Endothelin regulation of neuropeptide release from nerve endings of the posterior pituitary (original) (raw)
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Regulatory Peptides, 2004
Based upon the existence of high density of ET-receptors on catecholaminergic neurons of the hypothalamus, we studied the effects of endothelin-1 (ET-1) and endothelin-3 (ET-3) on neuronal norepinephrine (NE) release in the rat posterior hypothalamus. The intracellular pathways and receptors involved were also investigated. Neuronal NE release was enhanced by ET-1 and ET-3 (10 DM). The selective antagonists of subtype A and B ET receptors (ET A , ET B ) (100 DM BQ-610 and 100 DM BQ-788, respectively) abolished the increase induced by ET-1 but not by ET-3. The PLC inhibitor, U73122 (10 AM), abolished ET-1 and ET-3 response. GF-109203X (100 DM) (PKC inhibitor) blocked the increase in NE release produced by ET-3 and partially blocked ET-1 response. The inositol 1,4,5-trisphosphate-induced calcium release inhibitor, 42 AM 2-APB, inhibited the stimulatory effect induced by ET-3 but not by ET-1. The PKA inhibitor, 500 DM H-89, blocked the increase in neuronal NE release evoked by ET-1 but not by ET-3. Our results showed that ET-1 as well as ET-3 displayed an excitatory neuromodulatory effect on neuronal NE release in the rat posterior hypothalamus. ET-1 through an atypical ET A or ET B receptor activated the PLC/PKC signalling pathway as well as the cAMP pathway, whereas ET-3 through a non-ET A /non-ET B receptor activated the phosphoinositide pathway. Both ETs would enhance the sympathoexcitatory response elicited by the posterior hypothalamus and thus participate in cardiovascular regulation. D
AJP: Endocrinology and Metabolism, 2004
The endothelins (ET) have been implicated in vasopressin (AVP) release in vivo and in vitro. The effects of ET in this system are complex, and the net AVP secretory response likely depends on a unique combination of ET isoform, ET receptor subtype, and neural locus. The purpose of these studies was to examine the role of ET receptor subtypes at hypothalamic vs. neurohypophysial sites on somatodendritic and neurohypophysial AVP secretion. Experiments were done in cultured explants of the hypothalamo-neurohypophysial system of Long Evans rats. Either the whole explant (standard) or only the hypothalamus or posterior pituitary (compartmentalized) was exposed to log dose increases (0.01-10 nM) of the agonists ET-1 (ETA selective), ET-3 (nonselective), or IRL-1620 (ETB selective) with or without selective ETA (BQ-123, 2-200 nM) or ETB (IRL-1038, 6-600 nM) receptor antagonism. In standard explants, ET-1 and ET-3 dose-dependently increased, whereas IRL-1620 decreased net AVP release. Hypot...
Molecular and Cellular Endocrinology, 1992
Endothelins (ET-l, ET-Z, ET-3 and vasoactive intestinal contractor, WC> and sarafotoxins (SRTX-b and SRTX-c) appear to bind with high affinity to a homogeneous class of binding sites in cultured rat pituitary cells. All of these ligands seem to interact with the same receptor (ETA-R), except for SRTX-c which apparently binds to a separate receptor. Binding was followed by phosphodiesteric cleavage of phosphoinositides, resulting in the formation of inositol phosphates. No consistent effect on basal or gonadotropin-releasing hormone (GnRH)-induced release of luteinizing hormone (LH) was exerted by ET or SRTX during 2 h of static incubation. On the other hand, both groups of vasoactive peptides inhibited basal and thyrotropin-releasing hormone (TRH)-induced prolactin secretion. Surprisingly, activation of phosphoinositide turnover by TRH in pituitary mammotrophs led to stimulation of prolactin secretion, whereas activation of the same pathway by ET or SRTX resulted in inhibition of prolactin secretion. ET and SRTX stimulated inositol phosphate formation in GH3 cell line and in the gonadotroph-like cell line aT-3 (which is capable of producing the cr subunit of the gonadotrophin& indicating that the peptides interact with both pituitary mammotrophs and gonadotrophs. The very low concentrations (nM range) needed to stimulate phosphoinositide turnover and to inhibit prolactin secretion, as well as the recent finding that ETs are present in the hypothalamo-pituita~ axis suggest that ET might participate in the neuroendocrine modulation of pituitary functions. One such possibility is that ETs might be members of the prolactin inhibiting factors (PIFs) family.
