Multiple factors involved in the control of ACTH and alpha-MSH secretion.

Alpha 1-adrenergic agents are potent stimulators of ACTH secretion directly at the pituitary level as observed using anterior pituitary cells in primary culture and by in vivo studies. On the other hand, beta-adrenergic as well as antidopaminergic agents are also potent stimulators of ACTH secretion but at a suprapituitary level, since no effect of these compounds are observed in vitro. CRF administration has been found to lead to rapid and parallel increases in ACTH and alpha-MSH concentrations in rat plasma and the mechanism of action of CRF has been studied in vitro using rat anterior and intermediate lobe of pituitary gland for ACTH and alpha-MSH secretion, respectively. In both cases, CRF stimulates adenylate cyclase activity at ED50 values of 70 and 350 nM for ACTH and alpha-MSH, respectively. CRF stimulates adenylate cyclase activity at least partly through a guanyl nucleotide-dependent mechanism. Using rat pars intermedia cells in culture, we have demonstrated the presence, in addition of a CRF receptor, of a beta 2-adrenergic receptor which stimulates cyclic AMP accumulation and alpha-MSH secretion and of a dopaminergic receptor which inhibits cellular activity. These results have been confirmed in in vivo studies where isoproterenol and thioproperazine (a dopamine antagonist) lead to a rapid increase of alpha-MSH secretion.

Synthesis and central dopaminergic activities of (+/-)-hexahydro-7H-indolo[3,4-gh][1,4]benzoxazine derivatives [(+/-)-9-oxaergolines].

The synthesis and biological activities of a series of (+/-)-hexahydro-7H-indolo[3,4-gh][1,4]benzoxazine derivatives [(+/-)-trans-9-oxaergolines] with central dopamine (DA) agonist properties are described. The compounds were prepared from [2aRS-(2a alpha,4 beta,5 alpha)]-4-amino-1,2,2a,3,4, 5-hexahydro-1-(phenylmethyl)benz[cd]indol-5-ol (6b) by alkaline cyclization of the corresponding N-chloracetamide 7b, followed by reduction of the amido group [5aRS-(5a alpha, 6a beta, 10a alpha)]-4,5,5a,6,6a,7,9, 10a-octahydro-4-(phenylmethyl)-7H-indolo[3,4-gh][1,4]benzoxazin-8-one (8b) with LiAlH4. After debenzylation of the resulting amine 9a, the indoline ring of [5aRS-(5a alpha, 6a beta, 10a alpha)]-4,5,5a,6,6a,8,9, 10a-octahydro-7H-indolo[3,4-gh][1,4 ]benzoxazine (10a) was dehydrogenated with MnO2 to give (+/-)-trans-9-oxaergoline (11a), which can be alkylated on the nitrogen (11b,c and 12) and brominated in position 2 (13a,b). The compounds were examined in vitro for their ability to bind to DA receptors and to inhibit prolactin (PRL) secretion in pituitary cells in culture, in vivo both for their DA stimulant effects at the striatal level (circling in 6-OHDA-lesioned animals, DA turnover, and stereotypy) and inhibitory effects on plasma PRL levels in rats, and for their emetic effects in dogs. Most of the tested compounds were active in these tests, and the potency of (+/-)-trans-6-n-propyl-9-oxaergoline (11c) was comparable to that of pergolide mesylate.

Corticotropin-releasing factor stimulates secretion of melanocyte-stimulating hormone from the rat pituitary.

Administration of synthetic ovine corticotropin-releasing factor led to rapid, parallel increases in adrenocorticotropin and alpha-melanocyte-stimulating hormone concentrations in rat plasma. Prior treatment with dexamethasone almost completely blocked the adrenocorticotropin response but not the increase in melanocyte-stimulating hormone. These data demonstrate that corticotropin-releasing factor is a potent stimulator not only of adrenocorticotropin secretion from the corticotrophs of the anterior pituitary gland but also of peptide secretion from the intermediate lobe. Such data suggest that melanocyte-stimulating hormone and beta-endorphin play a role in the physiological response to stress.

Alpha 1-adrenergic stimulation of ACTH secretion in vivo in the rat.

The alpha-adrenergic agonist phenylephrine (100 micrograms, i.v.) causes a rapid 5- to 10-fold elevation of plasma ACTH levels 5 min after its administration in adult ovariectomized rats, the concentration of the hormone remaining elevated up to at least 2h. Epinephrine (10 micrograms) causes also a rapid but shorter-lived stimulation of ACTH secretion. While having no effect alone under basal conditions (conscious freely-moving animals), the highly specific alpha 1-adrenergic antagonist prazosin (0.25 micrograms) almost completely reverses the stimulatory effect of phenylephrine. Pretreatment with dexamethasone inhibits basal plasma ACTH levels by 70% and almost completely prevents the stimulatory effect of phenylephrine on this parameter. Plasma levels of alpha-MSH, on the other hand, are only stimulated 1-fold above control 5 min after the administration of phenylephrine and are insensitive to corticosteroid treatment. Based on the specificity of action of prazosin on postsynaptic alpha 1-adrenergic receptors and of dexamethasone on the anterior lobe of the pituitary gland, the present data indicate that phenylephrine is a potent stimulator of ACTH secretion by a direct action on an alpha 1-adrenergic receptor in corticotrophs of the adenohypophysis. They also support the suggestion that epinephrine and/or norepinephrine could be involved as physiological corticotropin-releasing factor(s).