45 results on '"Endothelin-1 adverse effects"'
Search Results
2. Post-injury Inhibition of Endothelin-1 Dependent Renal Vasoregulation Mitigates Rhabdomyolysis-Induced Acute Kidney Injury.
- Author
-
Afolabi JM, Kanthakumar P, Williams JD, Kumar R, Soni H, and Adebiyi A
- Subjects
- Rats, Animals, Endothelin-1 adverse effects, Glycerol adverse effects, Myoglobin adverse effects, Rats, Wistar, Kidney, Acute Kidney Injury etiology, Rhabdomyolysis complications
- Abstract
In patients with rhabdomyolysis, the overwhelming release of myoglobin into the circulation is the primary cause of kidney injury. Myoglobin causes direct kidney injury as well as severe renal vasoconstriction. An increase in renal vascular resistance (RVR) results in renal blood flow (RBF) and glomerular filtration rate (GFR) reduction, tubular injury, and acute kidney injury (AKI). The mechanisms that underlie rhabdomyolysis-induced AKI are not fully understood but may involve the local production of vasoactive mediators in the kidney. Studies have shown that myoglobin stimulates endothelin-1 (ET-1) production in glomerular mesangial cells. Circulating ET-1 is also increased in rats subjected to glycerol-induced rhabdomyolysis. However, the upstream mechanisms of ET-1 production and downstream effectors of ET-1 actions in rhabdomyolysis-induced AKI remain unclear. Vasoactive ET-1 is generated by ET converting enzyme 1 (ECE-1)-induced proteolytic processing of inactive big ET to biologically active peptides. The downstream ion channel effectors of ET-1-induced vasoregulation include the transient receptor potential cation channel, subfamily C member 3 (TRPC3). This study demonstrates that glycerol-induced rhabdomyolysis in Wistar rats promotes ECE-1-dependent ET-1 production, RVR increase, GFR decrease, and AKI. Rhabdomyolysis-induced increases in RVR and AKI in the rats were attenuated by post-injury pharmacological inhibition of ECE-1, ET receptors, and TRPC3 channels. CRISPR/Cas9-mediated knockout of TRPC3 channels attenuated ET-1-induced renal vascular reactivity and rhabdomyolysis-induced AKI. These findings suggest that ECE-1-driven ET-1 production and downstream activation of TRPC3-dependent renal vasoconstriction contribute to rhabdomyolysis-induced AKI. Hence, post-injury inhibition of ET-1-mediated renal vasoregulation may provide therapeutic targets for rhabdomyolysis-induced AKI., Competing Interests: None., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Physiological Society.)
- Published
- 2023
- Full Text
- View/download PDF
3. Effect of Captopril and BQ123 Endothelin-1 Antagonist on Experimentally Induced Hyperlipidemic Nephropathy in Rats.
- Author
-
Jaiswal A, Semwal BC, and Singh S
- Subjects
- Animals, Rats, Captopril, Endothelin-1 adverse effects, Hyperlipidemias drug therapy, Kidney Diseases chemically induced, Kidney Diseases drug therapy
- Abstract
Background: Kidney disease is a universal public health problem, and epidemiological studies demonstrated that the incidences of chronic kidney disease are increasing day by day. However, the efficiency of currently available drugs on the progression of nephropathy is limited. Therefore, the current research was designed to evaluate the therapeutic efficacy of captopril and BQ123 against hyperlipidemia-induced nephropathy in rats., Objective: The objective of this study was to examine the implication of Endothelin-1 in experimentally induced hyperlipidemic nephropathy in rats., Methods: Animals were divided into various groups, and the administration of a high-fat diet for six weeks induced hyperlipidemia. After confirmation of hyperlipidemia, treatment was started for the next 14 days. At the end of the experimental period, the animals were sacrificed, and various biochemical parameters and histopathological studies were performed., Results: Treatment of both the agents in combination effectively decreased BUN levels, serum creatinine, serum nitrite, and proinflammatory markers and ameliorated the pathological injuries to kidneys., Conclusion: Furthermore, both treatments also inhibited oxidative stress and restored the hyperlipidemia-induced reduction in the level of antioxidant enzymes., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
- Published
- 2023
- Full Text
- View/download PDF
4. First-in-Man Demonstration of Direct Endothelin-Mediated Natriuresis and Diuresis.
- Author
-
Hunter RW, Moorhouse R, Farrah TE, MacIntyre IM, Asai T, Gallacher PJ, Kerr D, Melville V, Czopek A, Morrison EE, Ivy JR, Dear JW, Bailey MA, Goddard J, Webb DJ, and Dhaun N
- Subjects
- Adult, Animals, Diuresis drug effects, Diuresis physiology, Double-Blind Method, Endothelin Receptor Antagonists administration & dosage, Endothelin Receptor Antagonists adverse effects, Endothelin Receptor Antagonists pharmacokinetics, Female, Glomerular Filtration Rate, Humans, Kidney Tubules metabolism, Kidney Tubules physiopathology, Male, Natriuresis drug effects, Natriuresis physiology, Receptors, Endothelin metabolism, Treatment Outcome, Water-Electrolyte Balance drug effects, Endothelin-1 administration & dosage, Endothelin-1 adverse effects, Endothelin-1 pharmacokinetics, Renal Insufficiency, Chronic drug therapy, Renal Insufficiency, Chronic metabolism, Renal Insufficiency, Chronic physiopathology, Sodium metabolism
- Abstract
Endothelin (ET) receptor antagonists are potentially novel therapeutic agents in chronic kidney disease and resistant hypertension, but their use is complicated by sodium and water retention. In animal studies, this side effect arises from ET
B receptor blockade in the renal tubule. Previous attempts to determine whether this mechanism operates in humans have been confounded by the hemodynamic consequences of ET receptor stimulation/blockade. We aimed to determine the effects of ET signaling on salt transport in the human nephron by administering subpressor doses of the ET-1 precursor, big ET-1. We conducted a 2-phase randomized, double-blind, placebo-controlled crossover study in 10 healthy volunteers. After sodium restriction, subjects received either intravenous placebo or big ET-1, in escalating dose (≤300 pmol/min). This increased plasma concentration and urinary excretion of ET-1. Big ET-1 reduced heart rate (≈8 beats/min) but did not otherwise affect systemic hemodynamics or glomerular filtration rate. Big ET-1 increased the fractional excretion of sodium (from 0.5 to 1.0%). It also increased free water clearance and tended to increase the abundance of the sodium-potassium-chloride cotransporter (NKCC2) in urinary extracellular vesicles. Our protocol induced modest increases in circulating and urinary ET-1. Sodium and water excretion increased in the absence of significant hemodynamic perturbation, supporting a direct action of ET-1 on the renal tubule. Our data also suggest that sodium reabsorption is stimulated by ET-1 in the thick ascending limb and suppressed in the distal renal tubule. Fluid retention associated with ET receptor antagonist therapy may be circumvented by coprescribing potassium-sparing diuretics., (© 2017 The Authors.)- Published
- 2017
- Full Text
- View/download PDF
5. A pilot study on transient ischemic stroke induced with endothelin-1 in the rhesus monkeys.
- Author
-
Dai P, Huang H, Zhang L, He J, Zhao X, Yang F, Zhao N, Yang J, Ge L, Lin Y, Yu H, and Wang J
- Subjects
- Animals, Brain pathology, Disease Models, Animal, Macaca mulatta, Magnetic Resonance Imaging, Male, Motor Activity, Psychomotor Performance, Stroke diagnosis, Stroke physiopathology, Endothelin-1 adverse effects, Ischemic Attack, Transient complications, Stroke etiology, Vasoconstrictor Agents adverse effects
- Abstract
Endothelin-1 (ET-1), a vasoconstrictor, has recently been used to induce focal ischemia in rodents and marmoset monkeys. The rhesus monkey, however, has numerous advantages to the rodent and marmoset that make it a superior and irreplaceable animal model for studying stroke in the brain. In the present study, after mapping the preferred hand representation in two healthy male monkeys with intracortical micro-stimulation, ET-1 was microinjected into the contralateral motor cortex (M1) to its preferred hand. The monkeys had been trained in three manual dexterity tasks before the microinjection and were tested for these tasks following the ET-1 injection. Brain Magnetic Resonance Imaging scans were performed 1, 7, 14 and 28 days post ischemia. It was found that ET-1 impaired the manual dexterity of the monkeys in the vertical slot and rotating Brinkman board tasks 3-8 days after the injection. Brain imaging found that severe edema was present 7 days after the focal ischemia. This data suggest that ET-1 can induce transient ischemic stroke in rhesus monkey and that ET-1 induced focal ischemia in non-human primates is a potential model to study the mechanism of stroke and brain repair after stroke.
