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Borovac JA, D'Amario D, Bozic J, Glavas D. Sympathetic nervous system activation and heart failure: Current state of evidence and the pathophysiology in the light of novel biomarkers. World J Cardiol 2020; 12:373-408. [PMID: 32879702 PMCID: PMC7439452 DOI: 10.4330/wjc.v12.i8.373] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Revised: 05/19/2020] [Accepted: 07/19/2020] [Indexed: 02/06/2023] Open
Abstract
Heart failure (HF) is a complex clinical syndrome characterized by the activation of at least several neurohumoral pathways that have a common role in maintaining cardiac output and adequate perfusion pressure of target organs and tissues. The sympathetic nervous system (SNS) is upregulated in HF as evident in dysfunctional baroreceptor and chemoreceptor reflexes, circulating and neuronal catecholamine spillover, attenuated parasympathetic response, and augmented sympathetic outflow to the heart, kidneys and skeletal muscles. When these sympathoexcitatory effects on the cardiovascular system are sustained chronically they initiate the vicious circle of HF progression and become associated with cardiomyocyte apoptosis, maladaptive ventricular and vascular remodeling, arrhythmogenesis, and poor prognosis in patients with HF. These detrimental effects of SNS activity on outcomes in HF warrant adequate diagnostic and treatment modalities. Therefore, this review summarizes basic physiological concepts about the interaction of SNS with the cardiovascular system and highlights key pathophysiological mechanisms of SNS derangement in HF. Finally, special emphasis in this review is placed on the integrative and up-to-date overview of diagnostic modalities such as SNS imaging methods and novel laboratory biomarkers that could aid in the assessment of the degree of SNS activation and provide reliable prognostic information among patients with HF.
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Affiliation(s)
- Josip Anđelo Borovac
- Department of Pathophysiology, University of Split School of Medicine, Split 21000, Croatia
- Working Group on Heart Failure of Croatian Cardiac Society, Zagreb 10000, Croatia
| | - Domenico D'Amario
- Department of Cardiovascular and Thoracic Sciences, IRCCS Fondazione Policlinico A. Gemelli, Universita Cattolica Sacro Cuore, Rome 00168, Italy
| | - Josko Bozic
- Department of Pathophysiology, University of Split School of Medicine, Split 21000, Croatia
| | - Duska Glavas
- Working Group on Heart Failure of Croatian Cardiac Society, Zagreb 10000, Croatia
- Clinic for Cardiovascular Diseases, University Hospital of Split, Split 21000, Croatia
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Becker BK, Speed JS, Powell M, Pollock DM. Activation of neuronal endothelin B receptors mediates pressor response through alpha-1 adrenergic receptors. Physiol Rep 2017; 5:5/4/e13077. [PMID: 28219980 PMCID: PMC5328762 DOI: 10.14814/phy2.13077] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Revised: 11/10/2016] [Accepted: 11/12/2016] [Indexed: 12/20/2022] Open
Abstract
Abnormalities in activity of the endothelin (ET) system have been widely reported in a number of cardiovascular disease states such as hypertension and heart failure. Although the vascular responses to ET are well established, the interaction between ET and other important modulators of blood pressure, such as the sympathetic nervous system, are less understood. Previous reports implicate ET signaling through ET type B (ETB) receptors in increasing neuronal activity. Therefore, we hypothesized that activation of ETB receptors on sympathetic nerves would increase blood pressure through an adrenergic‐mediated mechanism. Thus, we used anesthetized ETB‐deficient rats, which only express functional ETB receptors on adrenergic neurons, and genetic controls, which express functional ETB receptors in vascular tissue and kidney epithelium. We determined the pressor response to the selective ETB receptor agonist sarafotoxin c (S6c). Separate groups of rats were treated with the α1‐adrenergic receptor antagonist prazosin or the β‐adrenergic receptor antagonist propranolol to elucidate the role of adrenergic signaling in mediating the blood pressure response. We observed a dose‐dependent pressor response to S6c in ETB‐deficient rats that was reversed by prazosin treatment and augmented by propranolol. In genetic control rats, the effects of S6c on sympathetic neurons were mostly masked by the direct activity of ETB receptor activation on the vasculature. Heart rate was mostly unaffected by S6c across all groups and treatments. These results suggest that ETB activation on sympathetic neurons causes an increase in blood pressure mediated through α1‐adrenergic receptor signaling.
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Affiliation(s)
- Bryan K Becker
- Division of Nephrology, Department of Medicine, Cardio-Renal Physiology and Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - Joshua S Speed
- Division of Nephrology, Department of Medicine, Cardio-Renal Physiology and Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - Mackenzie Powell
- Division of Nephrology, Department of Medicine, Cardio-Renal Physiology and Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - David M Pollock
- Division of Nephrology, Department of Medicine, Cardio-Renal Physiology and Medicine, University of Alabama at Birmingham, Birmingham, Alabama
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Potential role for ET-2 acting through ETA receptors in experimental colitis in mice. Inflamm Res 2016; 66:141-155. [PMID: 27778057 DOI: 10.1007/s00011-016-1001-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2016] [Revised: 09/20/2016] [Accepted: 10/19/2016] [Indexed: 01/16/2023] Open
Abstract
OBJECTIVE AND DESIGN This study attempted to clarify the roles of endothelins and mechanisms associated with ETA/ETB receptors in mouse models of colitis. MATERIALS AND METHODS Colitis was induced by intracolonic administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS, 1.5 mg/animal) or dextran sulfate sodium (DSS, 3%). After colitis establishment, mice received Atrasentan (ETA receptor antagonist, 10 mg/kg), A-192621 (ETB receptor antagonist, 20 mg/kg) or Dexamethasone (1 mg/kg) and several inflammatory parameters were assessed, as well as mRNA levels for ET-1, ET-2 and ET receptors. RESULTS Atrasentan treatment ameliorates TNBS- and DSS-induced colitis. In the TNBS model was observed reduction in macroscopic and microscopic score, colon weight, neutrophil influx, IL-1β, MIP-2 and keratinocyte chemoattractant (KC) levels, inhibition of adhesion molecules expression and restoration of IL-10 levels. However, A192621 treatment did not modify any parameter. ET-1 and ET-2 mRNA was decreased 24 h, but ET-2 mRNA was markedly increased at 48 h after TNBS. ET-2 was able to potentiate LPS-induced KC production in vitro. ETA and ETB receptors mRNA were increased at 24, 48 and 72 h after colitis induction. CONCLUSIONS Atrasentan treatment was effective in reducing the severity of colitis in DSS- and TNBS-treated mice, suggesting that ETA receptors might be a potential target for inflammatory bowel diseases.
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Lim K, van den Buuse M, Head GA. Effect of Endothelin-1 on Baroreflexes and the Cardiovascular Action of Clonidine in Conscious Rabbits. Front Physiol 2016; 7:321. [PMID: 27516742 PMCID: PMC4963462 DOI: 10.3389/fphys.2016.00321] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Accepted: 07/13/2016] [Indexed: 12/20/2022] Open
Abstract
We studied the influence of pretreatment with endothelin–1 on cardiac baroreflexes and on the effect of clonidine on blood pressure and heart rate. In order to avoid the complication of the direct vasoconstrictor effects of endothelin-1, initial dose-response studies in animals treated with a ganglion blocker were performed. Intravenous administration of 50, 200, and 1200 ng/kg of endothelin-1 produced biphasic changes in blood pressure, consisting of an immediate depressor response, followed by a long lasting and dose-dependent pressor effect (peak response 3 ± 1, 9 ± 3, and 33 ± 5 mmHg, respectively). Thus, the 50 ng/kg dose of endothelin-1 was used in subsequent studies. Conscious rabbits were pretreated on separate days with endothelin-1, either intravenously (50 ng/kg) or intracisternally (10 and 50 ng/kg), or with vehicle. The animals then received an intravenous dose (20 μg/kg) or an intracisternal dose (1 μg/kg) of clonidine and the effects on blood pressure and heart rate were measured. In vehicle-treated rabbits, the intravenous administration of clonidine induced a significant decrease in blood pressure and heart rate (15 min after injection: −15.7 ± 4.7 mmHg and −33 ± 4 b/min, respectively). Similarly, the intracisternal injection of clonidine lowered blood pressure (−16.0 ± 2.5 mmHg), but produced a less pronounced bradycardia (−18 ± 4 b/min). Endothelin pretreatment, either 50 ng/kg centrally or peripherally, had no significant effect on the hypotension or bradycardia produced either by central or peripheral injection of clonidine. At this dose, endothelin by itself did not produce significant changes in blood pressure or heart rate. There was a reduction of the gain of the baroreceptor-heart rate reflex with intracisternal endothelin-1. These results suggest that central 2–adrenoceptor mechanisms involved in clonidine-induced hypotension and bradycardia do not appear to be influenced by activation of endothelin receptors.
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Affiliation(s)
- Kyungjoon Lim
- Neuropharmacology Laboratory, Baker IDI Heart and Diabetes Research Institute Melbourne, VIC, Australia
| | - Maarten van den Buuse
- School of Psychology and Public Health, La Trobe UniversityMelbourne, VIC, Australia; Department of Pharmacology, University of MelbourneMelbourne, VIC, Australia
| | - Geoffrey A Head
- Neuropharmacology Laboratory, Baker IDI Heart and Diabetes Research InstituteMelbourne, VIC, Australia; Department of Pharmacology, Monash UniversityClayton, VIC, Australia
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Nakashima S, Sugita Y, Miyoshi H, Arakawa F, Muta H, Ishibashi Y, Niino D, Ohshima K, Terasaki M, Nakamura Y, Morioka M. Endothelin B receptor expression in malignant gliomas: the perivascular immune escape mechanism of gliomas. J Neurooncol 2015; 127:23-32. [PMID: 26645886 DOI: 10.1007/s11060-015-2017-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2015] [Accepted: 11/23/2015] [Indexed: 12/15/2022]
Abstract
In order to clarify the role of endothelin B receptors (ETBRs) in gliomas, we analyzed cell cultures and surgical specimens of gliomas using RT-PCR and immunohistochemistry. RT-PCR measured the absolute expression of ETBR mRNA in twelve samples, which included gliomas that were classified using the World Health Organization (WHO) classification system Grade I-IV, as well as two glioblastoma cell lines (CCF-STTG1 and U87-MG). Using immunohistochemistry, 77 glioma specimens were evaluated for their expression of ETBR and infiltrating T lymphocytes, including an analysis of cytotoxic T cells (CTLs) and regulatory T lymphocytes (Tregs). The number of ETBR-positive vessels in the glioblastomas (Grade IV) was significantly higher than in other grades of gliomas (comparisons to Grade IV, Grade I: p = 0.0323, Grade II: p = 0.0009, Grade III: p = 0.0273). The ETBR expression rate (defined as the number of ETBR-positive blood vessels divided by the total number of blood vessels) in the glioblastomas was higher than the ETBR expression rate in the low-grade gliomas (compared to Grade IV, Grade I: p = 0.0132, Grade II: p = 0.0018, Grade III: p = 0.0745). In addition, the cases which had an ETBR expression rate of 50 % or higher exhibited fewer infiltrating CTLs and more infiltrating Tregs compared to the cases with an ETBR expression rate <50 % (CTLs: p = 0.0342; Tregs: p = 0.0175). Isocitrate dehydrogenase 1 (IDH-1) mutations were identified in 21 cases, but there was no correlation between ETBR expression and IDH-1 mutations for any WHO grade. These results suggest that ETBR expression during neo-angiogenesis may interfere with the homing of CTLs around the tumor and be involved in the immune escape mechanism of gliomas.
