Gamma-hydroxybutyric acid and growth hormone secretion studies in rats and dogs.
Gamma-hydroxybutyric acid, a gamma-aminobutyric acid metabolite, and baclofen, a gamma-aminobutyric acid B agonist, are endowed with a small growth hormone-releasing activity in human beings. In this study, we have investigated the reciprocal interactions of gamma-hydroxybutyric acid and the gamma-aminobutyric acid B system by evaluating the growth hormone-releasing activity of the two compounds and their respective antagonists in in vivo and in vitro experiments performed in rats and dogs. In in vivo experiments, neither gamma-hydroxybutyric acid (25, 100, 150, and 300 mg/kg, SC) nor baclofen (0.25, 1, 2, 4, and 8 mg/kg, SC) significantly modified growth hormone secretion in 9-day-old rat pups. Similarly, no growth hormone and prolactin release was observed in adult anesthetized rats after administration of gamma-hydroxybutyric acid (100 mg/kg, IP) or baclofen (10 mg/kg IP). Equally ineffective on the somatotropic response was the administration of gamma-hydroxybutyric acid (200 mg/kg, IP) alone or associated with its specific receptor antagonist NCS-382 (150 mg/kg, IP) given to adult anesthetized rats. In addition, a toxicological dose of gamma-hydroxybutyric acid (1500 mg/kg, IP) did not alter baseline growth hormone levels in adult conscious rats. gamma-Hydroxybutyric acid (50 mg/kg, IP) given for 10 days to adult conscious rats did not alter the growth hormone response to the same gamma-hydroxybutyric acid dose given acutely. In conscious dogs, gamma-hydroxybutyric acid (20 and 50 mg/kg, IV) and baclofen (0.15, 0.30 mg/kg, IV) also were ineffective in stimulating growth hormone secretion. In this species, growth hormone response to hexarelin (31.25 microg/kg, IV), a potent growth hormone-releasing peptide, was not modified by coadministration of gamma-hydroxybutyric acid (50 mg/kg, IV). In in vitro experiments, increasing doses of gamma-hydroxybutyric acid (10(-7), 10(-5), and 10(-3) M) did not alter growth hormone concentrations in media of rat pituitary cell cultures. In contrast, growth hormone-releasing hormone (10(-7) M) induced a significant growth hormone release into the media. In conclusion (1) gamma-hydroxybutyric acid is not an effective growth hormone secretagogue; (2) the reciprocal functional interactions between gamma-hydroxybutyric acid and the gamma-aminobutyric acid B system could not be investigated, due to the ineffectiveness of gamma-hydroxybutyric acid and baclofen to stimulate growth hormone release; and (3) short-term administration of gamma-hydroxybutyric acid does not induce adverse effects amenable to activation of the somatotropic function.
Rigamonti
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AE
Department of Pharmacology, Chemotherapy, and Toxicology, University of Milan, via Vanvitelli 32, 20129, Milan, Italy. antonello.rigamonti@unimi.it
Müller
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EE
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001418:Baclofen / Q000494:pharmacology; D003000:Clonidine / Q000494:pharmacology; D004285:Dogs; D005260:Female; D018755:GABA Agonists / Q000494:pharmacology; D013006:Growth Hormone / Q000378:metabolism*; D013007:Growth Hormone-Releasing Hormone / Q000494:pharmacology; D006801:Humans; D006885:Hydroxybutyrates / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism; D011388:Prolactin / Q000378:metabolism; D051381:Rats
D000316:Adrenergic alpha-Agonists; D018755:GABA Agonists; D006885:Hydroxybutyrates; D009842:Oligopeptides; C086184:hexarelin; C111420:4-hydroxybutyric acid; D011388:Prolactin; D013006:Growth Hormone; D013007:Growth Hormone-Releasing Hormone; D001418:Baclofen; D003000:Clonidine