Adenosine acts by A ₁ receptors to stimulate release of prolactin from anterior-pituitaries in vitro

Abstract

Adenosine has been identified in the anterior pituitary gland and is secreted from cultured folliculostellate (FS) cells. To determine whether adenosine controls the secretion of anterior pituitary hormones in vitro, adenosine was incubated with anterior pituitaries. It stimulated prolactin (PRL) release at the lowest concentration used (10 ؊10 M); the stimulation peaked at 10 ؊8 M with a threefold increase in release and declined to minimal stimulation at 10 ؊4 and 10 ؊3M. Follicle-stimulating hormone release was maximally inhibited at 10 ؊8 M, whereas luteinizing hormone release was not significantly inhibited. Two selective A 1 adenosine receptor antagonists (10 ؊7 or 10 ؊5 M) had no effect on basal PRL release, but either antagonist completely blocked the response to the most effective concentration of adenosine (10 ؊8 M). In contrast, a highly specific A 2 receptor antagonist (10 ؊7 or 10 ؊5 M) had no effect on basal PRL release or the stimulation of PRL release induced by adenosine (10 ؊8 M). We conclude that adenosine acts to stimulate PRL release in vitro by activating A 1 receptors. Since the A 1 receptors decrease intracellularfree calcium, this would decrease the activation of nitric oxide synthase in the FS cells, resulting in decreased release of nitric oxide (NO). NO inhibits PRL release by activating guanylate cyclase that synthesizes cGMP from GTP; cGMP concentrations increase in the lactotrophs leading to inhibition of PRL release. In the case of adenosine, NO release from the FS cells decreases, resulting in decreased concentrations of NO in the lactotrophs, consequent decreased cGMP formation, and resultant increased PRL release. In 1989 Gonzalez et al.(1) presented evidence for a substance of pituitary origin that acts as a trophic agent for hypothalamic dopaminergic neurons. Their findings included the observation that implantation of anterior pituitaries into the brain of rats increased secretory activity of hypothalamic dopaminergic neurons. The secretion of dopamine by dispersed hypothalamic cells in culture was later found to be increased by coincubation with pituitary cells (J. C. Porter, unpublished observations) or by inclusion of pituitary extract in the medium (2). This substance was named pituitary cytotrophic factor (3). Cytotrophic factor produced a dose-and time-related increase in dopamine release as well as the quantity of tryosine hydroxylase mRNA and the enzyme itself. Cytotrophic factor was subsequently identified as adenosine by Porter et al. (4). They hypothesized that adenosine secreted by pituitary cells reached the hypothalamus by retrograde blood flow in the pituitary stalk vasculature (5), where it increased the secretory activity of dopaminergic neurons.Adenosine was secreted by folliculostellate (FS) cells cloned from a pituitary tumor (J. C. Porter, unpublished observations). Therefore, it is plausible that adenosine secreted by such cells may affect the secretion of other pituitary cells. To test this possibility, we conducted studies on the effect of ade...

Stimulatory effects of adenosine on prolactin secretion in the pituitary gland of the rat

“…If we extrapolate this information to our results, we infer that both A1 and A2 receptors occur in the lactotroph since the biphasic effect on PRL secretion was observed at MECA doses of 1 to 10 µM. Recent studies have demonstrated an increase in PRL after administration of an A1 agonist (9) or A2A agonist and a decrease in PRL secretion after administration of an A1 agonist in vitro (10). These apparently contradictory results suggest that the differences may depend on the presence or absence of adenosine in the preparation and/or the type of agonist administered.…”

Folliculostellate cell network: A route for long-distance communication in the anterior pituitary

“…With their long cytoplasmic processes between other cell types, they are in an ideal position to play a role in intercellular communication mechanisms. Although FS cells do not secrete hormones, they are known to release biologically important factors and signaling molecules (e.g., IL-6, nitric oxide, vascular endothelial growth factor, basic fibroblast growth factor, follistatin) (14,29,36) and are responsive to central and peripheral stimuli [e.g., pituitary adenylate cyclaseactivating peptide (PACAP), vasoactive intestinal peptide, estrogens] (37-39) including immune factors (tumor necrosis factor ␣, transforming growth factor ␤3, IFN-␥) (40)(41)(42). Moreover and most remarkably, the FS cell network seems to provide a unique system of large-scale communication that may rapidly adjust cellular activities within the anterior pituitary.…”

Adenosine A1 receptor-mediated inhibition of in vitro prolactin secretion from the rat anterior pituitary

“…This suggests that adenosine has a regulatory action on PRL release via the A 2 receptor, but not under basal conditions. This evidence is reinforced by the fact that two selective A 1 adenosine receptor antagonists and a highly specific A 2 receptor antagonist had no effect on basal PRL release (14).…”