Inhibition of L-692,429-stimulated rat growth hormone release by a weak substance P antagonist: L-756,867.
H2N,D-Arg,Pro,Lys,Pro,D-Phe,Gln,D-Trp,Phe,D-Trp,Leu, Leu,NH2 (L-756,867), a weak substance P antagonist, inhibited L-692,429-stimulated GH release from rat primary pituitary cells in a dose-dependent manner. At a concentration of 50 nM, L-756,867 shifted the dose-response curve of L-692,429-induced GH release to the right by about tenfold. It also impaired the ability of L-692,429 to potentiate the effect of growth hormone-releasing factor (GRF) on GH release. Substance P (1 microM) had no effect on basal or L-692,429-stimulated GH release. When tested in anesthetized rats, L-756,867 inhibited L-692,429- and growth hormone-releasing hexapeptide- (GHRP-6)-stimulated GH secretion in a dose-dependent manner. Complete inhibition was observed at an i.v. dose of 100 micrograms/kg of L-756,867. However, at the same concentration, it had no effect on GRF-induced GH secretion D-Lys3-GHRP-6, a GHRP-6 antagonist, had no effect on GHRP-6 or L-692,429-induced GH secretion even at an i.v. dose of 2 mg/kg. These results indicate that L-692,429 and GHRP-6 stimulate GH release both in vitro and in vivo via a common receptor and signaling pathway which is different from that of substance P in spite of the fact that their effects are inhibited by a weak substance P antagonist.
Cheng
K
K
Department of Growth Biochemistry and Physiology, Merck Research Laboratories, Rahway, New Jersey 07065, USA.
Wei
L
L
Chaung
L Y
LY
Chan
W W
WW
Butler
B
B
Smith
R G
RG
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D002478:Cells, Cultured; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D005260:Female; D013006:Growth Hormone / Q000378:metabolism*; D013007:Growth Hormone-Releasing Hormone / Q000494:pharmacology; D008297:Male; D009842:Oligopeptides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013373:Substance P / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology*
D001552:Benzazepines; D009842:Oligopeptides; D013777:Tetrazoles; C054880:growth hormone releasing hexapeptide, Lys(6), thionated; C081455:L 692429; D013373:Substance P; C041048:growth hormone releasing hexapeptide; D013006:Growth Hormone; D013007:Growth Hormone-Releasing Hormone; C045800:substance P, Phe(5)-Trp(7,9)-Leu(11)-