Regulatory Peptides, 1997
The objective of the present study was to investigate whether the endogenous opioids are involved in the control of endothelin-1 release from the pituitary gland. To test this hypothesis we have measured the peripheral plasma concentration of ET-1 as well as the content of immunoreactive ET-1 (irET-1) in the pituitary in response to opioid receptors blockade in euhydrated and 24 h water-deprived Wistar-Kyoto rats. Placebo or naltrexone (50 mg / kg body wt.) were given i.v. in both groups. Trunk blood was collected to determine hematocrit, plasma sodium and ET-1 levels (RIA). Immunostaining of ET-1 in the whole pituitary glands was performed by colloidal gold labeling. The quantitative analysis of irET-1 was carried out under a light microscope using a computerized image analyzer (MultiScan). Results: (1) Twenty-four-hour dehydration resulted in marked increase of peripheral concentration of ET-1. Naltrexone injection induced a significant elevation of ET-1 plasma concentration in both, dehydrated and control animals. (2) The content of irET-1 in anterior and intermediate lobes of the pituitary in dehydrated rats was markedly higher than in control group. (3) Naltrexone injection caused a rapid and significant reduction irET-1 within the anterior, intermediate and posterior lobes in dehydrated and control animals. Conclusions: (1) An elevation of irET-1 in the pituitary gland and peripheral circulation in dehydrated animals may play a role in maintaining of water-electrolyte balance.
Expression and Signal Transduction Pathways of Endothelin Receptors in Neuroendocrine Cells
Frontiers in Neuroendocrinology, 1996
Endothelins (ETs) were initially thought to be primarily involved in the control of cardiovascular activity, but the presence of ETs and their receptors in a wide variety of other tissues has suggested a much broader range of functions. Specific receptors for ETs are found in nonvascular tissues including neuronal, neuroendocrine, and endocrine cells. In addition, immunoreactive ETs are present in the brain, pituitary, and peripheral endocrine tissues. However, the ET levels in hypothalamo-hypophysial portal and peripheral blood are low, suggesting that the ET system participates in neuroendocrine regulation through paracrine and/or autocrine mechanisms. Both ET A and ET B receptors are expressed in the hypothalamus, adrenal, parathyroid glands, pancreas, ovary, uterus, placenta, and prostate, while only ET A receptors are expressed in GT1 neurons, anterior pituitary cells, aT3-1 immortalized gonadotropes, parathyroid-derived cells, thyrocytes, testicular Leydig and Sertoli cells, normal and neoplastic ovarian granulosa cells, chondrocytes, and other cell types. Activation of ET receptors elicits the sequence of cellular events typical of Ca 21 -mobilizing receptors, with prominent increases in phosphoinositide hydrolysis and elevations of [Ca 21 ] i that occur in oscillatory and nonoscillatory modes depending on the cell type. ET-induced activation of the phosphoinositide/Ca 21mobilizing pathway in neuronal and endocrine cells is associated with rapid stimulation of secretory responses, including release of gonadotropin-releasing hormone, oxytocin, vasopressin, substance P, atrial natriuretic peptides, gonadotropins, thyrotropin, growth hormone, parathyroid hormone, aldosterone, and catecholamines. On the other hand, ET has inhibitory actions on prolactin, progesterone, and renin release. In addition to stimulating phospholipase C-dependent pathways, ETs also activate phospholipase Dand MAP-kinase-dependent pathways in some of their target cells, as well as expression of early response genes and increased mitogenic activity. In many neuroendocrine cells, ET induces rapid and marked desensitization of its signaling system, in association with extensive internalization of ET receptors and reduced signaling and secretory responses. These findings raise the possibility that ETs participate in the control of secretory responses in the hypothalamo-pituitary system and peripheral endocrine cells, as well as in long-term aspects of regulation in certain neuroendocrine cells.
Journal of Neuroscience, 2010
Endothelin (ET-1) given centrally has many reported actions on hormonal and autonomic outputs from the CNS. However, it is unclear whether these effects are due to local ischemia via its vasoconstrictor properties or to a direct neuromodulatory action. ET-1 stimulates the release of oxytocin (OT) and vasopressin (VP) from supraoptic magnocellular (MNCs) neurons in vivo; therefore, we asked whether ET-1 modulates the excitatory inputs onto MNCs that are critical in sculpting the activity of these neurons. To investigate whether ET-1 modulates excitatory synaptic transmission, we obtained whole-cell recordings and analyzed quantal glutamate release onto MNCs in the supraoptic nucleus (SON). Neurons identified as VP-containing neurosecretory cells displayed a decrease in quantal frequency in response to ET-1 (10-100 pM). This decrease was mediated by ET A receptor activation and production of a retrograde messenger that targets presynaptic cannabinoid-1 receptors. In contrast, neurons identified as OT-containing MNCs displayed a transient increase in quantal glutamate release in response to ET-1 application via ET B receptor activation. Application of TTX to block action potentialdependent glutamate release inhibited the excitatory action of ET-1 in OT neurons. There were no changes in quantal amplitude in either MNC type, suggesting that the effects of ET-1 were via presynaptic mechanisms. A gliotransmitter does not appear to be involved as ET-1 failed to elevate astrocytic calcium in the SON. Our results demonstrate that ET-1 differentially modulates glutamate release onto VPversus OT-containing MNCs, thus implicating it in the selective regulation of neuroendocrine output from the SON.
