Release of Substance P from Rat Hypothalamus and Pituitary by Endothelin

Abstract

Endothelin-1 is a 21 amino acid peptide originally isolated from porcine aortic endothelium and has recently been localized within the central nervous system. We have administered endothelin-1 in a dynamic perfusion system in order to study its possible effects on the rat hypothalamus and anterior pituitary. Tissue (hypothalami or quartered pituitaries) was placed into plastic chambers and was perfused with oxygenated Krebs-bicarbonate solution. After an interval to establish stable basal peptide release, endothelin-1 was administered at two doses (0.1 and 1 microM) and the release of substance P, vasoactive intestinal peptide, 7B2, and somatostatin was measured, the last being detectable only in hypothalamic perfusates. Both concentrations of endothelin-1 led to a significant increase (P less than 0.01) in the release of substance P from the hypothalamus and pituitary, but not of vasoactive intestinal peptide, 7B2, or somatostatin. Thus after the 0.1 microM and 1 microM endothelin-1 perfusion substance P release from the hypothalamus increased by 125 +/- 5% and 215 +/- 15% (mean +/- SEM) of basal and from the pituitary by 168 +/- 8% and 276 +/- 15% (mean +/- SEM). No change occurred in the output of ACTH or other pituitary hormones. The release of substance P from hypothalamus or pituitary after stimulation with endothelin-1 was not blocked when a calcium free medium was used. Endothelin-1 binding sites were identified on rat pituitary cell membranes. These findings suggest the possibility that endothelin may act as a paracrine substance, neurotransmitter, or neuromodulator in the hypothalamo-pituitary axis.

Receptors and neurosecretory actions of endothelin in hypothalamic neurons.

“…ET peptides may be involved in the control of vasopressin and oxytocin release from the posterior pituitary (19) and have been shown to promote the release of vasopressin and substance P from hypothalamic slices (27,28) and of luteinizing hormone, follicle-stimulating hormone, and substance P from pituitary cells (15,28 …”

Endothelin-1 and Endothelin-3 Stimulate Prostaglandin E2 Secretion from the Rat Median Eminence.

“…These siological effects on the central nervous system as an autacoid, neurotransmitter or neuromodulator. ET stimulates substance P release from rat hypothalamus and pituitary [ 12] and inhibitis prolactin release from rat pituitary [ 13] in vitro. In the present study, ET stimulated PGE2 release from the rat ME.…”

Hexapeptide and Cyclic Pentapeptide Endothelin Antagonists Directly Activate Pituitary Gonadotropin-Releasing Hormone Receptors

“…Nevertheless, we have shown that these peptides are recognized by the GnRH receptor (Table 3). Furthermore, these ET antagonists stimulate LH release, which is surprising because these peptides are expected to inhibit the ET-induced activation of LH release via the ET A receptor (Calvo et al, 1990;Stojilkovic et al, 1992). A GnRH antagonist (Fig.…”