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Affiliation(s)
- Shinji Nakashima
- Department of Pathology, Kurume University School of Medicine, 67 Asahimachi, Kurume, Fukuoka, 830-0011, Japan. .,Department of Neurosurgery, Kurume University School of Medicine, Kurume, Fukuoka, Japan.
| | - Yasuo Sugita
- Department of Pathology, Kurume University School of Medicine, 67 Asahimachi, Kurume, Fukuoka, 830-0011, Japan
| | - Hiroaki Miyoshi
- Department of Pathology, Kurume University School of Medicine, 67 Asahimachi, Kurume, Fukuoka, 830-0011, Japan
| | - Fumiko Arakawa
- Department of Pathology, Kurume University School of Medicine, 67 Asahimachi, Kurume, Fukuoka, 830-0011, Japan
| | - Hiroko Muta
- Department of Pathology, Kurume University School of Medicine, 67 Asahimachi, Kurume, Fukuoka, 830-0011, Japan
| | - Yukinao Ishibashi
- Department of Pathology, Kurume University School of Medicine, 67 Asahimachi, Kurume, Fukuoka, 830-0011, Japan
| | - Daisuke Niino
- Department of Pathology, Kurume University School of Medicine, 67 Asahimachi, Kurume, Fukuoka, 830-0011, Japan
| | - Koichi Ohshima
- Department of Pathology, Kurume University School of Medicine, 67 Asahimachi, Kurume, Fukuoka, 830-0011, Japan
| | - Mizuhiko Terasaki
- Department of Neurosurgery, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Yukihiko Nakamura
- Department of Neurosurgery, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Motohiro Morioka
- Department of Neurosurgery, Kurume University School of Medicine, Kurume, Fukuoka, Japan
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Abukar Y, May CN, Ramchandra R. Role of endothelin-1 in mediating changes in cardiac sympathetic nerve activity in heart failure. Am J Physiol Regul Integr Comp Physiol 2015; 310:R94-9. [PMID: 26468257 DOI: 10.1152/ajpregu.00205.2015] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Accepted: 10/14/2015] [Indexed: 12/20/2022]
Abstract
Heart failure (HF) is associated with increased sympathetic nerve activity to the heart (CSNA), which is directly linked to mortality in HF patients. Previous studies indicate that HF is associated with high levels of plasma endothelin-1 (ET-1), which correlates with the severity of the disease. We hypothesized that blockade of endothelin receptors would decrease CSNA. The effects of intravenous tezosentan (a nonselective ETA and ETB receptor antagonist) (8 mg·kg(-1)·h(-1)) on resting levels of CSNA, arterial pressure, and heart rate were determined in conscious normal sheep (n = 6) and sheep with pacing-induced HF (n = 7). HF was associated with a significant decrease in ejection fraction (from 74 ± 2% to 38 ± 1%, P < 0.001) and a significant increase in resting levels of CSNA burst incidence (from 56 ± 11 to 87 ± 2 bursts/100 heartbeats, P < 0.01). Infusion of tezosentan for 60 min significantly decreased resting mean aterial pressure (MAP) in both normal and HF sheep (-8 ± 4 mmHg and -4 ± 3 mmHg, respectively; P < 0.05). This was associated with a significant decrease in CSNA (by 25 ± 26% of control) in normal sheep, but there was no change in CSNA in HF sheep. Calculation of spontaneous baroreflex gain indicated significant impairment of the baroreflex control of HR after intravenous tezosentan infusion in normal animals but no change in HF animals. These data suggest that endogenous levels of ET-1 contribute to the baseline levels of CSNA in normal animals, but this effect is absent in HF.
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Affiliation(s)
- Yonis Abukar
- Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville Victoria, Australia; and
| | - Clive N May
- Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville Victoria, Australia; and
| | - Rohit Ramchandra
- Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville Victoria, Australia; and Department of Physiology, The University of Auckland, Auckland, New Zealand
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Kohan DE, Rossi NF, Inscho EW, Pollock DM. Regulation of blood pressure and salt homeostasis by endothelin. Physiol Rev 2011; 91:1-77. [PMID: 21248162 DOI: 10.1152/physrev.00060.2009] [Citation(s) in RCA: 313] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Endothelin (ET) peptides and their receptors are intimately involved in the physiological control of systemic blood pressure and body Na homeostasis, exerting these effects through alterations in a host of circulating and local factors. Hormonal systems affected by ET include natriuretic peptides, aldosterone, catecholamines, and angiotensin. ET also directly regulates cardiac output, central and peripheral nervous system activity, renal Na and water excretion, systemic vascular resistance, and venous capacitance. ET regulation of these systems is often complex, sometimes involving opposing actions depending on which receptor isoform is activated, which cells are affected, and what other prevailing factors exist. A detailed understanding of this system is important; disordered regulation of the ET system is strongly associated with hypertension and dysregulated extracellular fluid volume homeostasis. In addition, ET receptor antagonists are being increasingly used for the treatment of a variety of diseases; while demonstrating benefit, these agents also have adverse effects on fluid retention that may substantially limit their clinical utility. This review provides a detailed analysis of how the ET system is involved in the control of blood pressure and Na homeostasis, focusing primarily on physiological regulation with some discussion of the role of the ET system in hypertension.
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Affiliation(s)
- Donald E Kohan
- Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah 84132, USA.
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Kubota T. Role of vasoactive substances on endometrial and ovarian function. Reprod Med Biol 2007; 6:157-164. [PMID: 29662409 DOI: 10.1111/j.1447-0578.2007.00179.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
In this review, it is proposed that the vasoactive agents endothelin (ET), nitric oxide (NO)/NO synthase (NOS) and carbon monoxide(CO)/heme oxygenase(HO) act directly on human endometrial functions and on ovarian functions in the normal menstrual cycle and in implantation periods. These vasoactive substances are likely to be important autocrine/paracrine factors that regulate a variety of physiological and pathological processes. The main actions of these agents are differentiation and implantation in the endometrial functions, and follicular growth, luteinization and atresia in the ovarian functions, in the tight connection between endometrial and ovarian systems during normal menstrual periods and during implantation (Reprod Med Biol 2007; 6: 157-164).
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Affiliation(s)
- Toshiro Kubota
- Comprehensive Reproductive Medicine, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
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Anita I, Yaira M, María del Rosario G. Endothelin signaling pathways in rat adrenal medulla. Cell Mol Neurobiol 2006; 26:703-18. [PMID: 16897361 PMCID: PMC11881819 DOI: 10.1007/s10571-006-9111-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2005] [Accepted: 09/15/2005] [Indexed: 11/26/2022]
Abstract
1. We further characterized the effect of endothelins (ETs) on receptor-mediated phosphoinositide (PI) turnover, nitric oxide synthase (NOS) activation, and cGMP formation in whole rat adrenal medulla. 2. The PI hydrolysis was assessed as accumulation of inositol monophosphates (InsP(1)) in the presence of 10 mM LiCl in whole tissue and the analysis of inositol-1-phosphate by Dowex anion exchange chromatography. NOS activity was assayed by monitoring the conversion of radiolabeled L-arginine to L-citrulline. Cyclic GMP formation was assessed as accumulation of cGMP in whole tissue in the presence of phosphodiesterase inhibition, and the amount of cGMP formed was determined by radioimmuno-antibody procedure. 3. ET-1 and ET-3 increased PI turnover by 30% in whole adrenal medulla prelabeled with [(3)H] myoinositol. Both ETs isoforms, at equimolar doses, increased NOS activity and cGMP levels in similar degree. The selective ET(B) receptor agonist, IRL-1620, also increased cGMP formation, mimicking the effects of ETs, while IRL-1620 did not alter the PI metabolism. ETs-induced InsP(1) accumulation and cGMP was dependent on extracellular calcium. The effect of ETs on PI turnover was inhibited by neomycin. The L-arginine analogue, N-nitro-L-arginine (L-NAME), and two inhibitors of soluble guanylyl cyclase, methylene blue and ODQ, significantly inhibited the increase in cGMP production induced by ETs or IRL-1620. The selective ET(A) receptor antagonist, BQ 123, inhibited the ETs-induced increase in PI turnover, while the selective ET(B) receptor antagonist, BQ 788, was ineffective. Likewise, BQ 788, significantly inhibited ET-1- or ET-3-induced NOS activation and cGMP generation but not ETs-induced InsP(1) accumulation. 4. Our data indicate that stimulation of PI turnover and NO-induced cGMP generation constitutes ETs signaling pathways in rat adrenal medulla. The former action is mediated through activation of ET(A) receptor, while the latter through the activation of ET(B) receptor. These results support the role of endothelins in the regulation of adrenal medulla function.
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Affiliation(s)
- Israel Anita
- Laboratory of Neuropeptides, School of Pharmacy, UCV, Caracas, Venezuela.
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Yamamoto T, Hirohama T, Uemura H. Endothelin B receptor-like immunoreactivity in podocytes of the rat kidney. ARCHIVES OF HISTOLOGY AND CYTOLOGY 2002; 65:245-50. [PMID: 12389663 DOI: 10.1679/aohc.65.245] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
The distribution of endothelin B receptor (ETBR)-like immunoreactivity in the rat renal glomerulus was investigated using an affinity-purified antibody against a synthetic peptide corresponding to the amino acid residues 425-439 of the rat ETBR. Light microscopy showed ETBR-like immunoreactivity to be localized predominantly near the glomerular blood capillaries. By immunoelectron microscopy using the pre-embedding method, intense immunodeposits indicating ETBR were detected in podocytes, particularly in their foot processes, in contrast with the weak immunoreaction in endothelial cells of the glomerular blood capillaries and in the mesangial cells. In sections stained with the post-embedding method using immunogold particles, positive signals were also found on the plasma membrane of podocyte foot processes as well as the cytoplasm just beneath the cell membrane. These findings suggest that endothelin stimulates ETBR mainly on podocytes, thus resulting in a decrease of the glomerular blood flow and glomerular filtration rates.