- Published
- 2017
- Full Text
- View/download PDF
6. Endothelin-1 Treatment Induces an Experimental Cerebral Malaria-Like Syndrome in C57BL/6 Mice Infected with Plasmodium berghei NK65.
- Author
-
Martins YC, Freeman BD, Akide Ndunge OB, Weiss LM, Tanowitz HB, and Desruisseaux MS
- Subjects
- Animals, Blood-Brain Barrier drug effects, Brain pathology, Cell Adhesion, Disease Models, Animal, Endothelin-1 therapeutic use, Endothelium, Vascular pathology, Female, Leukocytes pathology, Malaria, Cerebral drug therapy, Mice, Mice, Inbred C57BL, Parasitemia, Endothelin-1 adverse effects, Malaria, Cerebral pathology, Plasmodium berghei physiology
- Abstract
Plasmodium berghei ANKA infection of C57BL/6 mice is a widely used model of experimental cerebral malaria (ECM). By contrast, the nonneurotropic P. berghei NK65 (PbN) causes severe malarial disease in C57BL/6 mice but does not cause ECM. Previous studies suggest that endothelin-1 (ET-1) contributes to the pathogenesis of ECM. In this study, we characterize the role of ET-1 on ECM vascular dysfunction. Mice infected with 10
6 PbN-parasitized red blood cells were treated with either ET-1 or saline from 2 to 8 days postinfection (dpi). Plasmodium berghei ANKA-infected mice served as the positive control. ET-1-treated PbN-infected mice exhibited neurological signs, hypothermia, and behavioral alterations characteristic of ECM, dying 4 to 8 dpi. Parasitemia was not affected by ET-1 treatment. Saline-treated PbN-infected mice did not display ECM, surviving until 12 dpi. ET-1-treated PbN-infected mice displayed leukocyte adhesion to the vascular endothelia and petechial hemorrhages throughout the brain at 6 dpi. Intravital microscopic images demonstrated significant brain arteriolar vessel constriction, decreased functional capillary density, and increased blood-brain barrier permeability. These alterations were not present in either ET-1-treated uninfected or saline-treated PbN-infected mice. In summary, ET-1 treatment of PbN-infected mice induced an ECM-like syndrome, causing brain vasoconstriction, adherence of activated leukocytes in the cerebral microvasculature, and blood-brain barrier leakage, indicating that ET-1 is involved in the genesis of brain microvascular alterations that are the hallmark of ECM., (Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)- Published
- 2016
- Full Text
- View/download PDF
7. ATP release mechanisms of endothelial cell-mediated stimulus-dependent hyperalgesia.
- Author
-
Joseph EK, Green PG, and Levine JD
- Subjects
- ATP-Binding Cassette Transporters antagonists & inhibitors, ATP-Binding Cassette Transporters metabolism, Animals, Disease Models, Animal, Endothelial Cells drug effects, Endothelin-1 pharmacology, Enzyme Inhibitors pharmacology, Hyperalgesia pathology, Ion Channels antagonists & inhibitors, Ion Channels physiology, Male, Pain Measurement, Pain Threshold drug effects, Rats, Rats, Sprague-Dawley, Time Factors, Adenosine Triphosphate metabolism, Endothelial Cells physiology, Endothelin-1 adverse effects, Hyperalgesia chemically induced
- Abstract
Unlabelled: Endothelin-1 (ET-1) acts on endothelial cells to enhance mechanical stimulation-induced release of adenosine triphosphate (ATP), which in turn can act on sensory neurons innervating blood vessels to contribute to vascular pain, a phenomenon we have referred to as stimulus-dependent hyperalgesia (SDH). In the present study, we evaluated the role of the major classes of ATP release mechanisms to SDH: vesicular exocytosis, plasma membrane-associated ATP synthase, ATP-binding cassette transporters, and ion channels. Inhibitors of vesicular exocytosis (ie, monensin, brefeldin A, and bafilomycin), plasma membrane-associated ATPase (ie, oligomycin and pigment epithelium-derived factor peptide 34-mer), and connexin ion channels (carbenoxolone and flufenamic acid) but not ATP-binding cassette transporter (ie, dipyridamole, nicardipine, or CFTRinh-172) attenuated SDH. This study reports a role of ATP in SDH and suggests novel targets for the treatment of vascular pain syndromes., Perspective: ET-1 acts on endothelial cells to produce mechanical stimulation-induced hyperalgesia. Inhibitors of 3 different ATP release mechanisms attenuated this SDH. This study provides support for a role of ATP in SDH and suggests novel targets for the treatment of vascular pain syndromes., (Copyright © 2014 American Pain Society. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
8. Brain remodelling following endothelin-1 induced stroke in conscious rats.
- Author
-
Abeysinghe HC, Bokhari L, Dusting GJ, and Roulston CL
- Subjects
- Animals, Brain drug effects, Brain immunology, Brain Infarction complications, Cell Differentiation drug effects, Cell Movement drug effects, Cell Proliferation drug effects, Lateral Ventricles drug effects, Lateral Ventricles immunology, Lateral Ventricles pathology, Lateral Ventricles physiopathology, Macrophage Activation drug effects, Male, Microglia drug effects, Microglia pathology, Neovascularization, Physiologic drug effects, Rats, Rats, Wistar, Stroke chemically induced, Stroke immunology, Brain pathology, Brain physiopathology, Consciousness, Endothelin-1 adverse effects, Stroke pathology, Stroke physiopathology
- Abstract
The extent of stroke damage in patients affects the range of subsequent pathophysiological responses that influence recovery. Here we investigate the effect of lesion size on development of new blood vessels as well as inflammation and scar formation and cellular responses within the subventricular zone (SVZ) following transient focal ischemia in rats (n = 34). Endothelin-1-induced stroke resulted in neurological deficits detected between 1 and 7 days (P<0.001), but significant recovery was observed beyond this time. MCID image analysis revealed varying degrees of damage in the ipsilateral cortex and striatum with infarct volumes ranging from 0.76-77 mm3 after 14 days, where larger infarct volumes correlated with greater functional deficits up to 7 days (r = 0.53, P<0.05). Point counting of blood vessels within consistent sample regions revealed that increased vessel numbers correlated significantly with larger infarct volumes 14 days post-stroke in the core cortical infarct (r = 0.81, P<0.0001), core striatal infarct (r = 0.91, P<0.005) and surrounding border zones (r = 0.66, P<0.005; and r = 0.73, P<0.05). Cell proliferation within the SVZ also increased with infarct size (P<0.01) with a greater number of Nestin/GFAP positive cells observed extending towards the border zone in rats with larger infarcts. Lesion size correlated with both increased microglia and astrocyte activation, with severely diffuse astrocyte transition, the formation of the glial scar being more pronounced in rats with larger infarcts. Thus stroke severity affects cell proliferation within the SVZ in response to injury, which may ultimately make a further contribution to glial scar formation, an important factor to consider when developing treatment strategies that promote neurogenesis.
