UNIPROT:P20366 - FACTA Search

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Query: UNIPROT:P20366 (substance P)
21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study compared the effects of endothelin-1 (ET-1), ET-2 and ET-3 on the guinea pig field-stimulated ileum. All ETs (0.3-30 nM) caused graded inhibitions of nerve-mediated responses followed by sustained contractions. The rank order of potencies for the twitch depressor effect (IC50S) was ET-3 = ET-1 greater than ET-2, with ET-3 causing greater maximal inhibition than ET-1 or ET-2. The rank order of potencies for contraction (EC50S) was ET-1 = ET-2 greater than ET-3, with ET-1 causing greater maximal contraction than ET-2 or ET-3. Twitch inhibition by ET-1 (3 nM) was unaffected by indomethacin (5.6 microM), cromakalim (10 microM), glibenclamide (3 microM) or nicardipine (0.1 microM). ET-1-induced contraction was unaltered by tetrodotoxin (0.3 microM), atropine (0.3 microM) or glibenclamide, but was reduced by indomethacin. Cromakalim and nicardipine virtually abolished ET-1-induced contraction. ET-1 (up to 30 nM) did not potentiate submaximal contractions induced by acetylcholine, histamine, bradykinin or substance P. ET-3 relaxed ileal segments precontracted with either acetylcholine (0.3 microM) or histamine (1 microM). Pretreatment of guinea pigs with pertussis toxin (50 micrograms/kg i.p., 6 days beforehand) did not influence either effects of ET-1 on the field-stimulated ileum. Our data suggest that the dual effects of ETs on the guinea pig isolated ileum are mediated by distinct receptors and possibly involve different mechanisms of action. The transient inhibition of responses to field stimulation seems unrelated to activation of ATP-sensitive potassium channels and is rather insensitive to L-type Ca++ channel blockade.
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PMID:Dual effects of endothelins -1, -2 and -3 on guinea pig field-stimulated ileum: possible mediation by two receptors coupled to pertussis toxin-insensitive mechanisms. 137 59

Specific binding sites for 125I-endothelin-1 (125I-ET-1) in the spinal cord were investigated using quantitative receptor autoradiographic and chemical cross-linking methods. The binding sites were highly concentrated in porcine and human spinal cord areas corresponding anatomically to the dorsal horn (Rexed's laminae I-III), an area around the central canal (lamina X) and the principal part of the intermediolateral nucleus (IMLp). The localization of the binding sites differed from those of 125I-omega-conotoxin GVIA (125I-CgTx) and 125I-Bolton-Hunter substance P (125I-BH-SP), with the exception that the IMLp shared 125I-ET-1 with 125I-CgTx and 125I-BH-SP binding sites. Specific 125I-ET-1 binding sites in the areas examined were characteristically single and of high affinity. There were no differences between the potencies of unlabeled ET family peptides, ET-1, ET-2, ET-3 and sarafotoxin S6b at inhibiting 125I-ET-1 binding to the areas. Chemical cross-linking studies showed that 125I-ET-1 and 125I-ET-3 mainly bound to a protein with molecular mass of 43 kDa in the porcine and human thoracic spinal cord membranes. The present finding shows the neuronal significance of this newly discovered peptide in the spinal cord.
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PMID:Specific binding sites for 125I-endothelin-1 in the porcine and human spinal cord. 137 31

We have previously shown that porcine endothelin (ET-1) releases endothelium-derived relaxing factor (EDRF) in the rat isolated perfused mesentery. Here we show that both ET-1 (1-100 pmol) and rat endothelin (ET-3, 1-300 pmol) release EDRF in this preparation and that ET-1 releases EDRF from the luminally perfused aorta of the rabbit. Furthermore, we confirm that, as a pressor agent, ET-1 is greater than 10 times more potent than ET-3. Vasodilatations in the rat isolated perfused mesentery in response to ET-1 and ET-3 were due to the release of EDRF since they were inhibited by removal of the endothelium, methylene blue (100 microM), or hemoglobin (30 microM). ET-3 was more selective than ET-1 as a vasodilator because ET-1 induced vasodilatations were limited and in the higher doses overwhelmed by concurrent vasoconstrictions. Release of EDRF from the rabbit aorta in response to ET-1 but not to other agonists (acetylcholine, substance P, or adenosine diphosphate) was potentiated by infusion of potassium chloride (3 mM). Bay K 8644 failed to release EDRF in either system or to constrict the nondepolarized rat mesentery. Thus, both ET-1 and ET-3 release EDRF by activation of receptors or channels that differ from dihydropyridine-sensitive calcium channels.
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PMID:Endothelin-1 and endothelin-3 release EDRF from isolated perfused arterial vessels of the rat and rabbit. 247 35