American Journal of Physiology - Regulatory, Integrative and Comparative Physiology, 2002
The existence of endothelin binding sites on the catecholaminergic neurons of the hypothalamus suggests that endothelins (ETs) participate in the regulation of noradrenergic transmission modulating various hypothalamic-controlled processes such as blood pressure, cardiovascular activity, etc. The effects of ET-1 and ET-3 on the neuronal release of norepinephrine (NE) as well as the receptors and intracellular pathway involved were studied in the rat anterior hypothalamus. ET-1 (10 nM) and ET-3 (10 nM) diminished neuronal NE release and the effect blocked by the selective ET type B receptor antagonist BQ-788 (100 nM). N ω-nitro-l-arginine methyl ester (10 μM), methylene blue (10 μM), and KT5823 (2 μM), inhibitors of nitric oxide synthase activity, guanylate cyclase, and protein kinase G, respectively, prevented the inhibitory effects of both ETs on neuronal NE release. In addition, both ETs increased nitric oxide synthase activity. Furthermore, 100 μM picrotoxin, a GABAA-receptor ant...
Endothelin-1 as a neuropeptide: neurotransmitter or neurovascular effects?
Journal of cell communication and signaling, 2010
Endothelin-1 (ET-1) is an endothelium-derived peptide that also possesses potent mitogenic activity. There is also a suggestion the ET-1 is a neuropeptide, based mainly on its histological identification in both the central and peripheral nervous system in a number of species, including man. A neuropeptide role for ET-1 is supported by studies showing a variety of effects caused following its administration into different regions of the brain and by application to peripheral nerves. In addition there are studies proposing that ET-1 is implicated in a number of neural circuits where its transmitter affects range from a role in pain and temperature control to its action on the hypothalamo-neurosecretory system. While the effect of ET-1 on nerve tissue is beyond doubt, its action on nerve blood flow is often ignored. Here, we review data generated in a number of species and using a variety of experimental models. Studies range from those showing the distribution of ET-1 and its recepto...
The Journal of Steroid Biochemistry and Molecular Biology, 1998
The acute effect of endothelin-1 (ET-1) on the hypothalamo±pituitary-adrenal (HPA) axis has been investigated in the rat. The plasma concentrations of arginine±vasopressin (AVP), ACTH, aldosterone and corticosterone have been measured by RIA 30 and 60 min after ET-1 administration. ET-1 (2.0 nmol kg À1 ) raised AVP plasma concentration at both 30 and 60 min. ET-1 did not alter the ACTH plasma level at 30 min, but markedly increased it at 60 min. ACTH response was unaffected by the simultaneous administration of AVP-receptor antagonists (AVP±As) Des±Gly±[Phaa 1 ,D-Tyr(Et) 2 ,Lys 6 ,Arg 8 ]±vasopressin or [Deamino±Pen 1 ,Tyr(Me) 2 ,Arg 8 ]±vasopressin (20 nmol kg À1 ), but abolished by the corticotropin-releasing hormone (CRH)-receptor antagonist a a-helical-CRH(9-41) (a a-CRH, 10 nmol kg À1 ). ET-1 evoked signi®cant rises in the blood levels of aldosterone and corticosterone at both 30 and 60 min. AVP±As abrogated the response at 30 min, while a a-CRH was ineffective. Both AVP±As and a a-CRH partially reversed adrenocortical secretory response at 60 min. Collectively, these ®ndings con®rm that systemically administered ET-1 stimulates rat HPA axis, and provide evidence that the mechanism underlying this effect may involve the sequential activation of AVP and CRH release. #
Endothelin-1 activates ETA receptors to increase intracellular calcium in model sensory neurons
Neuroreport, 2001
Endothelin-1 (ET-1) induces endothelin-A (ET A) receptormediated pain and selective excitation of nociceptors. Here we studied ET-1-induced changes in intracellular calcium (Ca 2 in) in Fura-2 loaded mouse neuroblastoma±rat dorsal root ganglion hybrid cells (ND7/104). ET-1 (1±400 nM) induced concentration-dependent, transient increases in Ca 2 in , probably of intracellular source. Responses to repeated application declined with increasing ET-1 concentration, implying receptor desensitization. Treatment of cells with the selective ET A receptor antagonist, BQ-123, produced a dose-dependent inhibition of the response that was 20% of ET-1 alone (IC50 20 nM, K I 7 nM). No inhibition of the calcium response was observed with the selective ET B antagonist, BQ-788 (10± 1000 nM). These results demonstrate that ET-1 induces doseand ET A receptor-dependent release of Ca 2 in in nociceptorlike neurons, and permit further examination of the pathways that underlie ET-1-induced pain signaling. NeuroReport 12:3853± 3857 & 2001 Lippincott Williams & Wilkins.