Perifusion of rat anterior pituitary cell aggregates, cultured in estrogen-supplemented serum-free medium with 1 nM of the bombesin (BBN)-like peptide, neuromedin C (NMC), significantly stimulates GH and PRL release. This effect is dose-dependently inhibited by the BBN receptor blocker L 686,095-001C002 [an N-pivaloyl-gastrin-releasing-peptide(20-25) alkylamide]. The IC50 was 0.20 nM in the case of the GH response and 0.16 nM in the case of the PRL response. The antagonist has no effect on basal PRL or GH release. [Leu13, psi CH2NH-Leu14]BBN (psi BBN) displays an IC50 of 0.41 microM for inhibiting the GH response and 0.36 microM for inhibiting the PRL response to NMC. At a concentration of 0.5 microM or 5 microM, however, the latter antagonist stimulates PRL and GH release when perifused alone. This stimulatory effect is dose dependent, augments when aggregates are cultured in 1 nM E2 (as is the case for NMC) and is abolished by 2 nM L 686,095-001C002. It is concluded that L 686,095-001C002 is a potent and pure antagonist of pituitary BBN receptors mediating PRL and GH release, whereas psi BBN is a relatively weak antagonist with considerable partial agonist activity.

Amides↗

PubMedDate not supplied

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.

Amino Acid Sequence↗

PubMedDate not supplied

Toward a functional significance of the morphological and functional heterogeneity of rat pituitary gonadotrophs and prolactin cells.

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Animals↗