- Published
- 2014
- Full Text
- View/download PDF
9. Ribosomal S6 kinase regulates ischemia-induced progenitor cell proliferation in the adult mouse hippocampus.
- Author
-
Karelina K, Alzate-Correa D, and Obrietan K
- Subjects
- Adult Stem Cells drug effects, Analysis of Variance, Animals, Brain Ischemia chemically induced, Bromodeoxyuridine metabolism, Cells, Cultured, Dose-Response Relationship, Drug, Endothelin-1 adverse effects, Endothelin-1 pharmacology, Enzyme Inhibitors pharmacology, Fluoresceins, Gene Expression Regulation drug effects, Hippocampus drug effects, Ki-67 Antigen metabolism, Mice, Mice, Inbred C57BL, Nerve Tissue Proteins metabolism, Time Factors, Adult Stem Cells physiology, Brain Ischemia pathology, Cell Proliferation drug effects, Hippocampus pathology, Ribosomal Protein S6 Kinases metabolism
- Abstract
Ischemia-induced progenitor cell proliferation is a prominent example of the adult mammalian brain's ability to regenerate injured tissue resulting from pathophysiological processes. In order to better understand and exploit the cell signaling mechanisms that regulate ischemia-induced proliferation, we examined the role of the p42/44 mitogen-activated protein kinase (MAPK) cascade effector ribosomal S6 kinase (RSK) in this process. Here, using the endothelin-1 ischemia model in wild type mice, we show that the activated form of RSK is expressed in the progenitor cells of the subgranular zone (SGZ) after intrahippocampal cerebral ischemia. Further, RSK inhibition significantly reduces ischemia-induced SGZ progenitor cell proliferation. Using the neurosphere assay, we also show that both SGZ- and subventricular zone (SVZ)-derived adult neural stem cells (NSC) exhibit a significant reduction in proliferation in the presence of RSK and MAPK inhibitors. Taken together, these data reveal RSK as a regulator of ischemia-induced progenitor cell proliferation, and as such, suggest potential therapeutic value may be gained by specifically targeting the regulation of RSK in the progenitor cell population of the SGZ., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
10. Astrocyte-derived endothelin-1 inhibits remyelination through notch activation.
- Author
-
Hammond TR, Gadea A, Dupree J, Kerninon C, Nait-Oumesmar B, Aguirre A, and Gallo V
- Subjects
- Animals, Astrocytes drug effects, Astrocytes ultrastructure, Calcium-Binding Proteins metabolism, Cell Count, Cell Differentiation drug effects, Demyelinating Diseases chemically induced, Demyelinating Diseases drug therapy, Demyelinating Diseases metabolism, Disease Models, Animal, Drug Delivery Systems, Endothelin-1 adverse effects, Gene Expression Regulation drug effects, Gene Expression Regulation genetics, Glial Fibrillary Acidic Protein genetics, Green Fluorescent Proteins genetics, Intercellular Signaling Peptides and Proteins metabolism, Jagged-1 Protein, Lipopolysaccharides pharmacology, Membrane Proteins metabolism, Mice, Mice, Inbred C57BL, Mice, Transgenic, Oligopeptides pharmacology, Platelet Endothelial Cell Adhesion Molecule-1 metabolism, Serrate-Jagged Proteins, Stem Cells drug effects, Stem Cells physiology, Astrocytes metabolism, Demyelinating Diseases pathology, Endothelin-1 metabolism, Gene Expression Regulation physiology, Receptors, Notch metabolism
- Abstract
Oligodendrocyte progenitor cells (OPCs) can repair demyelinated lesions by maturing into myelin-producing oligodendrocytes. However, the OPC potential to differentiate can be prevented by inhibitory signals present in the pathological lesion environment. Identification of these signals is essential to promote OPC differentiation and lesion repair. We identified an endogenous inhibitor of remyelination, Endothelin-1 (ET-1), which is highly expressed in reactive astrocytes of demyelinated lesions. Using both gain- and loss-of-function approaches, we demonstrate that ET-1 drastically reduces the rate of remyelination. We also discovered that ET-1 acts mechanistically by promoting Notch activation in OPCs during remyelination through induction of Jagged1 expression in reactive astrocytes. Pharmacological inhibition of ET signaling prevented Notch activation in demyelinated lesions and accelerated remyelination. These findings reveal that ET-1 is a negative regulator of OPC differentiation and remyelination and is potentially a therapeutic target to promote lesion repair in demyelinated tissue., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
11. Constraint-induced movement therapy overcomes the intrinsic axonal growth-inhibitory signals in stroke rats.
- Author
-
Zhao S, Zhao M, Xiao T, Jolkkonen J, and Zhao C
- Subjects
- Animals, Axons pathology, Disease Models, Animal, Endothelin-1 adverse effects, GAP-43 Protein metabolism, GPI-Linked Proteins metabolism, Injections, Intraventricular, Male, Myelin Proteins metabolism, Neuronal Plasticity physiology, Nogo Proteins, Nogo Receptor 1, Rats, Rats, Wistar, Receptors, Cell Surface metabolism, Stroke chemically induced, Synaptophysin metabolism, rhoA GTP-Binding Protein metabolism, Axons physiology, Movement, Physical Therapy Modalities, Restraint, Physical, Signal Transduction physiology, Stroke physiopathology, Stroke therapy
- Abstract
Background and Purpose: Constraint-induced movement therapy (CIMT) improves functional outcome in patients with stroke possibly through structural plasticity. We hypothesized that CIMT could enhance axonal growth by overcoming the intrinsic growth-inhibitory signals, leading eventually to improved behavioral performance in stroke rats., Methods: Focal cerebral ischemia was induced by intracerebral injection of endothelin-1. Adult Wistar rats were divided into a sham-operated group, an ischemic group, and an ischemic group treated with CIMT. CIMT started at postoperative day 7 and continued for 3 weeks. Biotinylated dextran amine was injected into the contralateral sensorimotor cortex at postoperative day 14 to trace crossing axons at the cervical spinal cord. The expressions of Nogo-A, Nogo receptor, RhoA, and Rho-associated kinase in the peri-infarct cortex, and the expressions of biotinylated dextran amine, growth associated protein-43, synaptophysin, vGlut1, and postsynaptic density-95 in the denervated spinal cord were measured by immunohistochemistry and Western blots. Behavioral recovery was analyzed at postoperative days 29 to 32., Results: Infarct volumes were not different between groups after stroke. CIMT significantly increased the length and the number of midline crossings of contralateral corticospinal axons to the denervated cervical spinal cord. CIMT significantly decreased the expressions of Nogo-A/Nogo receptor and RhoA/Rho-associated kinase in the peri-infarct cortex, and increased the expressions of growth associated protein-43, synaptophysin, vGlut1, and postsynaptic density-95 in the denervated cervical spinal cord. Behavioral performances assessed by the beam-walking test and the water maze test were improved significantly by CIMT., Conclusions: CIMT promoted poststroke synaptic plasticity and axonal growth at least partially by overcoming the intrinsic growth-inhibitory signaling, leading to improved behavioral outcome.
- Published
- 2013
- Full Text
- View/download PDF
12. Chemokines and neurodegeneration in the early stage of experimental ischemic stroke.
- Author
-
Wolinski P and Glabinski A
- Subjects
- Animals, Brain metabolism, Brain Ischemia chemically induced, Brain Ischemia metabolism, Chemokine CCL2 metabolism, Chemokine CCL3 metabolism, Chemokine CCL5 metabolism, Chemokine CXCL2 metabolism, Endothelin-1 adverse effects, Enzyme-Linked Immunosorbent Assay, Female, Gene Expression Profiling, Gene Expression Regulation, Inflammation metabolism, Lymphocytes cytology, Macrophages metabolism, Mice, Neurodegenerative Diseases pathology, Real-Time Polymerase Chain Reaction, Stroke chemically induced, Stroke metabolism, Brain Ischemia pathology, Chemokines metabolism, Neurodegenerative Diseases metabolism, Stroke pathology
- Abstract
Neurodegeneration is a hallmark of most of the central nervous system (CNS) disorders including stroke. Recently inflammation has been implicated in pathogenesis of neurodegeneration and neurodegenerative diseases. The aim of this study was analysis of expression of several inflammatory markers and its correlation with development of neurodegeneration during the early stage of experimental stroke. Ischemic stroke model was induced by stereotaxic intracerebral injection of vasoconstricting agent endothelin-1 (ET-1). It was observed that neurodegeneration appears very early in that model and correlates well with migration of inflammatory lymphocytes and macrophages to the brain. Although the expression of several studied chemotactic cytokines (chemokines) was significantly increased at the early phase of ET-1 induced stroke model, no clear correlation of this expression with neurodegeneration was observed. These data may indicate that chemokines do not induce neurodegeneration directly. Upregulated in the ischemic brain chemokines may be a potential target for future therapies reducing inflammatory cell migration to the brain in early stroke. Inhibition of inflammatory cell accumulation in the brain at the early stage of stroke may lead to amelioration of ischemic neurodegeneration.
