Inhibition of pulsatile growth hormone (GH) secretion and somatic growth in immature rats with a synthetic GH-releasing factor antagonist.
We previously reported that systemic administration of the recently described GRF peptide antagonist (N-Ac-Tyr1,D-Arg2)GRF-(1-29)-NH2 to adult male rats would suppress the pulsatile release of GH. In the present study, we have sought to determine whether this same antagonist would be efficacious in immature male rats to block spontaneous GH secretion and, as a result, retard several parameters of somatic growth. Indwelling Silastic catheters were placed into the jugular veins of immature male rats (120-140 g) at 29 days of age. After a recovery period of 48 h, beginning at 1000 h, 100-400 micrograms/kg GRF antagonist or its vehicle (controls) were injected iv immediately after withdrawing an initial blood sample from conscious undisturbed animals. Subsequent samples were obtained every 20 min until 1520 h. Red blood cells were resuspended in a restorative volume of saline and reinjected after each blood sample. Results showed that both doses of antagonist prevented the two major periods of episodic GH release observed in controls. For example, mean plasma GH (+/- SEM; nanograms per ml) at 1120 h was 9.0 +/- 2.7 in antagonist-treated rats and 37.1 +/- 5.1 in controls (P less than 0.05). Mean plasma GH (+/- SEM) at 1340 h was 10.8 +/- 3.7 in antagonist-treated rats and 38.8 +/- 9.6 in controls (P less than 0.05). Injection of 400 micrograms/kg of the structurally related VIP antagonist (N-Ac-Tyr1,D-Phe2)GRF-(1-29)-NH2, iv failed to suppress spontaneous GH release. GRF antagonist (100 micrograms/kg) was next administered twice daily iv for 4 days to 31-day-old rats in metabolic cages. This treatment essentially arrested the normal rapid body weight gain, significantly suppressed increases in body and tail lengths, and reduced increases in heart and kidney weights (P less than 0.01). Food intake and fecal output were unchanged by antagonist treatment and, therefore, did not contribute to the observed effects. These results support the idea that a number of tissues and organs are stimulated by the pulsatile secretion of GH and that a peptidic GRF receptor antagonist is useful in blocking episodic GH release in immature animals. As a consequence, this specific antagonist is effective in suppressing numerous aspects of somatic growth.
Lumpkin
M D
MD
Department of Physiology and Biophysics, Georgetown University School of Medicine, Washington, D.C. 20007.
Mulroney
S E
SE
Haramati
A
A
D000818:Animals; D006128:Growth / Q000187:drug effects*; D013006:Growth Hormone / Q000378:metabolism*; D013007:Growth Hormone-Releasing Hormone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D017337:Sermorelin / Q000031:analogs & derivatives; D014660:Vasoactive Intestinal Peptide / Q000037:antagonists & inhibitors; D015430:Weight Gain / Q000187:drug effects
D010446:Peptide Fragments; D014660:Vasoactive Intestinal Peptide; D017337:Sermorelin; D013006:Growth Hormone; D013007:Growth Hormone-Releasing Hormone; C058677:somatotropin releasing hormone (1-29)amide, N-acetyl-tyrosyl(1)-arginyl(2)-; C045616:somatotropin releasing hormone (1-29)-amide, N-Ac-Tyr(1)-Phe(2)-