In conscious rats, the intrathecal (i.t.) injection of endothelin-1 (ET-1; 65-650 pmol) and endothelin-3 (ET-3; 162-650 pmol) produced dose-dependent increases of mean arterial blood pressure (MAP) accompanied by either a tachycardia or a bradycardia. A number of animals died by a sudden respiratory arrest. ET-3 was less toxic and less potent than ET-1 on MAP and heart rate (HR) while BQ-3020, a selective ETB agonist, had no toxic effect and exhibited only a weak pressor effect on blood pressure. The prior i.t. injection of 65 nmol BQ-123, a selective ETA receptor antagonist, blocked both the cardiovascular and toxic effects of ET-1 but failed to modify the cardiovascular effect evoked by i.t. substance P (6.5 nmol) or to cause intrinsic cardiovascular and toxic effects. While the pressor response to ET-1 was significantly inhibited after i.v. injection of phentolamine, the bradycardia was blocked by pentolinium. The cardiovascular response to ET-1 was, however, unaffected in rats either sympathectomized with 6-hydroxydopamine or pretreated with capsaicin. Furthermore, big ET-1 (100 pmol) caused toxic effects and delayed cardiovascular changes which were prevented by the prior i.t. administration of either BQ-123 (65 nmol) or 100 nmol phosphoramidon, an endothelin-converting enzyme (ECE) inhibitor. These results suggest: (1) that the cardiovascular and toxic effects of i.t. endothelins are mediated by ETA receptors in the rat spinal cord; (2) that the pressor response and bradycardia are likely due to the activation of the sympatho-adrenal nervous system and to a vagal reflex mechanism, respectively; and (3) that a phosphoramidon-sensitive ECE converts big ET-1 to ET-1 in the rat spinal cord.
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PMID:Cardiovascular effects of intrathecally administered endothelins and big endothelin-1 in conscious rats: receptor characterization and mechanism of action. 752 26

Subepithelial fibroblasts of rat duodenal villi were cultured and the physiological characteristics were studied using fura-2 fluorescence. The intracellular calcium concentration (Ca2+i) responded to various substances, i.e., endothelins (ET1 and ET3), substance P, serotonin, angiotensin II, ATP, and bradykinin. The Ca2+i responses to ET1 (> 0.1 nM) and ET3 (> 1 nM) were transient and sometimes followed oscillations that consisted of an initial Ca2+ release from the intracellular store and a sustained Ca2+ influx. Simultaneously with Ca2+i measurement, changes in the cell shape were monitored using fluorescence intensity upon 360-nm excitation. Stellate cells (with thick cell body and slender processes), formed as a result of 1 mM dibutyryl(Bt2)-cAMP treatment, began to change immediately after the short-term application of the endothelin and became flat about 20 min later. This process was not affected by the depletion of extracellular Ca2+ or by the treatment with BAPTA acetoxymethyl ester that completely suppressed the Ca2+i response. Substance P (> 100 nM) increased Ca2+i, but did not induce any morphological changes. The conversion of the shape from flat to stellate, induced by Bt2cAMP treatment, was not accompanied by any Ca2+i change. BQ-123, a specific blocker of the ETA-type receptor, did not block either Ca2+i change or shape conversion at low (100 nM) concentration. The results indicated that shape conversion in subepithelial fibroblasts did not require any Ca2+i response. Our findings regarding the characteristics of subepithelial fibroblasts in intestinal villi imply a functional similarity to astrocytes in the brain.
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PMID:Intracellular calcium responses and shape conversions induced by endothelin in cultured subepithelial fibroblasts of rat duodenal villi. 797 Nov 78