- Published
- 2013
- Full Text
- View/download PDF
13. The neuroprotective effect of post ischemic brief mild hypothermic treatment correlates with apoptosis, but not with gliosis in endothelin-1 treated rats.
- Author
-
Zgavc T, Ceulemans AG, Hachimi-Idrissi S, Kooijman R, Sarre S, and Michotte Y
- Subjects
- Animals, Antigens, CD metabolism, Antigens, Differentiation, Myelomonocytic metabolism, Apoptosis physiology, Brain Infarction etiology, Caspase 3 metabolism, Cell Count, Cerebrovascular Circulation drug effects, Disease Models, Animal, Gene Expression Regulation drug effects, Gene Expression Regulation physiology, Glial Fibrillary Acidic Protein metabolism, Gliosis therapy, Laser-Doppler Flowmetry, Male, Movement Disorders etiology, Neurologic Examination, Random Allocation, Rats, Rats, Wistar, Time Factors, Apoptosis drug effects, Brain Ischemia chemically induced, Brain Ischemia complications, Brain Ischemia therapy, Endothelin-1 adverse effects, Gliosis etiology, Hypothermia, Induced methods, Statistics as Topic
- Abstract
Background: Stroke remains one of the most common diseases with a serious impact on quality of life but few effective treatments exist. Mild hypothermia (33°C) is a promising neuroprotective therapy in stroke management. This study investigated whether a delayed short mild hypothermic treatment is still beneficial as neuroprotective strategy in the endothelin-1 (Et-1) rat model for a transient focal cerebral ischemia. Two hours of mild hypothermia (33°C) was induced 20, 60 or 120 minutes after Et-1 infusion. During the experiment the cerebral blood flow (CBF) was measured via Laser Doppler Flowmetry in the striatum, which represents the core of the infarct. Functional outcome and infarct volume were assessed 24 hours after the insult. In this sub-acute phase following stroke induction, the effects of the hypothermic treatment on apoptosis, phagocytosis and astrogliosis were assessed as well. Apoptosis was determined using caspase-3 immunohistochemistry, phagocytic cells were visualized by CD-68 expression and astrogliosis was studied by glial fibrillary acidic protein (GFAP) staining., Results: Cooling could be postponed up to 1 hour after the onset of the insult without losing its positive effects on neurological deficit and infarct volume. These results correlated with the caspase-3 staining. In contrast, the increased CD-68 expression post-stroke was reduced in the core of the insult with all treatment protocols. Hypothermia also reduced the increased levels of GFAP staining, even when it was delayed up to 2 hours after the insult. The study confirmed that the induction of the hypothermia treatment in the Et-1 model does not affect the CBF., Conclusions: These data indicate that in the Et-1 rat model, a short mild hypothermic treatment delayed for 1 hour is still neuroprotective and correlates with apoptosis. At the same time, hypothermia also establishes a lasting inhibitory effect on the activation of astrogliosis.
- Published
- 2012
- Full Text
- View/download PDF
14. Sexual dimorphism in endothelin-1 induced mechanical hyperalgesia in the rat.
- Author
-
Joseph EK and Levine JD
- Subjects
- Animals, Disease Models, Animal, Dose-Response Relationship, Drug, Female, Male, Ovariectomy, Pain Measurement, Rats, Rats, Sprague-Dawley, Time Factors, Endothelin-1 adverse effects, Hyperalgesia chemically induced, Pain Threshold drug effects, Sex Characteristics
- Abstract
While the onset of mechanical hyperalgesia induced by endothelin-1 was delayed in female rats, compared to males, the duration was much longer. Given that the repeated test stimulus used to assess nociceptive threshold enhances hyperalgesia, a phenomenon we have referred to as stimulus-induced enhancement of hyperalgesia, we also evaluated for sexual dimorphism in the impact of repeated application of the mechanical test stimulus on endothelin-1 hyperalgesia. In male and female rats, endothelin-1 induced hyperalgesia is already maximal at 30 min. At this time stimulus-induced enhancement of hyperalgesia, which is observed only in male rats, persisted for 3-4h. In contrast, in females, it develops only after a very long (15 day) delay, and is still present, without attenuation, at 45 days. Ovariectomy eliminated these differences between male and female rats. These findings suggest marked, ovarian-dependent sexual dimorphism in endothelin-1 induced mechanical hyperalgesia and its enhancement by repeated mechanical stimulation., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
15. Serial semiquantitative imaging of brain damage using micro-SPECT and micro-CT after endothelin-1-induced transient focal cerebral ischemia in rats.
- Author
-
Ceulemans AG, Hernot S, Zgavc T, Caveliers V, Hachimi-Idrissi S, Sarre S, Lahoutte T, and Michotte Y
- Subjects
- Animals, Brain Ischemia pathology, Brain Ischemia therapy, Hypothermia, Induced, Male, Rats, Rats, Wistar, Reproducibility of Results, Technetium Tc 99m Exametazime, Time Factors, Brain Ischemia chemically induced, Brain Ischemia diagnosis, Endothelin-1 adverse effects, Tomography, Emission-Computed, Single-Photon, X-Ray Microtomography
- Abstract
Unlabelled: In this study, we validated the use of (99m)Tc-hexamethylpropyleneamine oxime ((99m)Tc-HMPAO) micro-SPECT combined with micro-CT for semiquantification of the infarct size after an experimental stroke in rats and compared our observations with those obtained from histology. This imaging strategy was applied to measure the longitudinal effect of mild hypothermia on the progression of brain damage after stroke in rats., Methods: The endothelin-1 model was used to elicit a transient focal cerebral ischemia in rats. This resulted in a reproducible insult in which the core is represented by the striatum and the penumbra by the cortex. Micro-SPECT and micro-CT images were taken at 1, 3, and 7 d after infusion of endothelin-1 and compared with those taken before the insult. After the last acquisition, rats were sacrificed and the infarct volume was determined via Nissl staining. The results obtained with micro-SPECT and micro-CT were compared with histology at the same time points. Mild hypothermia (33°C) was induced for 2 h, starting 20 min after the insult., Results: Brain damage was estimated using micro-SPECT and micro-CT and was reproducible with minimal interobserver variability. Normothermic stroke rats had reduced (99m)Tc-HMPAO uptake at 1 and 3 d after the insult, whereas hypothermia improved damage after stroke. These findings corroborate with histology at the same time points. At 1 wk after the insult, no reduction of radioactive uptake was observed in any treatment group., Conclusion: Micro-SPECT and micro-CT allow quick and reproducible semiquantification of brain damage as an interesting alternative to histology to measure the extent of infarcted tissue in small animals after stroke.
- Published
- 2011
- Full Text
- View/download PDF
16. [The influence of stress factors on liver function and lipid metabolism in an animal model of arterial hypertension].
