Unexpected effects of peptide and nonpeptide substance P receptor antagonists on basal prolactin and growth hormone release in vitro.
The effect of peptide and nonpeptide substance P antagonists on prolactin (PRL) and growth hormone (GH) secretion was evaluated in three-dimensional rat anterior pituitary cell aggregates. [D-Arg1,D-Phe5,D-Trp7,9,Leu11]Substance P inhibited basal growth hormone (GH) release at a concentration range of 1-10 microM. At higher concentrations (50 microM), the analogue inhibited basal prolactin (PRL) release but provoked a tenfold stimulation of GH release. However, these latter two effects could neither be mimicked nor antagonized by the tachykinins substance P (10 microM), neurokinin A (10 microM), and neurokinin B (3.3 microM). The effects could also not be explained by agonism or antagonism at the level of other receptors (e.g., vasopressin, bombesin, angiotensin II, thyroid hormone-releasing hormone, vasoactive intestinal peptide, dopamine, adrenaline, acetylcholine). Remarkably the nonpeptide substance P antagonists R 30732 (10 microM), R 32602 (10 microM), and CP-96,345 (10 microM) showed a similar inhibition of PRL release and a stimulation of GH release. At a one hundredfold lower concentration, sufficient to block substance P receptors in other tissues. CP-96,345 did not affect PRL or GH release. It is concluded that substance P antagonists, when used at high concentrations, have profound intrinsic activities on PRL and GH release that are not mediated by substance P receptors. The failure of the more potent substance P antagonist, CP-96,345, to influence basal PRL or GH release when used at lower concentrations suggests that endogenous substance P in the anterior pituitary does not play a tonic paracrine role on GH or PRL secretion.
Houben
H
H
Laboratory of Cell Pharmacology, University of Leuven, School of Medicine, Belgium.
Denef
C
C
D000595:Amino Acid Sequence; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D013006:Growth Hormone / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D010903:Pituitary Gland, Anterior / Q000187:drug effects / Q000378:metabolism; D011388:Prolactin / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D018040:Receptors, Neurokinin-1; D017981:Receptors, Neurotransmitter / Q000037:antagonists & inhibitors*; D013373:Substance P / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015320:Tachykinins / Q000494:pharmacology
D001713:Biphenyl Compounds; D010455:Peptides; D018040:Receptors, Neurokinin-1; D017981:Receptors, Neurotransmitter; D015320:Tachykinins; D013373:Substance P; D011388:Prolactin; D013006:Growth Hormone; C066892:CP 96345