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Yip AWC, Krukoff TL. Endothelin-A receptors and NO mediate decrease in arterial pressure during recovery from restraint. Am J Physiol Regul Integr Comp Physiol 2002; 282:R881-9. [PMID: 11832411 DOI: 10.1152/ajpregu.00308.2001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
We investigated the role of central endothelin-A (ET(A)) receptors and nitric oxide (NO) in regulating arterial pressure during restraint stress and recovery from stress. Rats received intracerebroventricular (icv) injections of the ET(A) receptor antagonist BQ123 (24 microg/kg) and were then subjected to two restraint-rest cycles (1 h of restraint and 1 h of rest/cycle). Although mean arterial pressure (MAP) values in BQ123-treated and control rats increased at the onset of restraint and remained elevated during restraint, MAP values in BQ123-treated rats were consistently greater than in control rats. During rest periods, MAP values in control rats decreased to below baseline levels, whereas those in BQ123-treated rats remained significantly higher. NO content was decreased in the brain stems of BQ123-treated compared with control rats after the 4-h protocol. Injections (icv) of the NO synthase (NOS) inhibitor N(G)-nitro-L-arginine (L-NNA) eliminated the decreases in MAP values during rest periods in both BQ123-treated and control rats. Inhibition of neuronal NOS with icv injection of 7-nitroindazole sodium salt resulted in MAP values intermediate between control rats and rats receiving L-NNA. These results support the hypothesis that endothelin acts through ET(A) receptors in the brain, possibly via release of NO, to decrease arterial pressure during restraint and recovery from restraint.
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Affiliation(s)
- Avery W C Yip
- Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada
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Naidoo V, Mahabeer R, Raidoo DM. Cellular distribution of endothelin-1 mRNA in human brain by in situ RT-PCR. Metab Brain Dis 2001; 16:207-18. [PMID: 11769333 DOI: 10.1023/a:1012597128870] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Endothelins (ETs) are a family of potent vasoconstrictor and comitogenic polypeptides consisting of 21-amino acids. Using in situ hybridization, ET-1 mRNA has previously been localized to neuronal cell bodies in fourteen human brain regions. However, because in situ hybridization has a limited detection sensitivity of 20 mRNA copies per cell, ET-1 mRNA may be present in previously undetected areas. Hence, our objective was to localize ET-1 mRNA in specific human brain regions and astrocytic tumours using the more sensitive in situ reverse transcriptase polymerase chain reaction (in situ RT-PCR). Human brain autopsy tissue and surgical cerebral tumour tissue were treated with proteinase K and DNase, followed by RT-PCR using primers specific for ET-1 mRNA and digoxygenin-labelled dUTP in the PCR mixture. The DIG-dUTP was localized with an immunodetection system. We demonstrate ET-1 mRNA labelling in twenty two of the twenty four brain regions studied including those regions in which ET-1 mRNA has been observed by in situ hybridization. In addition, the localization of ET-1 mRNA observed in astrocytomas suggests a role for ET-1 in tumour pathogenesis. In situ RT-PCR has proven to be highly sensitive in its ability to detect low mRNA expression at the cellular level. Our results confirm a role for ET-1 in the human nervous system.
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Affiliation(s)
- V Naidoo
- Department of Pharmacology, Nelson R Mandela School of Medicine, University of Natal, Durban, Congella, South Africa
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Ryu JS, Shin CY, Yang SJ, Lee TS, La HO, Song HJ, Yom YK, Huh IH, Sohn UD. NMDA receptor and NO mediate ET-1-induced behavioral and cardiovascular effects in periaqueductal gray matter of rats. Arch Pharm Res 2001; 24:64-8. [PMID: 11235814 DOI: 10.1007/bf02976495] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Endothelin-1 (ET-1), a novel and potent vasoconstrictor in blood vessel, is known to have some functions in the rat central nervous system (CNS). In order to investigate the central functions of ET-1, ET-1 was administered to the periaqueductal gray area (PAG) of anesthetized rats to induce barrel rolling and increase the arterial blood pressure (ABP). ET-1 had a modulatory effect on central cardiovascular and behavioral control. The selective N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (3 micromol/kg, i.p.) blocked the ET-1 induced responses, and both the nitric oxide synthase (NOS) inhibitor L-NAME (N-nitro-L-arginine methylester 1 mmol/rat) and the nitric oxide (NO) scavenger hemoglobin (15 nmol/rat) had similar effects in reducing the ET-1 (10 pmol/rat)-induced behavioral changes and ABP elevation. However, NO donor sodium nitroprusside (SNP 10 microg, 1 microg/rat) decreased the ET-1 induced ABP elevation, and recovered the ET-1-induced barrel rolling effect that was reduced by MK-801. These results suggest that ET-1 might have neuromodulatory functions such as ABP elevation and barrel rolling induction in the PAG of the rats via the NMDA receptor and NO.
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Affiliation(s)
- J S Ryu
- Department of Pharmacology, College of Pharmacy, Chung Ang University, Seoul, Korea
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Rossi NF, Chen H. PVN lesions prevent the endothelin 1-induced increase in arterial pressure and vasopressin. Am J Physiol Endocrinol Metab 2001; 280:E349-56. [PMID: 11158940 DOI: 10.1152/ajpendo.2001.280.2.e349] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Endothelin (ET) acts within the central nervous system to increase arterial pressure and arginine vasopressin (AVP) secretion. This study assessed the role of the paraventricular nuclei (PVN) in these actions. Intracerebroventricular ET-1 (10 pmol) or the ET(A) antagonist BQ-123 (40 nmol) was administered in conscious intact or sinoaortic-denervated (SAD) Long-Evans rats with sham or bilateral electrolytic lesions of the magnocellular region of the PVN. Baseline values did not differ among groups, and artificial cerebrospinal fluid (CSF) induced no significant changes. In sham-lesioned rats, ET-1 increased mean arterial pressure (MAP) 15.9 +/- 1.3 mmHg in intact and 22.3 +/- 2.7 mmHg in SAD (P < 0.001 ET-1 vs. CSF) rats. PVN lesions abolished the rise in MAP: -0.1 +/- 2.8 mmHg in intact and 0.0 +/- 2.9 mmHg in SAD. AVP increased in only in the sham-lesioned SAD group 8.6 +/- 3.5 pg/ml (P < 0.001 ET-1 vs. CSF). BQ-123 blocked the responses. Thus the integrity of the PVN is required for intracerebroventricularly administered ET-1 to exert pressor and AVP secretory effects.
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Affiliation(s)
- N F Rossi
- Department of Medicine, Wayne State University School of Medicine and John D. Dingell Veterans Affairs Medical Center, Detroit, Michigan 48201, USA.
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15
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Kurihara Y, Kurihara H, Morita H, Cao WH, Ling GY, Kumada M, Kimura S, Nagai R, Yazaki Y, Kuwaki T. Role of endothelin-1 in stress response in the central nervous system. Am J Physiol Regul Integr Comp Physiol 2000; 279:R515-21. [PMID: 10938240 DOI: 10.1152/ajpregu.2000.279.2.r515] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Endothelin (ET)-1 is a 21-amino acid peptide that induces a variety of biological activities, including vasoconstriction and cell proliferation, and its likely involvement in cardiovascular and other diseases has recently led to broad clinical trials of ET receptor antagonists. ET-1 is widely distributed in the central nervous system (CNS), where it is thought to regulate hormone and neurotransmitter release. Here we show that CNS responses to emotional and physical stressors are differentially affected in heterozygous ET-1-knockout mice, which exhibited diminished aggressive and autonomic responses toward intruders (emotional stressors) but responded to restraint-induced (physical) stress more intensely than wild-type mice. This suggests differing roles of ET-1 in the central pathways mediating responses to different types of stress. Hypothalamic levels of ET-1 and the catecholamine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) were both increased in wild-type mice subjected to intruder stress, whereas MHPG levels were not significantly affected in ET-1-knockout mice. Furthermore, immunohistochemical analysis showed that ET-1 and tyrosine hydroxylase, an enzyme in the catecholamine synthesis pathway, were colocalized within certain neurons of the hypothalamus and amygdala. Our findings suggest that ET-1 modulates central coordination of stress responses in close association with catecholamine metabolism.
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Affiliation(s)
- Y Kurihara
- Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Japan.
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Liu BH, Chen HS, Zhou JH, Xiao N. Effects of endotoxin on endothelin receptor in hepatic and intestinal tissues after endotoxemia in rats. World J Gastroenterol 2000; 6:298-300. [PMID: 11819583 PMCID: PMC4723511 DOI: 10.3748/wjg.v6.i2.298] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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17
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Kuwaki T, Kurihara H, Cao WH, Kurihara Y, Unekawa M, Yazaki Y, Kumada M. Physiological role of brain endothelin in the central autonomic control: from neuron to knockout mouse. Prog Neurobiol 1997; 51:545-79. [PMID: 9153073 DOI: 10.1016/s0301-0082(96)00063-9] [Citation(s) in RCA: 94] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Although endothelin (ET) was discovered as a potent vascular endothelium-derived constricting peptide, its presumed physiological and pathophysiological roles are now considered much more diverse than originally though. Endothelin in the brain is thought to be deeply involved in the central autonomic control and consequent cardiorespiratory homeostasis, possibly as a neuromodulator or a hormone that functions locally in an autocrine/paracrine manner or widely through delivery by the cerebrospinal fluid (CSF). This notion is based on the following lines of evidence. (1) Mature ET, its precursors, converting enzymes, and receptors all are detected at strategic sites in the central nervous system (CNS), especially those controlling the autonomic functions. (2) The ET is present in the CSF at concentrations higher than in the plasma. (3) There is a topographical correspondence of ET and its receptors in the CNS. (4) The ET is released by primary cultures of hypothalamic neurons. (5) When ET binds to its receptors, intracellular calcium channels. (6) An intracerebroventricular or topical application of ET to CNS sites elicits a pattern of cardiorespiratory changes accompanied by responses of vasomotor and respiratory neurons. (7) Recently generated knockout mice with disrupted genes encoding ET-1 exhibited, along with malformations in a subset of the tissues of neural crest cell lineage, cardiorespiratory abnormalities including elevation of arterial pressure, sympathetic overactivity, and impairment of the respiratory reflex. Definitive evidence is expected from thorough analyses of knockout mice by applying conventional experimental methods.
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Affiliation(s)
- T Kuwaki
- Department of Physiology, Faculty of Medicine, University of Tokyo, Japan.
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St Rammos K, Koullias GJ, Hatzibougias JD, Argyrakis NP, Panagopoulos PG. Plasma endothelin-1 levels in adult patients undergoing coronary revascularization. CARDIOVASCULAR SURGERY (LONDON, ENGLAND) 1996; 4:808-12. [PMID: 9013015 DOI: 10.1016/s0967-2109(96)00036-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Cardiopulmonary bypass is thought to injure all endothelial cells, mainly by cell-to-cell interaction with activated granulocytes which, augmented by endothelin-1 (ET-1), enhance the generation of superoxide radicals. These radicals on the other hand, may sustain and prolong endothelial injury. In the present study, by means of a magnetic separation radioimmunoassay procedure, ET-1 levels were measured in 10 adult patients undergoing coronary artery bypass surgery, in 10 perioperative phases, in order to reconfirm and further elucidate the effect of cardiopulmonary bypass on endothelial secretion of ET-1. ET-1 levels before cardiopulmonary bypass showed a definite rising trend, especially after median sternotomy. After induction of cardiopulmonary bypass, ET-1 levels increased significantly compared with preoperative values (P < 0.01). ET-1 levels in stable angina patients during and after aortic cross-clamping were strongly and positively correlated with preoperative mean pulmonary artery pressure (r = 0.79, n = 7, P < 0.05 and r = 0.92, n = 7, P = 0.05) respectively. After the first hour in the intensive care unit, ET-1 levels in three patients with unstable angina were considerably higher than in those with stable angina, a fact that deserves further consideration and study.
