments were performed to monitor the GH response to PD. I) Five groups of male rats were food deprived for 72 h. The groups were then treated iv with saline, SS antibody (SS-ab), and 10, 100, and 1000 micrograms/kg PD, respectively. Blood samples were drawn before and after treatment. II) Two groups of male rats were pretreated iv with GHRH antibody (GHRH-ab) and either SS-ab or normal sheep serum (NSS). Blood samples were drawn every 30 min for 8.5 h, during which time each animal was injected with PD (10 micrograms/kg) in the third hour and again in the sixth hour. III) Male rats received a PD injection (10 micrograms/kg, iv) during a spontaneous GH trough period and a second PD injection during a spontaneous GH peak period. Blood samples were drawn at regular intervals preceding and following treatments. In Exp I, PD induced a clear 4- to 5-fold increase in GH concentrations in food-deprived rats. The maximal GH responses occurred after the 10 and 100 micrograms/kg doses, although the pattern and duration were different with these two doses. In Exp II, PD induced an approximately 2-fold increase in GH values in animals pretreated with GHRH-ab and NSS, but failed to induce a change in GH in the animals treated with GHRH-ab and SS-ab. In Exp III, PD failed to induce any change in GH concentration when administered during spontaneous GH peaks or troughs. The first two experiments suggest that PD increases GH secretion in the rat via inhibition of SS. The failure of PD to alter GH during a spontaneous peak is consistent with the current hypothesis that the level of SS is low at this time. Its failure to alter GH during trough periods may be related to very high SS tone. In conclusion, our results support the hypothesis that PD acts via inhibition of SS secretion.

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Glucocorticoids are known to inhibit GH secretion via somatostatin. The aim of our study was to elucidate the involvement of somatostatin in the GH-releasing action of the alpha 2 agonist clonidine and the cholinergic agent pyridostigmine in conscious, freely-moving rats chronically treated with dexamethasone. After seven days of chronic glucocorticoid treatment, animals received an i.v. injection of either saline (1 ml/kg) or clonidine (150 micrograms/kg) or pyridostigmine (100 micrograms/kg) at -15 min. Three blood samples were then drawn (-10 min, -5 min, and 0 min) to assess the GH response to either clonidine or pyridostigmine alone. After the 0 min sample, saline (1 ml/kg) or GNRH (500 ng/kg) was injected i.v. and additional blood samples were drawn from 5 to 30 min. The GH response to clonidine alone or combined with GNRH in rats treated with dexamethasone was significantly lower (p < 0.05) as compared to vehicle-treated rats. The GH response to pyridostigmine alone or combined with GNRH did not significantly differ between vehicle- and dexamethasone-treated rats. These data suggest that in the rat the mechanism of action of clonidine is mainly to stimulate endogenous GNRH secretion, while pyridostigmine appears to predominantly act by decreasing hypothalamic somatostatin.

Interruption of hypothalamic growth hormone-releasing hormone (GHRH) secretion by administration of antiserum against GHRH (GHRH-ab) decreases growth hormone (GH) secretion and inhibits growth in rats. The present study was undertaken to investigate whether there is a period of accelerated or catch-up growth following a period of growth arrest induced by GHRH-ab treatment. Neonatal male and female rats were injected daily on days 1-14 of age. Animals received normal rabbit serum (NRS) or GHRH-ab subcutaneously at a dose of 5 µl/l0 g body weight. Body weight, serving as an index of somatic growth, was monitored over the next 3 months. The increase in absolute body weight and growth velocity of GHRH-ab-treated rats, regardless of gender, was lower than the increase of NRS-treated animals. Significant decreases were observed by day 13 of age in the female rats and day 17 in the male rats. The percent differences and absolute difference in weight between the two treatment groups clearly demonstrated that the GHRH-ab-treated rats did not demonstrate any period of catch-up growth. A second group of animals was treated in a similar fashion to evaluate serum GH concentrations at three months of age. Pulsatile GH secretion, as assessed by peak frequency and amplitude, was normal in all of the rats, suggesting that the failure of catch-up growth in the GHRH-ab-treated animals was not due to decreased GH secretion. The failure of cateh-up growth following transient growth arrest induced by GHRH deprivation suggests that a functional GHRH/GH neuroendocrine system is critical during the neonatal period to establish normal growth of the animal on a long-term basis.

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