Disease relevance of Edn1

• Role of the stress-activated protein kinases in endothelin-induced cardiomyocyte hypertrophy [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 [2].
• In different experiments, intracisternal administration of ET-1 (10 pmol) evoked an initial decrease in BP and heart rate (HR), followed by pronounced hypertension, bradycardia, and, in 70% of the animals, death from cardiorespiratory failure [3].
• The role of endothelin-1 and the endothelin B receptor in the pathogenesis of hepatopulmonary syndrome in the rat [4].
• During endotoxemia, liver microcirculation disruption is characterized by a hypersensitivity to the constrictor effects of endothelin 1 (ET-1) [5].

Psychiatry related information on Edn1

• 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 [6].
• Additionally, chronic alcohol consumption down-regulated endothelin B receptor, eNOS protein levels, and eNOS phosphorylation [7].
• Endothelin-1 (ET-1) and nitric oxide are emerging key mediators in the maintenance of mucosal homeostasis, but little is known about these substances in soft oral tissue with alcohol abuse [8].
• Endothelin-like immunoreactive products in the posterior pituitary of the rat were depleted by water deprivation, suggesting a release of ET under physiological conditions [9].
• Drinking behavior stimulated by intravenous infusion of hypertonic saline was significantly inhibited by increases in arterial pressure caused by intravenous infusion of phenylephrine or endothelin-1, and this inhibition of drinking was proportional to the induced increase in pressure [10].

High impact information on Edn1

• A purinoceptor blocker had a greater effect than an endothelin receptor blocker in decreasing endothelially derived vasoconstriction in the isolated perfused rat kidney [11].
• Stimulation with adenosine 5'-triphosphate (ATP), uridine 5'-triphosphate (UTP), acetylcholine, endothelin, A23187 and mechanical stress releases Up(4)A from endothelium, suggesting that Up(4)A contributes to vascular autoregulation [11].
• ET-1 is synthesized by keratinocytes in normal skin and is locally released after cutaneous injury [12].
• Nitric oxide, released from non-adrenergic/non-cholinergic nerves, is considered the principle stimulator of cavernosal smooth muscle relaxation, however, the inhibition of vasoconstrictors (that is, norepinephrine and endothelin-1, refs. 5-9) cannot be ignored as a potential regulator of penile erection [13].
• Several hypertrophic agonists, such as angiotensin II, phenylephrine, and endothelin-1, have been shown to promote the sarcomere organization [14].

Chemical compound and disease context of Edn1

• We have recently reported that endothelin-1 (ET-1) mediates angiotensin II-induced hypertrophy of cardiomyocytes as an autocrine/paracrine factor [2].
• Extracellular signal-regulated kinase plays an essential role in hypertrophic agonists, endothelin-1 and phenylephrine-induced cardiomyocyte hypertrophy [15].
• Accumulating evidence suggests that endothelin (ET) contributes to the pathophysiology of such disorders as acute renal failure, cyclosporine-mediated renal and vascular toxicity, and perhaps even glomerular inflammation [16].
• In addition, the effect of the specific endothelin type A receptor antagonist FR 139317 on FK 506-induced hypertension in rats was studied [17].
• Endothelin-1, a potent vasoconstrictor and regulator of sodium reabsorption in the nephron, has a pathophysiological potential in the development of hypertension [18].

Biological context of Edn1

• These data indicate that endothelin-mediated spatiotemporal control of rhythmic tubular contractility might be operated by Sertoli cells through the cyclic expression of ECE-1, which is, in turn, dependent upon the timing of spermatogenesis [19].
• Blood pressure (BP) was monitored intra-arterially, and cerebrospinal fluid (CSF) was collected through an intracisternal catheter for radioimmunoassay of endothelin-1 (ET-1) [3].
• Saturation and competition binding experiments have shown that neonatal cardiac membranes from both atria and ventricle have two distinct binding sites for endothelin, that is, a low-affinity and a high-affinity site [20].
• The shift of ET-1-mediated effects toward vasoconstriction may result from depressed ET-1-mediated vasodilation through decreased ET-1-induced nitric oxide (NO) production [5].
• Furthermore, 6 hours of ET-1 treatment exerted the same effects on eNOS activity, phosphorylation, and CAV-1 expression as LPS treatment [5].

Anatomical context of Edn1

• Endothelin (ET)-3 stimulates cyclic guanosine 3',5'-monophosphate production via ETB receptor by producing nitric oxide in isolated rat glomerulus, and in cultured rat mesangial cells [21].
• ET-1 also induced a significant increase in atrial natriuretic factor mRNA expression as well as in the percentage of cells with highly organized sarcomeres, responses which were also blocked by expression of SEK-1(KR) [1].
• The potent smooth muscle agonist endothelin-1 (ET-1) is involved in the local control of seminiferous tubule contractility, which results in the forward propulsion of tubular fluid and spermatozoa, through its action on peritubular myoid cells [19].
• Endothelin-1 inhibits endothelin-converting enzyme-1 expression in cultured rat pulmonary endothelial cells [22].
• However, mRNA for ET-1 was significantly increased in activated lipocytes, suggesting an autocrine loop for the initiation of lipocyte contraction [23].