- Author
-
Diaconu C, Tarţău L, and Lupuşoru CE
- Subjects
- Alanine Transaminase blood, Animals, Aspartate Aminotransferases blood, Blood Pressure, Cholesterol blood, Cholesterol, HDL blood, Cholesterol, LDL blood, Disease Models, Animal, Endothelin-1 administration & dosage, Hypertension physiopathology, Immersion, Liver physiopathology, Male, Rats, Rats, Wistar, Restraint, Physical, Stress, Physiological, Stress, Psychological, Triglycerides blood, Water, Biomarkers blood, Endothelin-1 adverse effects, Hypertension metabolism, Liver metabolism
- Abstract
Aim: to investigate the influence of some stress factors on hepatic function and lipid metabolism in an experimental-induced hypertension., Material and Methods: The experiment was carried out on Wistar rats, treated intraperitoneally, for 4 weeks, as follows: Group 1: saline solution (0.5ml/100g weight); Group 2: saline solution + stress; Group 3: Endotelin-1; Group 4: Endotelin-1 + stress; Group 5: Endotelin-1 + cholesterol diet (0.2g/kbw/day); Group 6: Endotelin-1 + cholesterol diet + stress. Endotelin-1 0.25nmol/kbw was initially administered, followed by 0.5nmol/kbw 15 min later, 2 times/week. Stress-inducing factors were immobilization and water immersion. In the 28th day of the experiment blood pressure was measured and blood samples were taken from retro-orbitary plexus to assess glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT) and lactic dehydrogenase (LDH) activity, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides levels., Results: Using immobilization and water immersion as chronic stress, our study proved an increase of GOT, GTP and total and LDL cholesterol in rats with endotelin-1-induced hypertension., Conclusions: In this animal model of endothelin-1-induced hypertension the blood pressure increased significantly under chronic exposure to stress, reaching the highest values when associating stress and experimentally induced dyslipidemia.
- Published
- 2011
17. Halogenated aromatic amino acid 3,5-dibromo-D: -tyrosine produces beneficial effects in experimental stroke and seizures.
- Author
-
Cao W, Glushakov A, Shah HP, Mecca AP, Sumners C, Shi P, Seubert CN, and Martynyuk AE
- Subjects
- Animals, Blood Pressure drug effects, Brain drug effects, Brain metabolism, Brain physiopathology, Caspase 3 analysis, Disease Models, Animal, Endothelin-1 adverse effects, Epilepsy chemically induced, Epilepsy physiopathology, Heart Rate drug effects, Hydrocarbons, Brominated administration & dosage, Hydrocarbons, Brominated chemical synthesis, Infarction, Middle Cerebral Artery chemically induced, Male, Motor Activity drug effects, Pentylenetetrazole adverse effects, Rats, Rats, Sprague-Dawley, Severity of Illness Index, Stroke chemically induced, Stroke physiopathology, Tyrosine administration & dosage, Tyrosine chemical synthesis, Tyrosine therapeutic use, Epilepsy drug therapy, Hydrocarbons, Brominated therapeutic use, Stroke drug therapy, Tyrosine analogs & derivatives
- Abstract
The effects of the halogenated aromatic amino acid 3,5-dibromo-D: -tyrosine (3,5-DBr-D: -Tyr) were studied in rat models of stroke and epileptic seizures caused by middle cerebral artery occlusion (MCAo) through respective intracerebral injection of endothelin-1 (ET-1) and intraperitoneal (i.p.) injection of pentylenetetrazole (PTZ). 3,5-DBr-D: -Tyr was administered as three bolus injections (30 or 90 mg/kg, i.p.) starting at 30, 90, and 180 min after ET-1 administration or as a single bolus (30 mg/kg, i.p.) 15 min prior to PTZ administration. Neurological deficits and infarct volume were estimated 3 days after ET-1 administration and seizure score was assessed during the first 20 min after PTZ administration. The safety of 3,5-DBr-D: -Tyr was evaluated in control animals using telemetry to measure cardiovascular parameters and immunostaining to assess the level of activated caspase-3. 3,5-DBr-D: -Tyr significantly improved neurological function and reduced infarct volume in the brain even when the treatment was initiated 3 h after the onset of MCAo. 3,5-DBr-D: -Tyr significantly depressed PTZ-induced seizures. 3,5-DBr-D: -Tyr did not cause significant changes in arterial blood pressure, heart rate and spontaneous locomotor activity, nor did it increase the number of activated caspase-3 positive cells in the brain. We conclude that 3,5-DBr-D: -Tyr, by alleviating the deleterious effects of MCAo and PTZ in rats with no obvious intrinsic effects on cardiovascular parameters and neurodegeneration, exhibits promising potential as a novel therapeutic direction for stroke and seizures.
- Published
- 2011
- Full Text
- View/download PDF
18. [Experimental research on the influence of stress factors in an animal model of hypertension].
- Author
-
Diaconu C, Tarţău L, and Lupuşoru CE
- Subjects
- Animals, Anti-Inflammatory Agents blood, Biomarkers blood, Disease Models, Animal, Endothelin-1 adverse effects, Hydrocortisone blood, Hypertension blood, Hypertension psychology, Immersion adverse effects, Injections, Intraperitoneal, Leukocyte Count, Male, Neutrophils immunology, Phagocytosis, Rats, Rats, Wistar, Restraint, Physical, Water, Endothelin-1 administration & dosage, Hypertension physiopathology, Stress, Physiological, Stress, Psychological
- Abstract
Aim: to investigate the influence of some stress factors in endothelin-1-induced hypertension., Material and Methods: The experiment was carried out on Wistar rats, treated intraperitoneally, for 4 weeks, as follows: Group 1: saline solution (0.5 ml/100 g weight); Group 2: saline solution + stress; Group 3: Endotelin-1; Group 4: Endotelin-l + stress; Group 5: Endotelin-1 + cholesterol diet (0.2 g/kbw/day); Group 6: Endotelin-1 + cholesterol diet + stress. Endotelin-1 0.25 nmol/kbw was initially administered, followed by 0.5 nmol/kbw 15 min later, 2 times/week. Stress-inducing factors were immobilization and water immersion. In the 28th day of the experiment blood pressure was measured and blood samples were taken from the retro-orbitary plexus to assess plasma cortisol, blood count, phagocytic capacity of peripheral neutrophils, and serum complement activity., Results and Discussions: Repeated administration of endotelin-1 determined an increase in blood pressure, statistically significant in stress conditions comparing to non-stressed animals. Our study proved a decrease of plasma cortisol, total leukocyte count, phagocytic capacity of peripheral neutrophils, without significant alterations in serum complement activity., Conclusions: Chronic exposure to complex stress conditions in rats with endothelin-1-induced hypertension determined a decrease of plasma cortisol levels, effect correlated with elevated blood pressure and decrease in the number and phagocytic function of peripheral neutrophils.
- Published
- 2011
19. Endothelin-1- and isoproterenol-induced differential protein expression and signaling pathway in HL-1 cardiomyocytes.