The contractile activity of endothelins (ETs) and their effect on twitch contraction evoked by electrical field stimulation were studied in the isolated rabbit iris sphincter and dilator muscles using the isometric tension recording method. ET-1, ET-2 and ET-3 caused slow contractile response of the sphincter as well as the dilator muscles, with sphincter muscle EC50 values of 37.3, 58.0 and 84.3 nM, and dilator muscle values of 31.7, 69.0 and 224.4 nM, respectively. These contractile responses were not affected by atropine (1 microM), prazosin (1 microM) or indomethacin (1 microM). ET-1 and ET-3 slightly but significantly inhibited the fast cholinergic component of twitch contraction of the sphincter muscle evoked by field stimulation, without affecting the response to carbachol. However, ET-1 did not affect the slow substance P-ergic component of twitch contraction of this preparation. In the dilator muscle, ET-1 and ET-3 had little effect on the contraction induced by phenylephrine but reduced the amplitude of the twitch contraction evoked by the field stimulation. The inhibitory effect of ETs on the dilator muscle was antagonized by pretreatment with BQ-123 (100 nM), which is a selective ETA receptor antagonist. Pretreatment with indomethacin (1 microM) also attenuated the inhibitory effect of ETs on the twitch contraction. These results suggest that ETs may have two sites of action, pre- and post-synaptic effects, on the rabbit iris sphincter muscle as well as the dilator muscle. All three ET isopeptides may have direct contractile activity on the smooth muscles of the sphincter as well as the dilator without mediation by prostaglandins or neuronal mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The presence of two sites of action of endothelins in the isolated rabbit iris sphincter and dilator muscles. 813 29

Human endothelin (ET) A receptor (hETAR) is a G-protein-mediated receptor that binds ET1 with high affinity and ET2 and ET3 with lower affinities. ET1 is the most potent endogenous vasoconstrictor known at this time. When expressed in Xenopus laevis oocytes, hETAR is rapidly desensitized after stimulation with ET1. This desensitization lasts 90-110 min. Human neurokinin A (hNKAR) and human serotonin type 2 receptors were also expressed in the Xenopus system for comparison to hETAR. hNKAR desensitizes for 25-35 min, while the serotonin receptor does not appear to desensitize. To examine the role of the cytoplasmic tail of hETAR in desensitization, deletion mutations were constructed which remove 11, 36, and 51 amino acids from the cytoplasmic tail. The mutations removing 11 and 36 residues were functional, but the mutation removing 51 amino acids was not functional. The two functional mutations have a resensitization time similar to that of hETAR. In summary, the prolonged desensitization time of hETAR is unique for G-protein-mediated receptors and may attenuate the adverse physiological effects of the endothelin family. In addition, the cytoplasmic tail of hETAR does not appear to play a role in desensitization or resensitization of this receptor.
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PMID:Prolonged desensitization of the human endothelin A receptor in Xenopus oocytes. Comparative studies with the human neurokinin A receptor. 825 20

The effects of endothelin-1 (ET-1) on protein synthesis and phosphoinositide (PI) hydrolysis were investigated in ventricular myocytes isolated by collagenase digestion of adult rat hearts. The maximum stimulation of protein synthesis by ET-1 was about 35% and the EC50 value was about 0.3 nM. The stimulation was exerted at the translational stage since it was insensitive to inhibition by actinomycin D. The maximum stimulation of PI hydrolysis by ET-1 as measured by the formation of [3H]inositol phosphates was about 11-fold and the EC50 value was about 0.7 nM. The ET-1 analogue sarafotoxin-6b stimulated protein synthesis by a maximum of 27% and stimulated PI hydrolysis about 8- to 9-fold. The EC50 values were 1.6 nM and 0.6 nM, respectively. Other endothelins stimulated protein synthesis and PI hydrolysis in the following order of potency: ET-1 approximately ET-2 > ET-3. This order of potency suggests that the stimulation of both protein synthesis and PI hydrolysis is mediated through the ETA receptor. Although both angiotensin II and [Arg]vasopressin stimulated PI hydrolysis significantly, the stimulation was less than 60%, i.e., much less than the stimulation by ET-1 and its analogues. Neither insulin nor substance P stimulated PI hydrolysis. Stimulation of protein synthesis by ET-1 and its analogues correlated strongly with the stimulation of PI hydrolysis and we suggest that the stimulation of protein synthesis may be dependent on the stimulation of PI hydrolysis. We hypothesize that the mechanism may involve a protein kinase C-mediated increase in intracellular pH.
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PMID:Stimulation of adult rat ventricular myocyte protein synthesis and phosphoinositide hydrolysis by the endothelins. 838 85

