Disease relevance of Edn3

• Endothelin-3 induces hypertrophy of cardiomyocytes by the endogenous endothelin-1-mediated mechanism [1].
• These results suggest that endogenous ET-1 locally generated and secreted by cardiomyocytes may contribute to ET-3-induced cardiac hypertrophy as an autocrine/paracrine factor [1].
• BQ-123 inhibits both endothelin 1 and endothelin 3 mediated C6 rat glioma cell proliferation suggesting an atypical endothelin receptor [2].
• The cGMP generation in the glomeruli induced by atrial natriuretic peptide and ET-1 was decreased, whereas the ET-3-induced cGMP generation was increased in rats with nephrotic syndrome [3].
• ET-1 and SRTX-b stimulated an increase in cGMP levels via a Ca2+-dependent NO pathway involving a pertussis toxin-insensitive G protein, whereas ET-3 and SRTX-c elevated cGMP levels via a Ca2+-independent CO pathway involving a pertussis toxin-sensitive G protein [4].

Psychiatry related information on Edn3

• The automated recording of motor activity revealed that, unlike ET (16-21), both ET-1 and ET-3 evoke a dose-regulated increase of the immobility time [5].
• ET-3 (10 nM) showed the response time to peak pulmonary arterial pressure generation by hypoxia, the size of the response being unchanged [6].
• We therefore examined the effects of endothelin-3 (ET-3) on ovulation and secretion of LH, FSH and prolactin in rats in which naturally occurring ovulation was blocked by the administration of sodium pentobarbital (40 mg/kg, i.p.) prior to the critical period (1330 h) on the day of pro-oestrus [7].

High impact information on Edn3

• Loss of Endothelin-3/Endothelin receptor B (EDNRB) signaling leads to aganglionosis of the distal gut (Hirschsprung's disease), but it is unclear whether it is required primarily for neural crest progenitor maintenance or migration [8].
• Interestingly, ET-3-induced skeletal alpha-actin gene expression and [3H]leucine incorporation were inhibited by a synthetic ETA receptor antagonist (BQ123) as well as by antisense oligonucleotides against peproET-1 mRNA [1].
• BQ-123 had no effect on the response to ET-3 (10(-8) M) [9].
• We conclude that ET-3 stimulates NO-induced cGMP generation through ETB receptor in glomerulus [10].
• ETA receptor antagonist BQ123-Na did not inhibit ET-3- or IRL 1620-stimulated cGMP generation [10].

Chemical compound and disease context of Edn3

• Effect of endothelin-1, endothelin-3 and C-terminal hexapeptide, endothelin (16-21) on motor activity in rats [5].
• Treatment with LU135252 reduced hypertension in part, but completely prevented activation of tissue ET-1 without affecting ET-3 levels [11].
• Hypoxia (8% O2) for six hours caused a 55-fold/1.6-fold increase of renal erythropoietin/endothelin-1 gene expression, whereas endothelin-3, PDGF-A, PDGF-B, and VEGF gene expression was unchanged [12].
• Altered microvascular reactivity to endothelin-1, endothelin-3 and NG-nitro-L-arginine methyl ester in streptozotocin-induced diabetes mellitus [13].
• 1 We have determined the dermal microvascular effects of the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 100 nmol/site), endothelin-1 (ET-1, 0.1-10 pmol/site) and ET-3 (0.1-30 pmol/site) in rats with streptozotocin (STZ)-induced diabetes mellitus [13].

Biological context of Edn3

• The characteristics of binding sites for ET-1 and ET-3 were very similar between the atria and the ventricles of the rat neonate [14].
• Here we investigated the effects of both ET-1 and ET-3 on the chemotaxis and replication of fibroblasts derived from pulmonary vessels [15].
• Moreover, both ET-1 and ET-3 dependent vasoconstrictions are slightly attenuated by concomitant NO production [16].
• Endothelin-3 i.c.v. (50 pmol) decreased both heart rate and core temperature (both recorded by telemetry) [17].
• 2. Intra-renal arterial infusion of ET-1 and ET-3, from 1 - 1000 ng had no effect on blood pressure, but reduced renal blood flow maximally by 82 and 81% with EC50 values of 510+/-18 and 1113+/-17 ng, respectively and correspondingly increased renal vascular resistance and decreased conductance [16].