- Author
-
Hong HM, Song EJ, Oh E, Kabir MH, Lee C, and Yoo YS
- Subjects
- Amino Acid Sequence, Animals, Cardiomegaly chemically induced, Cardiomegaly genetics, Cardiotonic Agents adverse effects, Cell Line, Electrophoresis, Gel, Two-Dimensional, Endothelin-1 adverse effects, Humans, Molecular Sequence Data, Myocytes, Cardiac drug effects, Myocytes, Cardiac metabolism, Proteins genetics, Tandem Mass Spectrometry, Cardiomegaly metabolism, Cardiotonic Agents pharmacology, Endothelin-1 metabolism, Gene Expression Regulation drug effects, Isoproterenol pharmacology, Proteins metabolism, Signal Transduction drug effects
- Abstract
It is well known that the two chemical compounds endothelin-1 (ET-1) and isoproterenol (ISO) can individually induce cardiac hypertrophy through G protein-coupled receptors in cardiomyocytes. However, the cardiac hypertrophy signaling pathway activated by ET-1 and ISO is not well defined. Therefore, we investigated the protein expression profile and signaling transduction in HL-l cardiomyocyte cells treated with ET-1 and ISO. Following separation of the cell lysates by using 2-DE and silver staining, we identified 16 protein spots that were differentially expressed as compared to the controls. Of these 16 spots, three changed only after treatment with ET-1, whereas four changed only after treatment with ISO, suggesting that these two stimuli could induce different signaling pathways. In order to reveal the differences between ET-1- and ISO-induced signaling, we studied the different events that occur at each step of the signaling pathways, when selected biocomponents were blocked by inhibitors. Our results indicated that ET-1 and ISO used different pathways for phosphorylation of glycogen synthase kinase-3β (GSK3β). ET-1 mainly used the mitogen-activated protein kinase and phosphatidylinositol-3-kinase/AKT pathways to activate GSK3β, whereas under ISO stimulation, only the phosphatidylinositol-3-kinase/AKT pathway was required to trigger the GSK3β pathway. Furthermore, the strength of the GSK3β signal in ISO-induced cardiac hypertrophy was stronger than that in ET-1-induced cardiac hypertrophy. We found that these two agonists brought about different changes in the protein expression of HL-1 cardiomyocytes through distinct signaling pathways even though the destination of the two signaling pathways was the same., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2011
- Full Text
- View/download PDF
20. Role of peripheral endothelin receptors in an animal model of complex regional pain syndrome type 1 (CRPS-I).
- Author
-
Millecamps M, Laferrière A, Ragavendran VJ, Stone LS, and Coderre TJ
- Subjects
- Analysis of Variance, Animals, Behavior, Animal, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Interactions, Endothelin Receptor Antagonists, Endothelin-1 adverse effects, Endothelin-2 adverse effects, Endothelins pharmacology, Hyperalgesia drug therapy, Hyperalgesia physiopathology, Keratinocytes drug effects, Male, Mice, Muscle, Skeletal drug effects, Naloxone pharmacology, Narcotic Antagonists pharmacology, Oligopeptides pharmacology, Pain Measurement drug effects, Pain Measurement methods, Pain Threshold drug effects, Pain Threshold physiology, Peptide Fragments pharmacology, Peptides, Cyclic therapeutic use, Physical Stimulation adverse effects, Piperidines pharmacology, Reflex Sympathetic Dystrophy chemically induced, Reflex Sympathetic Dystrophy drug therapy, Skin cytology, Skin drug effects, Muscle, Skeletal metabolism, Peripheral Nervous System metabolism, Receptors, Endothelin metabolism, Reflex Sympathetic Dystrophy metabolism, Reflex Sympathetic Dystrophy pathology, Skin metabolism
- Abstract
Chronic post-ischemic pain (CPIP) is an animal model of CRPS-I developed using a 3-h ischemia-reperfusion injury of the rodent hind paw. The contribution of local endothelin to nociception has been evaluated in CPIP mice by measuring sustained nociceptive behaviors (SNBs) following intraplantar injection of endothelin-1 or -2 (ET-1, ET-2). The effects of local BQ-123 (ETA-R antagonist), BQ-788 (ETB-R antagonist), IRL-1620 (ETB-R agonist) and naloxone (opioid antagonist) were assessed on ET-induced SNBs and/or mechanical and cold allodynia in CPIP mice. ETA-R and ETB-R expression was assessed using immunohistochemistry and Western blot analysis. Compared to shams, CPIP mice exhibited hypersensitivity to local ET-1 and ET-2. BQ-123 reduced ET-1- and ET-2-induced SNBs in both sham and CPIP animals, but not mechanical or cold allodynia. BQ-788 enhanced ET-1- and ET-2-induced SNBs in both sham and CPIP mice, and cold allodynia in CPIP mice. IRL-1620 displayed a non-opioid anti-nociceptive effect on ET-1- and ET-2-induced SNBs and mechanical allodynia in CPIP mice. The distribution of ETA-R and ETB-R was similar in plantar skin of sham and CPIP mice, but both receptors were over-expressed in plantar muscles of CPIP mice. This study shows that ETA-R and ETB-R have differing roles in nociception for sham and CPIP mice. CPIP mice exhibit more local endothelin-induced SNBs, develop a novel local ETB-R agonist-induced (non-opioid) analgesia, and exhibit over-expression of both receptors in plantar muscles, but not skin. The effectiveness of local ETB-R agonists as anti-allodynic treatments in CPIP mice holds promise for novel therapies in CRPS-I patients., (Copyright © 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
21. Regulation of major efflux transporters under inflammatory conditions at the blood-brain barrier in vitro.
- Author
-
von Wedel-Parlow M, Wölte P, and Galla HJ
- Subjects
- ATP-Binding Cassette Transporters classification, ATP-Binding Cassette Transporters genetics, Analysis of Variance, Animals, Anti-Inflammatory Agents pharmacology, Brain cytology, Cells, Cultured, Electric Impedance, Endothelial Cells drug effects, Endothelin-1 adverse effects, Gene Expression Regulation drug effects, Hydrocortisone pharmacology, Inflammation chemically induced, Inflammation drug therapy, Interleukin-1beta adverse effects, Swine, Time Factors, Tumor Necrosis Factor-alpha adverse effects, ATP-Binding Cassette Transporters metabolism, Blood-Brain Barrier physiology, Endothelial Cells physiology, Gene Expression Regulation physiology, Inflammation pathology
- Abstract
ATP-driven efflux transport proteins at the blood-brain barrier protect the healthy brain but impede pharmacotherapy of the disordered CNS. To investigate the question how ATP-binding cassette (ABC)-transporters are regulated during inflammation or infection we analysed the effects of the cytokines tumour necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) on the expression of brain multidrug resistance proteins in primary cultures of porcine brain capillary endothelial cells. We found that TNF-alpha and IL-1beta rapidly decrease Abcg2 (BMDP/BCRP) mRNA expression within 6 h. After 24 and 48 h the mRNA level came back to control values. The mRNA reduction at 6 h was counter-regulated by the anti-inflammatory glucocorticoid hydrocortisone. Abcg2 protein levels were suppressed at prolonged stimulations but not after 6 h of stimulation which correlates with Abcg2 specific substrate uptake measurements. Abcb1 (p-glycoprotein) protein expression was transiently increased after TNF-alpha addition within 6 h of incubation followed by a reduction after 24 and 48 h whereas the Abcb1 mRNA levels were not changed. IL-1beta caused a continuous decrease in protein expression of both ABC-transporters. Long-term treatment with an assumed TNF-alpha-downstream agent, the vasoconstrictor endothelin-1, induced Abcg2 protein expression but suppressed Abcb1. Other efflux pumps like multidrug resistance-associated proteins/Abcc were rarely affected. The present results imply a complex regulation of the two most abundant ABC-transporters at the blood-brain barrier during early inflammation stages suggesting that Abcb1 (p-glycoprotein) is an early target of TNF-alpha-signalling counterbalanced by Abcg2.