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Affiliation(s)
- K St Rammos
- Department of Cardiothoracic Surgery, Aristotle University, Medical School, A.H.E.P.A. General Hospital, Thessaloniki, Greece
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Niranjan V, Télémaque S, deWit D, Gerard RD, Yanagisawa M. Systemic hypertension induced by hepatic overexpression of human preproendothelin-1 in rats. J Clin Invest 1996; 98:2364-72. [PMID: 8941655 PMCID: PMC507688 DOI: 10.1172/jci119049] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Endothelin-1 (ET-1) has been implicated in the regulation of vascular tone in various pathological conditions. To examine the effect of in vivo overexpression of the peptide in rats, we prepared recombinant adenovirus stocks encoding the human preproET-1 cDNA (Ad.ET-1) or Escherichia coli lacZ (Ad.betaGal), each driven by cytomegalovirus early promoter. Ad.ET-1 or Ad.betaGal was injected into the caudal vein of rats and the animals were studied under anesthesia 96 h later. Hepatic overexpression of the virus-derived human ET-1 mRNA was accompanied by a 13-fold elevation of liver ET-1 content in the Ad.ET-1 group. Circulating plasma ET-1 levels in the Ad.ET-1 group were sixfold higher than those in the Ad.betaGal group. Mean arterial blood pressure was increased by 28 mmHg in the Ad.ET-1 group as compared with the Ad.betaGal group. In the Ad.ET-1 group, intravenous infusion of the ET(A) receptor antagonist FR 139317 reduced the blood pressure to levels seen in the Ad.betaGal group, whereas the same antagonist did not significantly alter the blood pressure in the Ad.betaGal group. Intravenous infusion of the ET(B) receptor antagonist BQ-788 caused a small but significant increase in blood pressure in both groups. These findings demonstrate that endogenous overexpression of preproET-1, accompanied by an elevation of plasma ET-1 concentrations to the levels seen in pathophysiological states, can cause systemic hypertension through the activation of the ETA receptor.
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Affiliation(s)
- V Niranjan
- Department of Pediatrics, The University of Texas Southwestern Medical Center at Dallas, 75235-9050, USA
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20
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D'Amico M, Dashwood MR, Warner TD. Endothelin-1 and the periaqueductal gray area of the rat: an autoradiographic and functional pharmacological study. Br J Pharmacol 1996; 118:21-6. [PMID: 8733571 PMCID: PMC1909490 DOI: 10.1111/j.1476-5381.1996.tb15361.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
Endothelin-1 (ET-1) injected centrally induces pressor effects and associated haemodynamic changes. Here we have evaluated the effects on systemic and regional cardiovascular parameters of injection of ET-1 into the periaqueductal gray (PAG) area of anaesthetized rats. In addition, we have used the ETA receptor-selective antagonist, FR 139317, the ETB receptor-selective antagonist, BQ-788, and the ETA/ ETB receptor non-selective antagonist, SB 209670, to identify the receptor(s) mediating these effects. We have also used in vitro autoradiography to identify binding sites for ET-1 in the PAG. 2. In vitro autoradiography showed dense binding of [125I]-PD 151242 (for ETA receptors) in the PAG area, with the binding sites being homogeneously distributed within the dorsal, lateral and ventral subregions. Tissues incubated with [125I]-BQ 3020 (for ETB receptors) had little binding. 3. Injection of ET-1 (0.1, 1 and 10 pmol per rat) in the dorsolateral PAG area significantly increased, in a dose-dependent manner the mean arterial blood pressure (MAP). The highest dose of ET-1 (10 pmol) also decreased the heart rate by 18 +/- 1%, n = 6 (P < 0.05). Increases in blood pressure induced by ET-1 (1 pmol; 31 +/- 6.6 mmHg, n = 6) were greatly reduced by pre-administration to the PAG area of FR 139317 (5 nmol per rat) or SB 209670 (3 nmol per rat) (97 and 94%, respectively), but were unaffected by BQ-788 (5 nmol per rat). Similarly, FR 139317 and SB 209670 prevented the decrease in heart rate induced by ET-1 while BQ-788 did not affect it. 4. Injection of ET-1 to the PAG area caused falls in renal blood flow (RBF) as measured by an ultrasonic flow probe, and increased renal vascular resistance (RVR). Pre-treatment of the PAG with FR 139317 or SB 209670, but not with BQ-788, prevented this ET-1-induced effect. 5. Injection of ET-1 (10 pmol) also increased total peripheral resistance (TPR; control, 2.39 +/- 0.2 mmHg ml-1 min 100 g body weight) by 100 +/- 9% (n = 5) and reduced the cardiac output (CO; control, 94.7 +/- 3.1 ml min-1) by 30 +/- 3% (n = 5), as determined by radioactive microspheres. Vascular resistances were increased in other organs, such as skeletal muscle (88 +/- 5%, n = 4), the colon (55 +/- 7%, n = 4) and the stomach (47 +/- 3%, n = 4). Pretreatment of the PAG area with FR 139317 or SB 209670 reduced the increases in TPR and vascular resistance, and the reduction in CO caused by ET-1. BQ-788 did not effect the responses to ET-1. 6. Thus, there are predominantly ETA binding sites within the PAG area and injection of ET-1 into the PAG area causes complex haemodynamic changes which are sensitive to ETA receptor antagonism. ETA receptors are, therefore, the predominant mediators of the actions of ET-1 in the PAG of the rat.
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Affiliation(s)
- M D'Amico
- Institute of Pharmacology and Toxicology, 2nd University of Naples, Italy
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Kajita H, Kotera T, Shirakata Y, Ueda S, Okuma M, Oda-Ohmae K, Takimoto M, Urade Y, Okada Y. A maxi Cl- channel coupled to endothelin B receptors in the basolateral membrane of guinea-pig parietal cells. J Physiol 1995; 488 ( Pt 1):65-75. [PMID: 8568666 PMCID: PMC1156701 DOI: 10.1113/jphysiol.1995.sp020946] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
1. To study endothelin (ET) receptors in guinea-pig stomach, ET-binding assays and in vitro autoradiography were performed on fundic cell suspensions and on sections of the fundus, respectively. ETA and ETB receptor subtypes were found to coexist in the parietal cells. 2. Endothelin 1 (ET-1) added to the (basolateral) bathing solution was found to activate noisy whole-cell Cl- currents within about 1 min in both single, isolated parietal cells and those within gastric glands obtained from the fundus. 3. ET-1-induced Cl- currents were rapidly blocked by a Cl- channel blocker (NPPB) added to the (basolateral) bathing solution in a concentration-dependent manner with a half-maximum inhibition concentration of 33 microM. 4. The anion selectivity sequence of the ET-1-induced conductance was I- > Br- > Cl- > F-, corresponding to Eisenman's sequence I. 5. Changes in extracellular pH between 5 and 8 did not affect the ET-1-induced activation of Cl- currents. 6. Similar activating effects were also observed with ET-3 and a specific ETB receptor agonist (IRL1620). An ETB receptor antagonist (IRL1720) prevented the ET-1 effect, whereas an ETA-selective antagonist (FR139317 or BQ123) failed to antagonize the ET-1 effect. 7. In the whole-cell mode, unitary Cl- channel events could be observed in association with ET-1-activated macroscopic currents. The single-channel conductances were around 200 and 350 pS at negative and positive membrane potentials, respectively. 8. It is concluded that gastric parietal cells of guinea-pig possess pH-insensitive 'maxi' Cl- channels coupled to ETB receptors in the basolateral membrane.
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Affiliation(s)
- H Kajita
- Department of Internal Medicine, Faculty of Medicine, Kyoto University, Japan
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22
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Rossi G, Albertin G, Belloni A, Zanin L, Biasolo MA, Prayer-Galetti T, Bader M, Nussdorfer GG, Palù G, Pessina AC. Gene expression, localization, and characterization of endothelin A and B receptors in the human adrenal cortex. J Clin Invest 1994; 94:1226-34. [PMID: 8083364 PMCID: PMC295207 DOI: 10.1172/jci117440] [Citation(s) in RCA: 63] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
Compelling evidence indicates that the endothelium-derived potent vasoconstrictor endothelin-1 (ET-1) stimulates aldosterone secretion by interacting with specific receptors. Although two different ET-1 receptors have been identified and cloned, the receptor subtype involved in mediating aldosterone secretion is still unknown. Accordingly, we wished to investigate whether the genes of ET-1 and of its receptors A and B are expressed in the normal human adrenal cortex. We designed specific primers for ET-1 and the ETA and ETB receptors genes and developed a reverse transcription polymerase chain reaction (RT-PCR) with chemiluminescent quantitation of the cDNA. In addition, we carried out 125I ET-1 displacement studies with cold ET-1, ET-3 and the specific ETA and ETB ligands BQ123 and sarafotoxin 6C. Localization of each receptor subtype was also investigated by autoradiography. Binding experiments were first individually analyzed by Scatchard and Hofstee plot and then coanalyzed by the nonlinear iterative curve fitting program Ligand. Histologically normal adrenal cortex tissue, obtained from kidney cancer patients (n = 7), and an aldosterone-producing adenoma (APA), which is histogenetically derived from the zona glomerulosa (ZG) cells, were studied. Results showed that the ET-1, ETA and ETB mRNA can be detected by RT-PCR in all adrenal cortices as well as in the APA. The best fitting of the 125I ET-1 displacement binding data was consistently provided by a two-site model both in the normal adrenal cortex (F = 22.1, P < 0.0001) and in the APA (F = 18.4, P < 0.0001). In the former the density (Bmax) of the ETA and ETB subtype was 2.6 +/- 0.5 pmol/mg protein (m +/- SEM) and 1.19 +/- 0.6, respectively. The dissociation constant (Kd) of ET-1, ET-3, S6C, and BQ-123 for each receptor subtype resulted to be within the range reported for human tissue for the ETA and ETB receptors. In the APA tissue the Bmax tended to be lower (1.33 and 0.8 pmol/mg protein, for the ETA and ETB, respectively) but the Kd were similar. Autoradiographic studies confirmed the presence of both receptor subtypes on the ZG as well as on APA cells. Thus, the genes of ET-1 and both its receptor subtypes ETA and ETB are actively transcribed in the human adrenal cortex. Furthermore, both receptor subtypes are translated into proteins in ZG and APA cells.
