Efficacy and specificity of L-692,429, a novel nonpeptidyl growth hormone secretagogue, in beagles.
L-692,429 is a substituted benzolactam that has recently been shown to stimulate GH secretion from rat pituitary cells in vitro with an ED50 of 60 nM. In the current studies, we evaluated the efficacy and specificity of L-692,429 as a GH secretagogue in beagles. L-692,429 at 0.1, 0.25, or 1.0 mg/kg or saline vehicle was administered iv to four male and four female beagles in a balanced cross-over design. Blood samples were collected up to 75 min posttreatment, and serum was assayed for GH, cortisol, PRL, and LH. Mean peak serum GH levels were significantly increased (P < 0.05) by L-692,429 to 13 +/- 2 (mean +/- SEM) ng/ml (0.1 mg/kg), 39 +/- 6 ng/ml (0.25 mg/kg), or 71 +/- 11 ng/ml (1.0 mg/kg) over the saline control value of 3.6 +/- 0.6 ng/ml. Mean peak GH levels occurred at 15 min and had returned to near-baseline levels by 75 min. There was no difference in response between sexes. Mean peak cortisol levels were significantly increased (P < 0.05) by 2.2-, 2.7-, and 3.1-fold above control levels (3.0 +/- 0.2 micrograms/dl) at 25-35 min and returned to near-baseline levels by 75 min. PRL was slightly decreased after L-692,429 treatment, whereas LH was not affected. In a second study, three groups of three male beagles each were administered 5.0 mg/kg L-692,429, iv; iv saline, or 2.2 U/kg ACTH, im. Blood was collected for 8 h posttreatment and assayed for GH, cortisol, ACTH, aldosterone, PRL, insulin, T3, and T4. L-692,429 administration significantly increased (P < 0.05) GH over the control level (6.0 +/- 3.6 ng/ml) to 133 +/- 14 ng/ml by 15 min, with a return to pretreatment levels by 120 min. Cortisol levels were significantly increased (P < 0.05) by 2.0-fold (L-692,429) or 2.9-fold (ACTH) over the saline control peak concentration of 5.6 +/- 1.6 micrograms/dl and were associated with concurrent increases in ACTH levels of 1.2-fold (L-692,429) or 2.1-fold (ACTH) over the saline control peak concentration of 67 +/- 20 pmol/L. Aldosterone, PRL, T3, and T4 were not significantly affected after L-692,429 administration; however, ACTH treatment significantly increased aldosterone (P < 0.05). These data demonstrate that L-692,429 is a novel nonpeptidyl secretagogue that stimulates a marked, but transient, increase in serum GH levels in the dog.(ABSTRACT TRUNCATED AT 400 WORDS)
Hickey
G
G
Department of Basic Animal Science Research, Merck Research Laboratories, Rahway, New Jersey 07065.
Jacks
T
T
Judith
F
F
Taylor
J
J
Schoen
W R
WR
Krupa
D
D
Cunningham
P
P
Clark
J
J
Smith
R G
RG
D000324:Adrenocorticotropic Hormone / Q000097:blood / Q000494:pharmacology; D000450:Aldosterone / Q000097:blood; D000818:Animals; D001552:Benzazepines / Q000008:administration & dosage / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D013006:Growth Hormone / Q000097:blood / Q000378:metabolism*; D006854:Hydrocortisone / Q000097:blood; D007275:Injections, Intravenous; D007328:Insulin / Q000097:blood; D007700:Kinetics; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D011388:Prolactin / Q000097:blood; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D013974:Thyroxine / Q000097:blood; D013997:Time Factors; D014284:Triiodothyronine / Q000097:blood
D001552:Benzazepines; D007328:Insulin; D013777:Tetrazoles; D014284:Triiodothyronine; C081455:L 692429; D000450:Aldosterone; D000324:Adrenocorticotropic Hormone; D011388:Prolactin; D007986:Luteinizing Hormone; D013006:Growth Hormone; D013974:Thyroxine; D006854:Hydrocortisone