Associations of Edn1 with chemical compounds

• The effects of ET-1 on ECE-1 mRNA and protein expression were shown to be mimicked by ionomycin, a calcium ionophore, but not by 12-O-tetradecanoylphorbol 13-acetate, a protein kinase C activator [22].
• Endothelin (ET), a potent vasoconstrictor peptide, is known to enhance the secretion of atrial natriuretic factor (ANF) by the heart [24].
• The specificity of the cardiovascular response to endothelin was demonstrated by the inhibitory effects of the receptor antagonist BQ-123 [3].
• In sinoaortic-denervated animals, phenylephrine failed to reduce CSF endothelin levels [3].
• The relevance of endothelin in central cardiovascular function was studied in urethane-anesthetized Sprague-Dawley rats [3].

Physical interactions of Edn1

• Although it is commonly accepted that endothelin-1 binding to endothelial cell ETB receptors stimulates nitric oxide (NO) synthesis and subsequent smooth muscle relaxation, the signaling pathways downstream of ETB receptor activation are unknown [25].
• The ET-1- binding sites were predominantly of ETA subtype since BQ123, but not IRL1038 (ETB receptor subtype agonist), effectively blocked 125I-ET-1 binding [26].
• Protein kinase C and protein tyrosine kinase activity contribute to mitogenic signaling by endothelin-1. Cross-talk between G protein-coupled receptors and pp60c-src [27].
• 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 [28].
• Endothelin receptor subtypes are coupled to adenylate cyclase via different guanyl nucleotide-binding proteins in vasculature [29].

Enzymatic interactions of Edn1

• The proportion of the total p42-MAPK pool phosphorylated in response to ET-1 (50%) was greater than with phenylephrine (20%) [30].
• The p44/42 MAP kinases were phosphorylated in cultured aortic smooth muscle cells and in physiologically contracted aortic vessels stimulated with angiotensin II and endothelin-1 for 5 min [31].
• Endothelin-converting enzyme is a phosphoramidon-sensitive metalloprotease that cleaves big endothelin to the potent vasoconstrictor peptide, endothelin [32].
• Transforming growth factor beta1 signaling in cholangiocytes in vivo was evident by increased phosphorylation and nuclear localization of Smad2, and hepatic endothelin 1 levels correlated directly with liver transforming growth factor beta1 and phosphorylated Smad2 levels [33].

Co-localisations of Edn1

• Double staining procedures showed big endothelin-1 immunoreactivity to be co-localized with alpha-actin immunoreactivity [34].

Regulatory relationships of Edn1

• Endothelin-3 induces hypertrophy of cardiomyocytes by the endogenous endothelin-1-mediated mechanism [2].
• LPS inhibits endothelin-1-induced endothelial NOS activation in hepatic sinusoidal cells through a negative feedback involving caveolin-1 [5].
• U0126 and SB-386023 blocked ET-1 and PE-induced ERK but not p38 and JNK activation in cardiomyocytes [15].
• Interestingly, endothelin-1 activated signaling converges via p38 mitogen-activated protein kinase-dependent mechanism on ETS binding site, whereas this element inhibits extracellular signal-regulated kinase activated transcription [35].
• ET-1 induces cyclooxygenase-2 (COX-2), an enzyme that converts arachidonic acid to pro-inflammatory eicosanoids [36].

Other interactions of Edn1

• LPS significantly inhibited ET-1-mediated eNOS activation [5].
• Antagonizing ET-1 effects and blocking its activation in LPS pretreated SECs decreased the LPS-induced overexpression of CAV-1 as well as the inhibition of ET-1-induced NOS activity [5].
• Endothelin-1-specific activation of B-type natriuretic peptide gene via p38 mitogen-activated protein kinase and nuclear ETS factors [35].
• Dexamethasone decreased ET-1-stimulated PGE2 release and COX-2 protein and mRNA levels [37].
• ET-1 rapidly increased association of EGFR and Shc with glutathione-S-transferase-Grb2 fusion protein [38].

Analytical, diagnostic and therapeutic context of Edn1

• The findings imply that ET-1 may play a role in regulating sinusoidal perfusion through its effect on lipocytes, particularly in injury states [23].
• ET receptors were localized by autoradiography on the surface of atrial myocytes, indicating that contaminating cells were not responsible for 125I-ET-1 binding [24].
• Microinjection of ET-1 (0.5, 1, 2, 4, and 6 pmol/60 nl) into the nucleus of the solitary tract or area postrema produced a decrease in BP and HR [3].
• Endothelin 1 aggravates acute liver injury in perfused livers of rats after treatment with D-galactosamine [39].
• ET-1 gene was induced by ET-1, as revealed with Northern blotting and ET-1 promoter activity assay [40].

References