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Affiliation(s)
- G Rossi
- Department of Clinical Medicine, University of Padova, Italy
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Ishikawa K, Ihara M, Noguchi K, Mase T, Mino N, Saeki T, Fukuroda T, Fukami T, Ozaki S, Nagase T. Biochemical and pharmacological profile of a potent and selective endothelin B-receptor antagonist, BQ-788. Proc Natl Acad Sci U S A 1994; 91:4892-6. [PMID: 8197152 PMCID: PMC43895 DOI: 10.1073/pnas.91.11.4892] [Citation(s) in RCA: 450] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
We describe the characteristics of a potent and selective endothelin (ET) B-receptor antagonist, BQ-788 [N-cis-2,6-dimethylpiperidinocarbonyl-L-gamma-methylleucyl-D -1- methoxycarbonyltryptophanyl-D-norleucine]. In vitro, this compound potently and competitively inhibits 125I-labeled endothelin 1 (ET-1) binding to ETB receptors on human Girardi heart cells (IC50, 1.2 nM) but only poorly inhibits the binding to ETA receptors on human neuroblastoma cell line SK-N-MC cells (IC50, 1300 nM). In isolated rabbit pulmonary arteries, BQ-788 shows no agonist activity up to 10 microM and competitively antagonizes the vasoconstriction induced by an ETB-selective agonist, BQ-3020 (pA2, 8.4). In rat, an ETA-selective antagonist, BQ-123 (1 mg/kg, i.v.), does not affect transient depressor response to ET-1 (0.3 nmol/kg, i.v.) but potently inhibits following sustained pressor response; vice versa, BQ-788 (1 mg/kg, i.v.) abolishes the depressor response, resulting in a rapid onset of apparently enhanced pressor response. Thus, being a potent and selective ETB receptor antagonist, BQ-788 may be considered as a powerful tool for investigating the role of ET in physiological and pathological processes.
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Affiliation(s)
- K Ishikawa
- New Drug Discovery Research Laboratories, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Japan
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Rogerson ME, Cairns HS, Fairbanks LD, Westwick J, Neild GH. Endothelin-1 in the rabbit: interactions with cyclo-oxygenase and NO-synthase products. Br J Pharmacol 1993; 108:838-43. [PMID: 7682141 PMCID: PMC1908050 DOI: 10.1111/j.1476-5381.1993.tb12887.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
1. Endothelin-1 infusion (5-40 pmol kg-1 min-1) in the normal anaesthetized rabbit, produced a dose-dependent increase in mean arterial blood pressure (MAP) and reduced renal blood flow (RBF) and glomerular filtration rate (GFR), when compared with an equivalent infusion of physiological saline. 2. Endothelin, 20 pmol kg-1 min-1, was also assessed in animals pretreated with either indomethacin (2 mg kg-1), methylene blue (1.6 mg kg-1 h-1) or NG-monomethyl L-arginine (L-NMMA, 10 mg kg-1 h-1). 3. The effect of endothelin on MAP and RBF was enhanced (P = 0.05 and < 0.01 respectively) by the cyclo-oxygenase inhibitor, indomethacin, without any significant change in the effect on GFR. 4. Methylene blue and L-NMMA, inhibitors of endothelium-derived relaxant factor (EDRF), enhanced the effect of endothelin on each of the parameters measured (P < 0.01). 5. Our results are consistent with endothelin having a predominant effect on pre-glomerular vascular resistance to reduce GFR. Endothelin appears to stimulate the release of vasodilator prostanoids and EDRF which oppose its effects. Thus endothelin may have an important role in the complex control of GFR in the rabbit.
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Affiliation(s)
- M E Rogerson
- Institute of Urology and Nephrology, University College and Middlesex School of Medicine, Middlesex Hospital, London
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Ritz MF, Stuenkel EL, Dayanithi G, Jones R, Nordmann JJ. Endothelin regulation of neuropeptide release from nerve endings of the posterior pituitary. Proc Natl Acad Sci U S A 1992; 89:8371-5. [PMID: 1325655 PMCID: PMC49920 DOI: 10.1073/pnas.89.17.8371] [Citation(s) in RCA: 27] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
We have investigated the role of endothelin (ET) in the stimulus-secretion coupling mechanism in the posterior pituitary. We report that isolated nerve endings contain immunoreactive endothelin, the level of which is regulated by homeostatic mechanisms involved in control of water balance. ET-1 and ET-3 potentiate vasopressin release induced by depolarization through interaction with specific receptors of the ETA subtype and this response is antagonized by sarafotoxin S6b. The second messenger for this effect, however, remains unknown since the potentiation of depolarization-induced vasopressin release occurs in the absence of an increase in cellular calcium.
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Affiliation(s)
- M F Ritz
- Centre National de la Recherche Scientifique, Strasbourg, France
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Ujiie K, Terada Y, Nonoguchi H, Shinohara M, Tomita K, Marumo F. Messenger RNA expression and synthesis of endothelin-1 along rat nephron segments. J Clin Invest 1992; 90:1043-8. [PMID: 1522212 PMCID: PMC329962 DOI: 10.1172/jci115918] [Citation(s) in RCA: 86] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
The kidney both produces and responds to endothelin. We examined the production and the expression of mRNA of endothelin-1 (ET-1) in tubule suspensions and microdissected nephron segments. ET-1 production was measured by RIA using an ET-1-specific antibody. We applied the reverse transcription and polymerase chain reaction (PCR) technique to detect ET-1 mRNA along the nephron segments. Stimulation of ET-1 production was observed in the presence of FCS and transforming growth factor-beta (TGF-beta) in inner medullary tubules but not in cortical or outer medullary tubule suspensions. Among dissected nephron segments, ET-1 production was observed in glomeruli and inner medullary collecting ducts (IMCD), whereas it was negligible in proximal convoluted tubules (PCT) and medullary thick ascending limbs (MAL). In addition, the PCR product of ET-1 mRNA was also higher in glomeruli and IMCD, whereas it was undetectable in PCT and MAL. Furthermore, FCS and TGF-beta increased ET-1 mRNA in microdissected glomeruli and IMCD. These data clearly demonstrated that the production sites of ET-1 are glomeruli and IMCD among the nephron segments. ET-1 is an autocrine factor in these sites.
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Affiliation(s)
- K Ujiie
- Second Department of Internal Medicine, Tokyo Medical and Dental University, Japan
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Warner TD, Budzik GP, Matsumoto T, Mitchell JA, Förstermann U, Murad F. Regional differences in endothelin converting enzyme activity in rat brain: inhibition by phosphoramidon and EDTA. Br J Pharmacol 1992; 106:948-52. [PMID: 1393292 PMCID: PMC1907670 DOI: 10.1111/j.1476-5381.1992.tb14440.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
1. It has been demonstrated previously that conversion of big endothelin-1 (bET-1) to endothelin-1 (ET-1) is inhibited in vitro and in vivo by phosphoramidon. In addition, ET-1 binding sites and mRNA have been shown within the brain. Here we expand upon our previous observation that rat brain contains phosphoramidon-inhibitable endothelin converting enzyme (ECE) and show that this activity is not uniformly distributed throughout the brain. 2. ECE activity was detected by a bioassay which depended upon the 10,000 fold difference in potency between bET-1 and ET-1 as stimulants of guanosine 3':5'-cyclic monophosphate (cyclic GMP) accumulation in kidney epithelial (PK1) cells of the pig. Data were confirmed by specific enzyme-linked immunosorbent assay (ELISA) employing antibody directed against ET-1/3(17-21). 3. Following homogenization of the whole brain and ultracentrifugation the 100,000 g pellet contained greater than 4 times more ECE activity than the cytosol. Washing of the pellet with KCl (1 M) and extraction with the detergent CHAPS (20 mM) revealed a phosphoramidon-inhibitable ECE within the residual particulate fraction (nominally classified as the cytoskeletal fraction). Phosphoramidon (IC50, approx. 5 microM) or EDTA inhibited the conversion of bET-1 to ET-1 by the cytoskeletal fraction of rat brain by more than 60%.2+ 4. Following dissection of rat brain into olfactory bulb, cerebral cortex, striatum, hippocampus, cerebellum, midbrain (including thalamus), hypothalamus and medulla oblongata (including pons) the greatest ECE was detected in the hypothalamus and medulla oblongata.After fractionation, the ECE-activities in the cytoskeletal fractions prepared from the hypothalamus or medulla oblongata were inhibited concentration-dependently by phosphoramidon or EDTA, with maximum inhibitions of>80% and >70%, respectively.5. These data show that rat brain contains a phosphoramidon- and EDTA-inhibitable ECE which maybe similar to that present in endothelial cells. The localization of this enzyme correlates with published reports of immunoreactive-ET-l, ET-1-binding sites, and messenger RNA for ET-1 in the rat brain, and suggests the presence of the entire synthetic pathway for ET-1.
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Affiliation(s)
- T D Warner
- Department of Pharmacology, Northwestern University Medical School, Chicago, IL 60611
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Abassi ZA, Tate JE, Golomb E, Keiser HR. Role of neutral endopeptidase in the metabolism of endothelin. Hypertension 1992; 20:89-95. [PMID: 1618556 DOI: 10.1161/01.hyp.20.1.89] [Citation(s) in RCA: 138] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Endothelin is a potent vasoconstrictor produced by endothelial cells. Although endothelin has been studied extensively, little is known about its metabolism in vivo. Neutral endopeptidase EC.3.4.24.11 is reported to degrade endothelin in vitro. Therefore, we studied the effect of neutral endopeptidase inhibition by SQ29,072 on plasma levels and urinary excretion of endogenous and exogenous endothelin. Injection of 30 or 60 mg/kg SQ29,072 into anesthetized rats increased the urinary excretion of endothelin nearly 14-fold. The response was maximal during the first 30 minutes of collection and lasted for 90 minutes. The larger dose of inhibitor caused a 37-43% increase (p less than or equal to 0.05) in the plasma concentration of endothelin. Only 0.20 +/- 0.04% of the total radioactivity injected as 125I-endothelin (1 microCi; 1,308 pg) into normal rats was recovered in the urine within 30 minutes. Urinary radioactivity increased to 0.54-0.63% (p less than or equal to 0.05) of the total infused in rats pretreated with SQ29,072. Chromatographic analysis of radioactivity in the urine revealed that intact endothelin accounted for only 6-9% of the total counts in control rats but 50-56% in rats pretreated with the inhibitor. We also studied the effects of another inhibitor of neutral endopeptidase, SQ28,063, on the distribution of radioactivity in the urine, kidney, and lung of rats injected with 125I-endothelin. SQ28,063 increased urinary excretion of labeled endothelin and increased total radioactivity accumulated in the lung and kidney from 157 and 105 pg to 234 and 157 pg, respectively. Intact endothelin accounted for 90% or more of the accumulated counts in both tissues. These results indicate that 1) little circulating endothelin is cleared into the urine, 2) endothelin in the urine is likely of renal origin, and 3) neutral endopeptidase EC.3.4.24.11 plays a major role in the inactivation of endothelin.
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Affiliation(s)
- Z A Abassi
- Hypertension-Endocrine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892
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Terada Y, Tomita K, Nonoguchi H, Marumo F. Different localization of two types of endothelin receptor mRNA in microdissected rat nephron segments using reverse transcription and polymerase chain reaction assay. J Clin Invest 1992; 90:107-12. [PMID: 1321837 PMCID: PMC443068 DOI: 10.1172/jci115822] [Citation(s) in RCA: 162] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Recent studies have revealed that endothelins (ETs) have at least two types of receptors. One receptor has high affinity to ET-1 and ET-2 and low affinity to ET-3 (A type). The other receptor binds almost equally to ET-1, ET-2, and ET-3 (B type). In this study, microlocalization of mRNA coding for the A-type and B-type ET receptors was carried out in the rat kidney using a reverse transcription and polymerase chain reaction assay of individual microdissected renal tubule segments along the nephron, glomeruli, vasa recta bundle, and arcuate arteries. Large signals for the B-type receptor polymerase chain reaction product were detected in the initial and terminal inner medullary collecting duct and the glomerulus, while small signals were found in the cortical collecting duct and outer medullary collecting duct, vasa recta bundle, and arcuate artery. In contrast, A-type receptor mRNA was detected only in the glomerulus, vasa recta bundle, and arcuate artery. Thus, the two ET receptor subtypes are distributed differently along the nephron. This suggests that the two types of receptors and ET families may affect kidney functioning in different ways.
