Unexpected effects of peptide and nonpeptide substance P receptor antagonists on basal prolactin and growth hormone release in vitro

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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-Arg 1, d-Phe 5, d-Trp 7,9,Leu 11]Substance P inhibited basal growth hormone (GH) release at a concentration range of 1–10 μ M. At higher concentrations (50 μ M), 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 μ M), neurokinin A (10 μ M), and neurokinin B (3.3 μ M). 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 μ M), R 32602 (10 μ M), and CP-96,345 (10 μ M) 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.