- Published
- 2009
- Full Text
- View/download PDF
22. Neurosensory changes in a human model of endothelin-1 induced pain: a behavioral study.
- Author
-
Hans G, Deseure K, Robert D, and De Hert S
- Subjects
- Adult, Behavior drug effects, Behavior physiology, Biophysics methods, Dose-Response Relationship, Drug, Double-Blind Method, Endothelin-1 adverse effects, Humans, Hyperalgesia chemically induced, Hyperalgesia metabolism, Hyperalgesia physiopathology, Injections, Intradermal adverse effects, Male, Models, Neurological, Neoplasms metabolism, Nociceptors drug effects, Pain chemically induced, Receptor, Endothelin A agonists, Receptor, Endothelin A metabolism, Sensory Receptor Cells drug effects, Sensory Receptor Cells physiopathology, Thermosensing drug effects, Thermosensing physiology, Endothelin-1 metabolism, Neoplasms complications, Neoplasms physiopathology, Nociceptors physiology, Pain metabolism, Pain physiopathology
- Abstract
Although pain is a frequent feature in patients with cancer, its etiology is still poorly understood. In recent years, endothelin-1 (ET-1) has become a major target molecule in the etiology of cancer pain. In this randomised, double-blind study the effects of intradermal injection of ET-1 on spontaneous pain, temperature perception and sensation of punctate stimulation were evaluated. Thirty-five subjects were randomised to receive either placebo or one of four concentrations of ET-1 (ranging from 10(-10) to 10(-6)M). Besides assessment of spontaneous pain, three neurosensory testings were performed: (1) cold and warm sensation, (2) cold and heat pain, and (3) punctate stimulation using a von Frey monofilament. ET-1 produced a dose-dependent flare zone that was absent after placebo injection. Subjects reported a short-lasting spontaneous pain upon administration of the highest concentrations of ET-1. Injection of ET-1 induced a long-lasting and dose-dependent punctate hyperalgesia in an area around the injection site (secondary hyperalgesia). Thermal testing revealed a short period of hypoesthesia to non-noxious warm and cold stimuli after some doses of ET-1. In addition to the mechanical hyperalgesia, intradermal injection of ET-1 almost instantaneously induced a state of cold hyperalgesia outlasting the study period (120 min). No development of heat hyperalgesia was observed. The observed psychophysical characteristics of this new model of ET-1 induced nociception indicate its potential as a human experimental model for cancer pain.
- Published
- 2007
- Full Text
- View/download PDF
23. Intrahippocampal injection of endothelin-1 in immature rats results in neuronal death, development of epilepsy and behavioral abnormalities later in life.
- Author
-
Mátéffyová A, Otáhal J, Tsenov G, Mares P, and Kubová H
- Subjects
- Age Factors, Animals, Animals, Newborn, Cerebral Arteries drug effects, Cerebral Arteries physiopathology, Cerebrovascular Circulation drug effects, Developmental Disabilities chemically induced, Developmental Disabilities physiopathology, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Administration Schedule, Electroencephalography drug effects, Epilepsy chemically induced, Hippocampus drug effects, Humans, Hypoxia-Ischemia, Brain chemically induced, Hypoxia-Ischemia, Brain physiopathology, Infant, Newborn, Male, Memory Disorders chemically induced, Memory Disorders physiopathology, Nerve Degeneration chemically induced, Nerve Degeneration pathology, Nerve Degeneration physiopathology, Rats, Rats, Wistar, Stroke chemically induced, Stroke physiopathology, Vasoconstrictor Agents adverse effects, Endothelin-1 adverse effects, Epilepsy physiopathology, Hippocampus pathology, Hippocampus physiopathology, Hypoxia-Ischemia, Brain complications, Stroke complications
- Abstract
The direct injection of endothelin-1 (ET-1) into brain parenchyma was recently suggested as a suitable model of stroke. The present study was designed to assess whether intrahippocampal injection of ET-1 in immature rats causes neurodegeneration and immediate seizures, and results in impairment of motor development, cognitive decline, epilepsy and chronic hippocampal lesion. ET-1 was injected unilaterally into the dorsal hippocampus in doses of 20 or 40 pmol at the age of 12 (P12) or 25 (P25) days. Video-electroencephalographic monitoring performed during 100 min after the injection of ET-1 demonstrated the development of convulsive epileptic seizures in 75-100% of animals of individual age-and-dose groups. Long-term behavioral follow-up did not reveal impairment of motor development in any dose-and-age group. At 2 months after ET-1 injection, impairment of spatial memory occurred only in rats with 40 pmol of ET-1 at P12. At 3 months after ET-1 injection spontaneous electrographic seizures occurred in 62.5-100% animals of both ages with no relation to the dose used. Seizures were always non-convulsive. The total seizure duration per 24 h was higher in the P12 than the P25 group, suggesting more severe epilepsy. The extent of the hippocampal lesion increased with the dose of ET-1 and was significantly higher in the P12 than the P25 group. The severity of the ET-1-induced lesion correlated positively with total seizure duration per 24 h at both ages. Our results document that early intrahippocampal injection of ET-1 results in lesion development and both immediate seizures and chronic epilepsy in either age group. Cognitive impairment occurred only in rats with ET-1 injection at P12.
- Published
- 2006
- Full Text
- View/download PDF
24. Endothelin-1 impairs retrograde axonal transport and leads to axonal injury in rat optic nerve.
- Author
-
Taniguchi T, Shimazawa M, Sasaoka M, Shimazaki A, and Hara H
- Subjects
- Animals, Axonal Transport physiology, Axons drug effects, Axons pathology, Disease Models, Animal, Dose-Response Relationship, Drug, Endothelin-1 metabolism, Glaucoma, Open-Angle complications, Male, Optic Disk blood supply, Optic Disk drug effects, Optic Neuropathy, Ischemic chemically induced, Optic Neuropathy, Ischemic pathology, Rats, Rats, Sprague-Dawley, Retinal Artery drug effects, Retinal Artery physiopathology, Retinal Degeneration chemically induced, Retinal Degeneration pathology, Retinal Ganglion Cells drug effects, Retinal Ganglion Cells pathology, Stilbamidines, Vasoconstriction drug effects, Vasoconstriction physiology, Wallerian Degeneration chemically induced, Wallerian Degeneration pathology, Wallerian Degeneration physiopathology, Axonal Transport drug effects, Endothelin-1 adverse effects, Glaucoma, Open-Angle physiopathology, Optic Disk physiopathology, Optic Neuropathy, Ischemic physiopathology, Retinal Degeneration physiopathology
- Abstract
The purpose of this study was to examine the effects of endothelin-1 (ET-1) on retrograde axonal transport in the rat optic nerve. Vehicle or ET-1 (0.2, 1, or 5 pmol/eye) were injected into the vitreous body in Sprague-Dawley rats. Retinal vessels were observed, using a fundus camera, before, and at 10 min, 3 days and 7 days after a single intravitreous injection. Two days after the injection, a neuronal tracer, fluoro gold, was administered via the superior colliculi to retrogradely label active retinal ganglion cells (RGCs). Five days after the tracer administration, retrogradely labeled RGCs were evaluated in the flat-mounted retina, and cross sections from each optic nerve were graded for injury by four independent, masked observers. ET-1 at 5 pmol/eye caused a significant constriction of retinal vessels (versus the vehicle-treated group) at 10 min after the injection. Intravitreous injection of ET-1 caused a dose-related decrease in the number of retrogradely labeled RGCs. Injection of 5 pmol/eye ET-1 led to a statistically significant decrease in the number of retrogradely labeled RGCs (versus the vehicle-treated group). ET-1 at 1 and 5 pmol/eye caused histological optic nerve damage (evaluated using a graded scale). The histological optic nerve damage correlated with the number of retrogradely labeled RGCs. In conclusion, a single intravitreous injection of ET-1 impaired retrograde axonal transport in the rat optic nerve and this impairment correlated with the histological optic nerve damage.
- Published
- 2006
- Full Text
- View/download PDF
25. Atrasentan for metastatic hormone refractory prostate cancer.
- Author
-
Murphy G
- Subjects
- Bone Neoplasms drug therapy, Bone Neoplasms secondary, Canada, Clinical Trials, Phase II as Topic, Clinical Trials, Phase III as Topic, Drug Approval, Endothelin-1 adverse effects, Endothelin-1 antagonists & inhibitors, Endothelin-1 physiology, Humans, Male, Neoplasm Metastasis, Prostatic Neoplasms complications, Pyrrolidines administration & dosage, Pyrrolidines adverse effects, Randomized Controlled Trials as Topic, Survival Rate, Treatment Outcome, United States, United States Food and Drug Administration, Endothelin Receptor Antagonists, Endothelin-1 therapeutic use, Prostatic Neoplasms drug therapy, Pyrrolidines therapeutic use
- Abstract
(1) Atrasentan (Xinlay(R)) is an anti-cancer drug from a new class of agents called selective endothelin-A receptor antagonists. The orally administered drug is being studied in a subset of patients with advanced prostate cancer. (2) Phase II and III studies evaluating time to clinical and radiographic progression failed to demonstrate a significant benefit with atrasentan versus placebo. (3) The adverse effects, observed more frequently in those treated with atrasentan than in placebo-treated patients, were peripheral edema, rhinitis, headache, infection, dyspnea, and heart failure. (4) Atrasentan's role in the various stages of advanced prostate cancer, and relative to the chemotherapeutic agent docetaxel, has not been determined.