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Affiliation(s)
- Y Terada
- Second Department of Internal Medicine, Tokyo Medical and Dental University, Japan
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Mortensen LH, Fink GD. Captopril prevents chronic hypertension produced by infusion of endothelin-1 in rats. Hypertension 1992; 19:676-80. [PMID: 1592467 DOI: 10.1161/01.hyp.19.6.676] [Citation(s) in RCA: 31] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Endothelin-1 (ET-1), a potent vasoconstrictor peptide synthesized by the vascular smooth muscle endothelium, has been previously shown to produce a sustained, salt-sensitive elevation in mean arterial pressure when chronically infused over a 7-day period into male Sprague-Dawley rats. In addition to other physiological actions, ET-1 has been shown to have potent effects on various renal functions, including renin production. Activation of the renin-angiotensin system, therefore, may contribute to the pressor response induced by ET-1. In this investigation, captopril ([2S]-1-[3-mercapto-2-methylpropionyl]-L-proline), a sulfhydryl-containing angiotensin I converting enzyme inhibitor, was chronically administered to endothelin-infused rats to elucidate the role of the renin-angiotensin system in this animal model of hypertension. Rats were catheterized, housed in metabolic cages, and maintained on a fixed 6.0 meq.day-1 sodium intake throughout the experiment, with daily measurements taken of mean arterial pressure, heart rate, water intake, urine output, and urinary sodium and potassium excretions. Infusion of ET-1 alone at a rate of 5.0 pmol.kg-1.min-1 for 7 days was associated with a significant and sustained increase in mean arterial pressure; concomitant chronic administration of captopril in another group of rats at a rate of 1.0 mg.kg-1.hr-1 prevented the ET-1-induced hypertension. In an additional study, however, increases in plasma angiotensin II concentration were not observed in rats administered ET-1 alone at 5.0 pmol.kg-1.min-1. These results indicate that endothelin-induced hypertension may involve stimulation of the renin-angiotensin system but not an increase in circulating angiotensin II concentration.
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Affiliation(s)
- L H Mortensen
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing 48824
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31
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Salom JB, Torregrosa G, Miranda FJ, Alabadí JA, Alborch E. Comparison of the contractile effects of endothelin-1 and sarafotoxin S6b in goat isolated cerebral arteries. Br J Pharmacol 1992; 106:95-100. [PMID: 1380386 PMCID: PMC1907440 DOI: 10.1111/j.1476-5381.1992.tb14299.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
1. The effects of endothelium-derived endothelin-1 and snake venom-derived sarafotoxin S6b, peptides with striking structural and functional similarities, were examined and compared in isolated middle cerebral arteries of goats. 2. Endothelin-1 and sarafotoxin S6b contracted cerebral arteries in a concentration-dependent manner. The potency of endothelin-1 (EC50 = 4.9 (3.9-6.2) x 10(-10) M) was about ten times higher than that of sarafotoxin S6b (EC50 = 5.5 (4.4-6.9) x 10(-9) M). The tension returned to basal values after repeated washings and contraction with endothelin-1 could be reproduced. Endothelin-1 and sarafotoxin S6b induced further contraction in arteries precontracted with prostaglandin F2 alpha (10(-5) M). 3. Mechanical removal of the endothelium or incubation with indomethacin (10(-5) M) displaced the concentration-response curves to endothelin-1 and, more pronouncedly, to sarafotoxin S6b to the left. The maximum response to sarafotoxin S6b was also increased by either of these two treatments. 4. Incubation in 'nominally' Ca(2+)-free medium attenuated the vasoconstrictor response to endothelin-1 but not to sarafotoxin S6b, which was inhibited after incubation in Ca(2+)-free medium to which EGTA (10(-4) M) had been added. Pretreatment with caffeine (2 x 10(-2) M) in Ca(2+)-free medium abolished responses to endothelin-1 and sarafotoxin S6b. 5. Bay K 8644 (10(-10) M, 10(-8) M) enhanced and nicardipine (10(-10) M, 10(-8) M) inhibited in a concentration-dependent manner vasoconstrictor response to endothelin-1. Response to sarafotoxin S6b was only affected by 10(-8) M Bay K 8644 or nicardipine.6. It is concluded that endothelin-1 and sarafotoxin S6b are potent vasoconstrictors of goat cerebral arteries, having direct effects on smooth muscle which are counteracted by the endothelium through the release of a vasodilatator substance, probably prostacyclin. Both endothelin-l and sarafotoxin S6b depend on extracellular Ca2+ and on intracellular, caffeine-sensitive Ca2+ stores to develop vasoconstriction.However, endothelin-l depends to a larger extent than sarafotoxin S6b on free extracellular Ca2+.
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Affiliation(s)
- J B Salom
- Centro de Investigación, Hospital La Fe, Valencia, Spain
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Abstract
BACKGROUND AND PURPOSE Endothelin is a potent vasoconstrictor in several tissues, including the choroid plexus. The goal of this study was to determine whether endothelin affects the production of cerebrospinal fluid. METHODS Ventriculocisternal perfusion was used to measure the production of cerebrospinal fluid in anesthetized rabbits. Changes in production of cerebrospinal fluid were examined in response to vehicle, intravenous endothelin (alone and in the presence of indomethacin), and intraventricular endothelin. RESULTS Under control conditions, the reduction in production of cerebrospinal fluid in response to endothelin administered intravenously was only modestly greater than that during infusion of vehicle. Because endothelin releases cyclooxygenase products that attenuate the direct effects of endothelin in several tissues, effects of endothelin on the production of cerebrospinal fluid were also examined after inhibition of cyclooxygenase. Production of cerebrospinal fluid in response to 1 micrograms/kg i.v. endothelin was reduced more in animals treated with indomethacin than in untreated animals (-34 +/- 7% [mean +/- SEM] versus -14 +/- 6%, p less than 0.05). Thus, effects of endothelin on the production of cerebrospinal fluid are attenuated by cyclooxygenase products. Finally, responses to intraventricular endothelin were examined. Intraventricular endothelin produced a modest, but significant, reduction in the production of cerebrospinal fluid. CONCLUSIONS In summary, endothelin may play a role in regulation of the brain fluid balance by affecting the rate of production of cerebrospinal fluid, and this effect is modulated by cyclooxygenase products.
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Affiliation(s)
- K A Schalk
- Department of Internal Medicine, University of Iowa College of Medicine, Iowa City 52242
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Withrington PG, Ansari N, Croxton R, de Nucci G, Vane JR. The actions of endothelins-1 and -3 on the vascular and capsular smooth muscle of the isolated blood perfused spleen of the dog. Br J Pharmacol 1992; 105:490-4. [PMID: 1559137 PMCID: PMC1908655 DOI: 10.1111/j.1476-5381.1992.tb14281.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
1. Endothelin-1 (ET-1), endothelin-3 (ET-3) and noradrenaline (NA) were administered as intra-arterial bolus injections into the isolated, blood-perfused spleen of the dog to assess agonist properties and relative molar potencies on the vascular and capsular smooth muscle. 2. An initial small vasodilatation was observed occasionally at low doses (1.0-10 pmol) of ET-1. 3. ET-1, ET-3 and NA all caused graded increases in splenic arterial vascular resistance. The molar ED50 for the splenic vasoconstrictor response to ET-1 was significantly less (P less than 0.001) than that to ET-3; both peptides were significantly more potent as vasoconstrictor agents than NA. The maximum increase in splenic arterial vascular resistance was not significantly different for either ET-1, ET-3 or NA. 4. The time course of the splenic vasoconstrictor response to ET-1 was significantly (P less than 0.01) longer than that to equieffective doses of ET-3 or NA. 5. The splenic vasoconstrictor responses to ET-1 and ET-3 were accompanied by reductions in spleen volume. The rank order of molar potency in causing splenic capsular contraction was ET-1 greater than ET-3 greater than NA. The maximum reduction in splenic volume was significantly greater for NA than for either ET-1 or ET-3. The two peptides (ET-1, ET-3) were equiefficacious in contracting splenic capsular smooth muscle. 6. The high molar potency of ET-1 as a splenic arterial vasoconstrictor, over 1,700 times more potent than NA, suggests that it may play an important local role in the control of splenic haemodynamics.
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Affiliation(s)
- P G Withrington
- Department of Pharmacology, Faculty of Basic Medical Sciences, Queen Mary and Westfield College, London
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Gandhi CR, Stephenson K, Olson MS. A comparative study of endothelin- and platelet-activating-factor-mediated signal transduction and prostaglandin synthesis in rat Kupffer cells. Biochem J 1992; 281 ( Pt 2):485-92. [PMID: 1310601 PMCID: PMC1130711 DOI: 10.1042/bj2810485] [Citation(s) in RCA: 48] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Endothelin-3 (ET-3) stimulated phosphoinositide metabolism and synthesis of prostaglandins in cultured rat Kupffer cells. ET-3-induced hydrolysis of phosphoinositides was characterized by the production of various inositol phosphates and of glycerophosphoinositol. The mechanism of ET-3-stimulated metabolism of phosphoinositides and synthesis of prostaglandins appeared to be distinct from the effect of platelet-activating factor (PAF) on these processes described previously [Gandhi, Hanahan & Olson (1990) J. Biol. Chem. 265, 18234-18241]. On a molar basis ET-3 was significantly more potent than PAF in stimulating phosphoinositide metabolism, e.g. ET-3-induced hydrolysis of phosphoinositides occurred at 1 pM, whereas PAF was ineffective at concentrations less than 1 nM. Upon challenging Kupffer cells with both ET-3 and PAF, an additive stimulation of phosphoinositide metabolism was observed, suggesting that the actions of these factors may be exerted on separate phosphoinositide pools. Treatment of Kupffer cells with pertussis toxin resulted in an inhibition of ET-3-induced phospholipase C activation; in contrast, cholera toxin treatment caused potentiation of ET-3-stimulated phospholipase C activity. Both toxins, however, inhibited PAF-stimulated phospholipase C activity. The present results suggest that the stimulatory effects of ET-3 and PAF on the phosphodiesteric metabolism of phosphoinositides in Kupffer cells require different guanine-nucleotide-binding proteins. Furthermore, the effects of bacterial toxins on ET-3- and PAF-induced phosphoinositide metabolism were not mediated by cyclic AMP. ET-3-induced metabolism of phosphoinositides was inhibited completely in Kupffer cells pretreated with ET-3, suggesting homologous ligand-induced desensitization of the ET-3 receptors. In contrast, similar experiments using PAF showed only a partial desensitization of subsequent PAF-induced phosphoinositide metabolism. In contrast to the increased production of prostaglandins E2 and D2 observed upon stimulation of Kupffer cells with PAF, ET-3 stimulated the biosynthesis of prostaglandin E2 only. Consistent with their additive effects on phosphoinositide metabolism, PAF and ET-3 exhibited an additive stimulation of the synthesis of prostaglandin E2.