1. The relative contribution of ETA and ETB receptors in the response of rat skin to endothelins was investigated by use of the selective ETB agonist IRL-1620 and the selective ETA antagonist BQ-123. 2. Binding data suggest the presence of ETA and ETB receptors as preincubation with [Ala3,11,18Nle7]-endothelin-1 reduced ET-1 binding by approximately 40%. 3. Intradermal injection of endothelin-1 (ET-1, 1-10 pmol/site) and ET-3 (3-100 pmol/site) induced a dose-dependent decrease in local blood flow assessed by 133Xe clearance at test sites in rat skin. 4. The endothelin analogue [Ala3,11,18Nle7]-ET-1 (30-1000 pmol/site) induced significant vasoconstriction (P < 0.05) at the highest doses used and the selective ETB receptor agonist, IRL-1620 [Suc[Glu9,Ala11,15] endothelin (8-21)], (0.01-100 pmol/site) acted in a potent manner to induce a significant (P < 0.01) dose-dependent decrease in 133Xe clearance. 5. Co-injection with the selective ETA receptor antagonist, BQ-123 (1 nmol/site), completely abolished the vasoconstriction to ET-1 and partially to ET-3, but had no effect on IRL-1620-induced vasoconstriction. In addition, IRL-1620 responses were not altered at sites treated with submaximal doses of a nitric oxide synthase inhibitor or a prostaglandin synthase inhibitor. 6. ET-1 and IRL-1620 (100 fmol-1 pmol/site) did not induce oedema formation as measured by [125I]-albumin accumulation in the presence or absence of the vasodilator, calcitonin gene-related peptide (CGRP). ET-1 (1-3 pmol/site) inhibited substance P-induced oedema formation and this effect,suggested to be secondary to a vasoconstrictor effect, was significantly reversed by BQ-123 (1 nmol/site).7. The findings in this study indicate that there are ETA and ETB receptors in rat skin and agents which activate either receptor act to mediate a decrease in cutaneous blood flow, but have no effect on increased microvascular permeability.
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PMID:Evidence for ETA and ETB receptors in rat skin and an investigation of their function in the cutaneous microvasculature. 854 85

In addition to their potent vasoconstrictor properties, the endothelins (endothelin-1 and -3) may possess neurotransmitter/neuromediator and neuroendocrine actions. The aim of the present study was to evaluate the role of endothelins (ET) in mediating neurogenic inflammation of cephalic tissues in the rat. For this purpose, bosentan, a specific non-peptide mixed antagonist of ET receptors, was tested in rat models of neurogenic and non-neurogenic plasma extravasation in the dura mater and extracranial tissues (eyelid, conjunctiva, lip, tongue). Bosentan was effective for preventing neurogenic inflammation in the dura mater induced by unilateral electrical stimulation of the trigeminal ganglion or intravenous injection of capsaicin, whereas it was ineffective in extracranial tissues or after injection of substance P (non-neurogenic inflammation). The effect of nerve fiber stimulation on ET plasma concentrations in superior sagittal sinus was measured using selective radioimmunoassays for ET-1 and -3. Endothelin-3 concentration significantly increased after intravenous injection of capsaicin, whereas ET-1 levels remained unchanged. Competition binding assays on microsomal membranes from the trigeminal ganglion revealed a single class of binding sites with equal affinity for ET-1 and ET-3, suggesting a homogenous population of ETB receptors. The role of ETB receptors in mediating inflammation was evidenced by the lack of efficacy of a selective ETA receptor antagonist, in contrast to the full efficacy of a selective ETB receptor antagonist, for preventing neurogenic inflammation induced by unilateral stimulation of the trigeminal ganglion. The role of ETB receptors was finally confirmed by the observation that exogenous administration of the ETB receptor agonist sarafotoxin S6c also induced plasma protein extravasation in the dura mater. This extravasation was not a direct effect of ETB receptor stimulation, because it was inhibited by spantide, a selective tachykinin receptor antagonist. These data strongly suggest that ET, acting through ETB receptors, may play an important role in mediating neurogenic inflammation in the meninges of rats. Since the profile of activity of bosentan is similar to that of the 5-HT1D/B agonists, sumatriptan and ergot alkaloids, one may speculate that ET receptor antagonists might be potentially effective in the treatment of acute migraine attacks.
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PMID:Role of endothelin in mediating neurogenic plasma extravasation in rat dura mater. 874 Jun 9

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