Inhibition of CRH-41 release by substance P, but not substance K, from the rat hypothalamus in vitro.

Substance P is one of a series of tachykinins which is present throughout the central nervous system, and has potent effects on neuroendocrine function. Recent studies have suggested that it inhibits pituitary-adrenal activity at a site above the level of the pituitary. We have therefore used a well-validated rat hypothalamic incubation system to investigate the effects of substance P on the release of the principal corticotrophin-releasing hormone, CRH-41. Substance P caused a dose-dependent inhibition of the 28-mM KCl-stimulated release of CRH-41, with a maximum effect at 100 nM (P less than 0.01). This effect was attenuated by 10 microM of the substance P antagonist (D-Pro2,-D-Trp7,9)-substance P. No statistically significant effect of substance K was seen at 1 or 100 nM. Substance P, at a dose of 100 nM, did not alter the 28-mM KCl-stimulated release of CRH-41 from isolated median eminences in vitro. It is concluded that substance P is a potent inhibitor of the stimulated release of CRH-41, probably acting at a site within the hypothalamic paraventricular nucleus.