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Affiliation(s)
- C R Gandhi
- Department of Biochemistry, University of Texas, San Antonio 78284-7760
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35
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Furuya S, Naruse S, Nakayama T, Nokihara K. Effect and distribution of intravenously injected 125I-endothelin-1 in rat kidney and lung examined by electron microscopic radioautography. ANATOMY AND EMBRYOLOGY 1992; 185:87-96. [PMID: 1736688 DOI: 10.1007/bf00213604] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The morphological effect of endothelin-1 (ET-1) and the distribution of endothelin-binding sites on the kidney and lung was investigated ultrastructually by intravenous injection of [125I]-ET-1 into rats. About 10% decrease of the diameter of glomeruli was observed at 10 min after the injections of ET-1 or [125I]-ET-1 (1.3-2.4 nmole/kg). When localization of [125I]-ET-1 in the kidney was examined by light and electron microscopic radioautography, silver grains were preferably localized on the fenestrated endothelial cells of glomeruli and peritubular capillary endothelial cells. Some grains were also localized on the interdigitating processes of urinary tubules. Quantitative analysis of silver grains in the glomeruli showed that 83% of grains were located on the fenestrated endothelial cells, 12% on the podocytes of visceral cells, and 5% on mesangial cells at 10 min. After 60 min, 50% of silver grains were incorporated into the cytoplasm of fenestrated endothelial cells. In contrast to glomeruli, silver grains were rare on the arteries and large arterioles. However, a few silver grains were often observed on the smooth muscle cells of small arterioles (8-20 microns in diameter). In the lung, 70% of silver grains were located on the alveolar capillary endothelial cells. These results indicate the abundance of ET receptors on the glomerular fenestrated endothelium, peritubular fenestrated endothelium and alveolar capillary endothelium.
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Affiliation(s)
- S Furuya
- National Institute for Physiological Sciences, Okazaki, Japan
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36
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Krsmanović LZ, Stojilković SS, Balla T, al-Damluji S, Weiner RI, Catt KJ. Receptors and neurosecretory actions of endothelin in hypothalamic neurons. Proc Natl Acad Sci U S A 1991; 88:11124-8. [PMID: 1662384 PMCID: PMC53086 DOI: 10.1073/pnas.88.24.11124] [Citation(s) in RCA: 57] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Primary cultures of rat hypothalamic neurons were found to secrete the potent calcium-mobilizing and mitogenic peptide endothelin (ET) and to contain specific ET binding sites with higher affinity for ET-1 and ET-2 than ET-3. ET receptors of similar specificity were also identified in two gonadotropin-releasing hormone (GnRH) neuronal cell lines (GT1-1 and GT1-7). In both primary cultures and GnRH neurons, receptor binding of ETs led to marked and dose-dependent increases of inositol phosphates; inositol bis-, tris-, and tetrakisphosphates increased promptly, reached a peak within 2 min, and returned toward the steady-state levels during the next 10 min. ET-1 was more potent than ET-3 in mobilizing inositol phosphates, consistent with its greater affinity for the ET receptors in these cells. ET also stimulated GnRH secretion from perifused hypothalamic cultures and GnRH cell lines, with a sharp increase followed by a prompt decline to the basal level. These data show that ET is produced in the hypothalamus and acts through calcium-mobilizing ET receptors in normal and transformed secretory neurons to stimulate GnRH release. These actions of locally produced ETs upon GnRH-secreting neurons indicate that the vasoconstrictor peptides have the capacity to regulate neurosecretion and could participate in the hypothalamic control of anterior pituitary function and gonadotropin secretion.
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Affiliation(s)
- L Z Krsmanović
- Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892
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Wada K, Fujii Y, Watanabe H, Satoh M, Furuichi Y. Cadmium directly acts on endothelin receptor and inhibits endothelin binding activity. FEBS Lett 1991; 285:71-4. [PMID: 1648515 DOI: 10.1016/0014-5793(91)80727-k] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The binding of endothelin (ET) to human placenta ET receptor was strongly inhibited by cadmium ions (Cd2+) (IC50 = 2 x 10(-5) M). Experiments with affinity cross-linking showed that the major 40 kDa receptor was inhibited to form a [125I]ET-1/receptor complex. The mode of inhibition was noncompetitive with respect to ET-1. The inhibitory effect of Cd2+ on solubilized ET receptor was partially reversed by the chelating agent, ethylenediaminetetraacetic acid (EDTA), whereas the effect was irreversible for the membrane-associated receptor. The rat aorta contractions by ET were prevented by pretreatment or addition of Cd2+.
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Affiliation(s)
- K Wada
- Department of Molecular Genetics, Nippon Roche Research Center, Kamakura, Japan
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Matsumura K, Abe I, Tsuchihashi T, Tominaga M, Kobayashi K, Fujishima M. Central effect of endothelin on neurohormonal responses in conscious rabbits. Hypertension 1991; 17:1192-6. [PMID: 2045164 DOI: 10.1161/01.hyp.17.6.1192] [Citation(s) in RCA: 47] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
It has been shown that endothelin-1 (ET-1) binding sites exist in the central nervous system and that the injection of intracerebroventricular ET-1 induces a pressor response. Therefore, we determined the neurohormonal and cardiovascular responses to intracerebroventricular ET-1 (25 pmol/kg) in conscious rabbits with chronically instrumented electrodes on the renal sympathetic nerve. Intracerebroventricular ET-1 provoked a prompt increase in arterial pressure and in renal sympathetic nerve activity within 5 minutes, and peak values were obtained at 20 and 40 minutes, respectively. Plasma epinephrine and norepinephrine reached peak values at 5-20 minutes. Plasma vasopressin and plasma glucose levels also increased significantly, but plasma osmolality, hematocrit, and serum sodium and potassium concentrations did not show any changes. Arterial blood gas analysis showed respiratory alkalosis. However, pretreatment with intravenous pentolinium (5 mg/kg), a ganglion blocking agent, abolished these neurohormonal and cardiovascular responses. Conversely, the same dose of intravenous ET-1 (25 pmol/kg) as that used in the intracerebroventricular experiment failed to cause any cardiovascular or renal sympathetic nerve responses. These results suggest that intracerebroventricular ET-1 acts in the central nervous system and causes a pressor response mainly through the enhancement of sympathoadrenal outflow.
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Affiliation(s)
- K Matsumura
- Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan
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Fujii Y, Moreira JE, Orlando C, Maggi M, Aurbach GD, Brandi ML, Sakaguchi K. Endothelin as an autocrine factor in the regulation of parathyroid cells. Proc Natl Acad Sci U S A 1991; 88:4235-9. [PMID: 1852000 PMCID: PMC51633 DOI: 10.1073/pnas.88.10.4235] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Endothelin, originally purified from porcine aortic endothelial cells, is widely distributed in tissues and is recognized as a product of epithelial cells, glial cells, and neurons in addition to endothelial cells. We found evidence by mRNA content and immunoreactivity that this peptide is synthesized in rat parathyroid epithelial cells (PT-r cells) and bovine parathyroid chief cells. The peptide synthesized by PT-r cells comigrated with synthetic endothelin 1 in reverse-phase HPLC and was diluted out in radioimmunoassay in parallel with the synthetic peptide. Bovine parathyroid endothelial cells (BPE-1 cells) did not express this peptide. Preproendothelin 1 mRNA expression by PT-r cells and endothelin 1 peptide production were regulated by calcium. Shifts in extracellular calcium either from high to low concentrations or vice versa elicited similar evanescent increases in expression of mRNA with a peak at 1 h. Synthesis of the peptide seems to be controlled by mRNA expression, and peptide in the medium appears to be continuously degraded or taken up by cells because its concentration in the medium showed a time course similar to that of mRNA expression. PT-r cells also bear a single class of receptors highly specific for endothelin 1, suggesting an autocrine regulation by endothelin 1 of the parathyroid. The facile regulation of endothelin concentrations in the medium by shifts in extracellular calcium concentration and possible autocrine regulation by endothelin 1 suggest that this peptide may mediate, at least in part, effects of calcium on the parathyroid system.
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Affiliation(s)
- Y Fujii
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892
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40
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Nishimura T, Akasu T, Krier J. Endothelin modulates calcium channel current in neurones of rabbit pelvic parasympathetic ganglia. Br J Pharmacol 1991; 103:1242-50. [PMID: 1652345 PMCID: PMC1908065 DOI: 10.1111/j.1476-5381.1991.tb12331.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
1. The effects of endothelin were studied, in vitro, on neurones contained in the rabbit vesical pelvic ganglion by use of intracellular and single-electrode voltage clamp techniques under conditions where sodium and potassium channels were blocked. 2. In the current-clamp experiments, endothelin (1 microM) caused a depolarization followed by a hyperpolarization of the membrane potential. In the voltage-clamp experiments, endothelin (0.01-1 microM) caused an inward current followed by an outward current in a concentration-dependent manner. 3. Membrane conductance was increased during the endothelin-induced depolarization and inward current. Membrane conductance was decreased during the endothelin-induced hyperpolarization and outward current. 4. The endothelin-induced inward and outward currents were not altered by lowering external sodium concentration or raising external potassium concentration. 5. The endothelin-induced inward current was depressed (mean 72%) in a Krebs solution containing nominally zero calcium and high magnesium. These results suggest that a predominent component of the endothelin-induced inward current is mediated by calcium ions. 6. The calcium-insensitive component of the inward current was abolished by a chloride channel blocker, 4-acetamide-4'-isothiocyanostilbene-2,2'-disulphonic acid. The mean reversal potential for the calcium-insensitive component of the inward current was -18 mV. This value is near the equilibrium potential for chloride. Thus, it is presumed that the calcium-insensitive component of the inward current is carried by chloride ions. 7. Endothelin caused an initial depression followed by a long lasting facilitation of both rapidly and slowly decaying components of high-threshold calcium channel currents (N- and L-type). 8. In summary, the data show that for neurones in the vesical pelvic ganglia, endothelin causes membrane depolarization and activates an inward current. The ionic mechanisms involve receptor-operated calcium and chloride currents. Also, endothelin causes an initial depression followed by a long-lasting facilitation of the voltage-dependent calcium current.
