Contrasting effects of nitric oxide on food intake and GH secretion stimulated by a GH-releasing peptide.
OBJECTIVE
Among the many actions of nitric oxide (NO) are those on endocrine and feeding behaviour. Based on NO involvement in the GH-releasing effect of the GH-releasing peptides (GHRPs) and the reported orexigenic activity of these compounds, we sought to evaluate the effect of the combined administration of a long-acting NO donor, molsidomine, and the newly synthesized GHRP EP92632 on food intake and GH secretion in rats. Moreover, to verify the specificity of a potential NO involvement, we evaluated whether or not the effects of GHRPs were abolished by a pre-treatment with an inhibitor of NO synthase, N-nitro-arginine-methyl-ester (NAME).


METHODS
In the food intake experiments, adult Sprague-Dawley male rats underwent acute administration of: (1) EP92632 (160 microg/kg, s.c.); (2) molsidomine (100 mg/kg, i.p.); (3) EP92632+molsidomine; (4) l-NAME (40 and 60 mg/kg, i.p.); (5) EP92632+l-NAME (60 mg/kg, i.p.); (6) EP92632+molsidomine+l-NAME (60 mg/kg, i.p.); and (7) 0.9% saline (0.1 ml/kg, i.p.). After treatments, the cumulative food intake in the 6 post-treatment hours was carefully evaluated. In the neuroendocrine experiments, rats were given the same compounds according to the above reported schedule, except for the use of one dose of NAME (60 mg/kg, i.p.) and a lower EP92632 dose (80 microg/kg, s.c.), and were sampled via atrial cannula.


RESULTS
EP92632 significantly stimulated food intake, an effect which was further enhanced by molsidomine, though the latter did not elicit per se any orexigenic effect. l-NAME given alone significantly decreased food intake and abolished the orexigenic effect of the GHRP and the enhancing effect of molsidomine. Plasma GH levels increased significantly following administration of EP92632 but, in contrast to the food intake experiments, molsidomine significantly inhibited both basal and EP92632-stimulated GH secretion; moreover, NAME had a biphasic effect on the EP92632-stimulated GH release: initially inhibitory and then, from 45 min on, stimulatory. NAME did not affect basal GH levels but, surprisingly, combined administration of molsidomine and NAME induced a striking inhibition of both basal and the peptide-stimulated GH release.


CONCLUSIONS
In summary, these data indicate that NO in the rat is physiologically involved in a stimulatory way in the GHRP-mediated effect on food intake, but exerts a dual action, probably stimulatory at hypothalamic and inhibitory at pituitary levels, on basal and GHRP-stimulated GH secretion.
Rigamonti
A E
AE
Department of Medical Pharmacology, University of Milan, via Vanvitelli 32 30129 Milan, Italy.
Cella
S G
SG
Cavallera
G M
GM
Deghenghi
R
R
Locatelli
V
V
Pitsikas
N
N
Müller
E E
EE
D000818:Animals; D004338:Drug Combinations; D004435:Eating / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D013006:Growth Hormone / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D008297:Male; D008981:Molsidomine / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D004338:Drug Combinations; C422742:EP92632 peptide; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D009569:Nitric Oxide; C041048:growth hormone releasing hexapeptide; D013006:Growth Hormone; D008981:Molsidomine; D019331:NG-Nitroarginine Methyl Ester