Anatomical context of Edn3

• On the other hand, injection of low concentrations of ET-3 into the nucleus of the solitary tract increased BP and HR (at 2 pmol, 17 +/- 3 mm Hg, 14 +/- 6 beats per minute, n = 7), whereas ET-3 in the area postrema produced a prominent dose-related decrease in BP and HR [18].
• Another, endothelin-3 (ET-3), is not secreted by endothelial cells and is less potent as a pulmonary vasoconstrictor [15].
• 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 [19].
• Both ET-1 and ET-3 induced chemotaxis of pulmonary artery fibroblasts and did so in a dose-dependent fashion [15].
• The pattern of c-fos induced by endothelin-3 and angiotensin II was different (particularly in the anteroventral region of the third ventricle) [17].

Associations of Edn3 with chemical compounds

• METHODS: Levels of ET-1 and ET-3 were determined by radioimmunoassay in ocular tissues of normal rats, and in rats with streptozotocin-induced diabetes of 6 and 12 weeks' duration, insulin-treated and untreated [20].
• Endothelin-3 concentration significantly increased after intravenous injection of capsaicin, whereas ET-1 levels remained unchanged [19].
• Moreover, the effects of ET-1 and ET-3 were completely abolished by the cyclooxygenase inhibitor indomethacin, 2 x 10(-5) M [21].
• Furthermore, prior infusions of endothelin-3 interfered with the expression of c-fos induced by subsequent angiotensin II, and also suppressed the latter's dipsogenic effect [17].
• Et-3 activated N+/H+ exchange activity in a manner that was sensitive to BQ-123 (Ki=6 nM) and FR 139317 (Ki = 0.6 nM) [22].

Physical interactions of Edn3

• The three monoiodo ET-3 derivatives bound to recombinant rat ETB receptors with a pM affinity [23].
• 125I-ET-1 binding was inhibited by ET-1 with an IC50 value of 0.17 nM but was only partially (approximately 60%) inhibited by 1 microM ET-3 [24].
• Furthermore, ET-3 binding in the inner medulla could be blocked with an ETA receptor antagonist in sl/sl rats but not in tissue from sl/+ rats [25].

Regulatory relationships of Edn3

• Compared with ET-1, ET-3 stimulated only a rapid increase of p42 MAP kinase activity [26].
• ET-3-induced ICAM-1 expression on endothelial cells was inhibited by BQ788 but not by S-0139 [27].
• Although ET-3 also activates ETA receptors in smooth muscle to induce contraction, this effect is overcome by the relaxant effect mediated by ETB receptors [28].
• These results indicate that the anterior pituitary cells secrete ET-3 and the secretion is stimulated by IGF-I [29].
• On the other hand, injection of C3 enzyme did not affect increase in cytoplasmic Ca2+ levels induced by ET-3 [30].

Other interactions of Edn3

• The increases in ECE-1, ET-1, and ET-3 and their receptor expression after balloon angioplasty suggest that these proteins play an active role in the pathogenesis of neointimal formation [31].
• [125I]Et-1 binding experiments showed the presence in rat brain capillary endothelial cells of typical ETA receptors that recognized Et-1, BQ-123 and FR139317 but not IRL1620, [Ala1,3.11,15]ET-1 or Et-3 [22].
• ET-3-induced [3H]leucine incorporation, skeletal alpha-actin mRNA and cell surface area were inhibited by a synthetic ETB receptor antagonist (BQ788) [1].
• ET-3 (10(-9)-10(-7) M) increased mRNA level for skeletal alpha-actin with a maximum response after 6 h [1].

Analytical, diagnostic and therapeutic context of Edn3

• Since the response of cardiac hypertrophy is characterized by enhanced expression of fetal isoforms of muscle specific genes, the effect of ET-3 on steady state levels of mRNA for skeletal alpha-actin was evaluated by Northern blot analysis [1].
• A similarly delayed increase in preproET-3 mRNA was observed at 7 days (2.8-fold increase, P < .05) and 14 days (2.6-fold increase, P < .05) after angioplasty [31].
• ET-1 (EC50 = 1.5 x 10(-10) M) and endothelin-3 (ET-3) (10(-11)-3 x 10(-8) M) caused dose-dependent increases in coronary perfusion pressure [32].
• Immunohistochemical distribution of ET-1 and ET-3, ligand binding, and autoradiography to determine ET receptor distribution were carried out [33].
• When either ET-1 or ET-3 was administered to the rat striatum via a microinjection needle, the dopamine release from the striatum dose-dependently increased [34].

References