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Affiliation(s)
- T Nishimura
- Department of Physiology, Kurume University School of Medicine, Japan
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Shichiri M, Hirata Y, Nakajima T, Ando K, Imai T, Yanagisawa M, Masaki T, Marumo F. Endothelin-1 is an autocrine/paracrine growth factor for human cancer cell lines. J Clin Invest 1991; 87:1867-71. [PMID: 2022753 PMCID: PMC295314 DOI: 10.1172/jci115210] [Citation(s) in RCA: 157] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
We studied whether a novel vasoconstrictor peptide, endothelin-1 (ET-1), is synthesized by and released from human carcinoma cell lines, and whether ET-1 stimulates proliferation of these tumor cells. ET-1-like immunoreactivity was released from both HeLa and HEp-2 cells as a function of time. Reverse-phase HPLC of the conditioned media from HeLa cells revealed a major peak coeluting with standard ET-1. Northern blot analysis demonstrated the expression of mRNA for ET-1 precursor in both tumor cell lines. Both cell lines contained a single class of specific binding sites for ET-1. ET-1 dose-dependently induced increases in cytosolic free Ca2+ concentration in fura-2-loaded tumor cells, whose effect was completely abolished by chelating extracellular Ca2+ or by Ca(2+)-channel blocker. ET-1 stimulated proliferation of the quiescent cell lines in a dose-dependent manner, whose effect was inhibited by Ca(2+)-channel blocker. Polyclonal antibody for ET-1 inhibited proliferation of these cell lines, whereas nonimmune serum had no effect. These results demonstrate that ET-1 is synthesized by and released from human epithelial carcinoma cell lines, and that exogenous and endogenous ET-1 stimulates proliferation of the cells possibly through Ca2+ influx, suggesting its role as an autocrine/paracrine growth factor for certain tumor cells.
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Affiliation(s)
- M Shichiri
- Department of Medicine, Tokyo Medical and Dental University, Japan
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MacNulty EE, Plevin R, Wakelam MJ. Stimulation of the hydrolysis of phosphatidylinositol 4,5-bisphosphate and phosphatidylcholine by endothelin, a complete mitogen for Rat-1 fibroblasts. Biochem J 1990; 272:761-6. [PMID: 2176477 PMCID: PMC1149774 DOI: 10.1042/bj2720761] [Citation(s) in RCA: 61] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
The mitogenic activity of endothelin and its ability to stimulate PtdIns(4,5)P2 and phosphatidylcholine turnover in Rat-1 fibroblasts was studied. Stimulated incorporation of [3H]thymidine occurred in the absence of any other added growth factors. The endothelins stimulated rapid generation of both Ins(1,4,5)P3 and choline. Endothelin-1 and endothelin-2 were equipotent in stimulating both responses, but endothelin-3 was less potent. Endothelin-1-stimulated Ins(1,4,5)P3 generation reached a maximum at 5 s and then declined; however, the response was long-lived, with a 4.5-fold elevation over basal still observed after 15 min. Endothelin-stimulated choline generation was observed with no increase in choline phosphate; indeed, the apparent level of this metabolite fell after 30 min of stimulation, presumably due to the observed stimulation of phosphatidylcholine synthesis. The endothelin-stimulated increase in choline generation was abolished in cells where protein kinase C was down-regulated. However, endothelin-stimulated choline generation was greater than that observed in response to a protein kinase C-activating phorbol ester, raising the possibility that the peptide activates phospholipase D by both protein kinase C-dependent and -independent mechanisms.
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Affiliation(s)
- E E MacNulty
- Department of Biochemistry, University of Glasgow, U.K
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Ehrenreich H, Anderson RW, Fox CH, Rieckmann P, Hoffman GS, Travis WD, Coligan JE, Kehrl JH, Fauci AS. Endothelins, peptides with potent vasoactive properties, are produced by human macrophages. J Exp Med 1990; 172:1741-8. [PMID: 1701822 PMCID: PMC2188743 DOI: 10.1084/jem.172.6.1741] [Citation(s) in RCA: 352] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Endothelins are peptides, originally isolated from endothelial cells, with potent vasoactive and mitogenic properties. In this study, we demonstrate that human macrophages synthesize and secrete endothelins. Cultured human macrophages were found by immunocytochemistry to stain positively for endothelin 1 and endothelin 3. Their capability to produce and release these peptides was confirmed by a combination of reverse-phase high-performance liquid chromatography and radioimmunoassays, specific for endothelin 1 and 3, respectively. Immunoreactive peptides were identified both in cellular extracts and in macrophage-conditioned medium. The secretion of endothelin 1, but not of endothelin 3, from macrophages could be stimulated 6-10-fold by lipopolysaccharide or phorbol myristate acetate (PMA). Northern blot analysis of total macrophage RNA using an endothelin 1 cDNA probe revealed induction of endothelin mRNA in PMA-treated macrophages. Furthermore, immunoreactive endothelin 1 and 3 were found in U937 cells, a human promonocytic line, and in freshly isolated human monocytes. In contrast, no immunoreactive endothelin was detected in cell extracts from human neutrophils and lymphocytes. The expression of endothelins in tissue macrophages was demonstrated in paraffin sections of human lung using immunohistochemistry. In conclusion, the finding that human macrophages produce endothelins suggests an important role for these peptides in the microenvironment of tissue macrophages. Macrophage-derived endothelins may have an essential function in blood vessel physiology, and aberrant production may contribute to vessel pathology.
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Affiliation(s)
- H Ehrenreich
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892
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Lee ME, de la Monte SM, Ng SC, Bloch KD, Quertermous T. Expression of the potent vasoconstrictor endothelin in the human central nervous system. J Clin Invest 1990; 86:141-7. [PMID: 2195059 PMCID: PMC296701 DOI: 10.1172/jci114677] [Citation(s) in RCA: 177] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Endothelin is a potent vasoconstrictive peptide initially characterized as a product of endothelial cells. To examine the potential role of endothelin as a neuropeptide, we studied its distribution in the human central nervous system. RNA blot hybridization provided evidence of endothelin gene transcription in a variety of functional regions of the brain. In situ hybridization confirmed the widespread pattern of endothelin transcription and indicated that the highest density of cells containing endothelin mRNA is in the hypothalamus. This technique localized endothelin transcription to cells of the nervous system as well as the vascular endothelium. Immunocytochemical studies detected endothelin immunoreactivity in neurons, providing evidence of the synthesis of the peptide in this cell type and confirming that endothelin is a neuropeptide. Although the prominent expression of endothelin in the hypothalamus may indicate a central vasoregulatory role for the peptide, the widespread distribution of endothelin in neurons in other areas of the brain implies a more fundamental role in the regulation of nervous system function.
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Affiliation(s)
- M E Lee
- Department of Medicine, Harvard Medical School, Massachusetts General Hospital, Boston 02114
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Tomita K, Nonoguchi H, Marumo F. Effects of endothelin on peptide-dependent cyclic adenosine monophosphate accumulation along the nephron segments of the rat. J Clin Invest 1990; 85:2014-8. [PMID: 1693379 PMCID: PMC296672 DOI: 10.1172/jci114667] [Citation(s) in RCA: 102] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
We investigated the tubular action of endothelin in rat nephron segments. The effects of endothelin on arginine vasopressin (AVP)-, parathyroid hormone-, glucagon-, calcitonin-, and isoproterenol-dependent cAMP accumulation were studied. The following nephron segments were microdissected: glomerulus (Gl), proximal convoluted tubule (PCT), cortical and medullary thick ascending limbs of Henle's loop (cTAL and mTAL, respectively), cortical collecting duct (CCD), outer medullary collecting duct (OMCD), and inner medullary collecting duct (IMCD). Endothelin dose dependently (10(-8)-10(-10)M) inhibited AVP-dependent cAMP accumulation in CCD, OMCD, and IMCD. This effect was independent of the presence or absence of phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine, Ca channel blocker nicardipine, or indomethacin, but was abolished in the presence of protein kinase C inhibitor H-7. Protein kinase C stimulator dioctanoyl glycerol mimicked the effect of endothelin. On the other hand, endothelin had no inhibitory effect on AVP-dependent cAMP accumulation in cTAL or mTAL, parathyroid hormone-dependent cAMP accumulation in Gl and PCT, or glucagon-, calcitonin-, and isoprotereol-dependent cAMP accumulation in OMCD. We conclude that endothelin specifically inhibits AVP-dependent cAMP accumulation in CCD, OMCD, and IMCD through activating protein kinase C. This effect possibly has a role in maintaining urine volume to counteract the decrease in GFR caused by endothelin itself.
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Affiliation(s)
- K Tomita
- 2nd Department of Internal Medicine, Tokyo Medical & Dental University, Japan
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Abstract
1. Endothelin, a novel potent vasoconstrictor peptide produced by vascular endothelial cells stimulated anion secretion by a cultured secretory epithelium derived from the rat epididymis as measured by changes in short-circuit current (SCC). 2. Stimulation of the SCC was observed when endothelin was added to the basolateral or the apical side of the epithelium. The response to basolateral application was greater than that to apical application. The EC50 values were found to be 1.3 nM and 3.0 nM for basolateral and apical application, respectively. These values were about half an order to one order of magnitude higher than that required for its vasoconstrictor action. 3. The stimulation of SCC by endothelin was accompanied by a rise in the intracellular adenosine 3':5'-cyclic monophosphate (cyclic AMP) content in epididymal monolayers. 4. The effect of endothelin on SCC was mediated through an increase in prostaglandin synthesis by the tissues and was not blocked by an antagonist of angiotensin II (Sar1 Ile8 angiotensin II) or of adrenaline (propranolol). 5. It is speculated that endogenous endothelin plays an important role in the control of water and electrolyte transport in the epididymis.
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Affiliation(s)
- P Y Wong
- Department of Physiology, University of Hong Kong
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Giaid A, Gibson SJ, Ibrahim BN, Legon S, Bloom SR, Yanagisawa M, Masaki T, Varndell IM, Polak JM. Endothelin 1, an endothelium-derived peptide, is expressed in neurons of the human spinal cord and dorsal root ganglia. Proc Natl Acad Sci U S A 1989; 86:7634-8. [PMID: 2678110 PMCID: PMC298121 DOI: 10.1073/pnas.86.19.7634] [Citation(s) in RCA: 228] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
The localization of endothelin 1 mRNA and endothelin-like immunoreactivity was investigated in samples of neurologically normal nervous system tissue from 10 adults by using in situ hybridization and immunocytochemistry. Tissue sections of spinal cord and dorsal root ganglia were hybridized with an 35S-radiolabeled endothelin 1 complementary RNA probe. Autoradiograms showed labeled neurons in the spinal cord (laminae IV-VI and many motoneurons) and numerous small and large neurons in the dorsal root ganglia. Endothelin 1 transcripts were also found in association with the endothelial layer of some blood vessels in the white matter of the spinal cord. A similar distribution of immunoreactivity was seen using three antisera to endothelin 1, but fewer cells were immunostained than were labeled after the hybridization. Two other endothelin 1 antisera immunostained the endothelial lining of blood vessels in the spinal cord white matter but not neurons. In the ganglia, endothelin 1 transcripts were localized to all cells expressing beta-preprotachykinin and most expressing calcitonin gene-related peptide mRNAs; in the majority of the motoneurons, coexistence of endothelin 1 and calcitonin gene-related peptide mRNAs was noted. There was a similar pattern of coexistence for respective peptide immunoreactivities in the ganglia and spinal cord. The expression of endothelin 1 mRNA in distinct neuronal cell types suggests that this peptide plays a part in neural transmission/modulation and adds a further dimension to the known vascular-related actions of endothelin 1.
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Affiliation(s)
- A Giaid
- Department of Histochemistry, Royal Postgraduate Medical School, London, United Kingdom
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