- Published
- 2005
26. On-line monitoring of striatum glucose and lactate in the endothelin-1 rat model of transient focal cerebral ischemia using microdialysis and flow-injection analysis with biosensors.
- Author
-
Gramsbergen JB, Skjøth-Rasmussen J, Rasmussen C, and Lambertsen KL
- Subjects
- Animals, Cerebral Infarction metabolism, Cerebral Infarction pathology, Cerebral Infarction physiopathology, Cerebrovascular Circulation physiology, Corpus Striatum pathology, Corpus Striatum physiopathology, Disease Models, Animal, Endothelin-1 adverse effects, Energy Metabolism physiology, Flow Injection Analysis, Glucose metabolism, Ischemic Attack, Transient pathology, Ischemic Attack, Transient physiopathology, Lactic Acid metabolism, Male, Microdialysis instrumentation, Neurochemistry methods, Rats, Rats, Sprague-Dawley, Signal Processing, Computer-Assisted, Time Factors, Up-Regulation drug effects, Up-Regulation physiology, Biosensing Techniques methods, Corpus Striatum metabolism, Glucose analysis, Ischemic Attack, Transient metabolism, Lactic Acid analysis, Microdialysis methods
- Abstract
In vivo studies on cerebral glucose and lactate metabolism following a brain insult require fast and sensitive monitoring techniques. Here we report on-line monitoring of ischemic events and metabolic changes following reperfusion in striatum of freely moving rats subjected to endothelin-1 (60-240 pmol) induced, transient focal cerebral ischemia using slow microdialysis (0.5 microl/min), fast sampling (every minute) and flow-injection analysis with biosensors for glucose and lactate. The high-time resolution provides detailed information on lactate rise times and duration of low glucose. In rats, developing large striatal lesions, lactate increased from 1.0 +/- 0.1 to 4.2 +/- 0.7 mM within 37 +/- 1 min, whereas glucose dropped from 0.3 +/- 0.1 mM to below detection levels (<0.05 mM) for a period of 80 +/- 18 min. The lactate increase measured over a 2-h period after endothelin-1 infusion was highly correlated with striatal infarct size. In some rats oscillatory changes are observed which cannot be detected in traditional assays. The here-described monitoring technique applied in a clinically relevant rat model is a sensitive tool to study post-ischemic energy metabolism, effects of therapeutic interventions and its relationship with histological outcome.
- Published
- 2004
- Full Text
- View/download PDF
27. Effects of endothelins on cardiac and vascular cells: new therapeutic target for the future?
- Author
-
Mohácsi A, Magyar J, Tamás B, and Nánási PP
- Subjects
- Animals, Electric Stimulation, Humans, Muscle, Smooth, Vascular metabolism, Muscle, Smooth, Vascular physiology, Myocytes, Cardiac metabolism, Protein Isoforms, Signal Transduction drug effects, Ventricular Fibrillation drug therapy, Calcium metabolism, Endothelin Receptor Antagonists, Endothelin-1 adverse effects, Endothelin-1 metabolism, Endothelin-1 physiology, Endothelins antagonists & inhibitors, Endothelins biosynthesis, Endothelins physiology, Muscle, Smooth, Vascular drug effects, Myocardial Contraction drug effects, Myocardial Contraction physiology, Myocytes, Cardiac drug effects, Vasoconstriction drug effects, Vasoconstriction physiology
- Abstract
The predominant isoform of the endothelin peptide family. endothelin-1 (ET-1) exerts various biological effects. These include effects on arterial smooth muscle cells causing intense vasoconstriction and stimulation of cardiac cells. ET-1 promotes changes in cardiomyocytes that are consistent with electrical remodelling such as changes in ionic current density and inhomogeneous prolongation of action potential duration resulting in increased dispersion. As for the underlying mechanisms, ET-1 was shown to suppress several cAMP-dependent ionic currents, such as ICa, IK and ICl in various mammalian cardiac preparations including human myocytes; however, the degree of suppression of these currents is different and highly dependent on experimental conditions. The proposed arrhythmogenic effects of ET-1 may also involve enhancement of Ca2+ release from intracellular stores, generation of IP3, and acidosis due to stimulation of the Na+/H+ exchange. Furthermore, ET-1 acts as the natural counterpart to endothelium-derived nitric oxide, which exerts vasodilator, antithrombotic and antiproliferative effects, and inhibits leukocyte adhesion to the vascular wall. Effects of ET-1 are mediated through interaction with two major types of cell surface receptors. ETA receptors have been associated with electrical remodelling, vasoconstriction and cell growth, while ETB receptors are involved in the clearance of ET-1, inhibition of endothelial apoptosis, release of NO and prostacyclins, and inhibition of the expression of ET-1 converting enzyme. The derangement of endothelial function in various cardiovascular diseases, such as cardiomyopathies, hypertension or arteriosclerosis, is a crucial element of the pathomechanism, thus ET receptors are considered as important therapeutic targets. Indeed, ET receptor antagonists may be able to preserve or restore endothelial integrity and may have antiarrhythmic properties; therefore, they are promising tools in cardiovascular medicine.
- Published
- 2004
- Full Text
- View/download PDF
28. Effect of phosphodiesterase III inhibitor (Olprinone) on thoracic duct lymph flow in anesthetized sheep with experimentally induced heart failure by endothelin-1.
- Author
-
Tomoyasu M, Onizuka M, Inagaki M, Sato Y, Yamamoto T, Ishikawa S, and Mitsui T
- Subjects
- 3',5'-Cyclic-AMP Phosphodiesterases antagonists & inhibitors, Animals, Cardiac Output drug effects, Central Venous Pressure drug effects, Cyclic Nucleotide Phosphodiesterases, Type 3, Disease Models, Animal, Endothelin-1 administration & dosage, Female, Lung chemistry, Lung drug effects, Male, Models, Cardiovascular, Renal Circulation drug effects, Sheep, Shock, Cardiogenic chemically induced, Shock, Cardiogenic drug therapy, Thoracic Duct drug effects, Time Factors, Treatment Outcome, Vascular Resistance drug effects, Endothelin-1 adverse effects, Enzyme Inhibitors therapeutic use, Heart Failure chemically induced, Heart Failure drug therapy, Imidazoles pharmacology, Pyridones pharmacology
- Abstract
We investigated the short-term effects of a phosphodiesterase III inhibitor (Olprinone) on hemodynamics and thoracic duct lymph flow in anesthetized open-chest sheep with heart failure induced by endothelin-1 (cardiogenic shock). Ultrasound transit-time flow probes were attached to the thoracic duct, the ascending aorta and the renal artery. Arterial, pulmonary and central venous pressures were monitored. Endothelin-1 was infused intravenously at a dosage that reduced cardiac output to 50% or more of baseline (n=11). The effects of Olprinone were examined (n=5) by intravenous infusion after endothelin-1 administration. Other sheep (n=6) were used as controls. Olprinone significantly increased cardiac output that had been decreased by endothelin-1 and further increased thoracic duct flow that had been increased by endothelin-1. Increased arterial and pulmonary pressures induced by endothelin-1 administration were rapidly decreased by Olprinone. Renal arterial flow and central venous pressure were, however, unchanged by Olprinone. Overall, Olprinone acutely improved experimental cardiogenic shock (heart failure) induced by endothelin-1, and maintained thoracic duct lymph flow at a high level after endothelin-1 administration.
- Published
- 2002
29. [Inhibitory action of metoprolol and gamma--aminobutyric acid on heart rhythm disorder induced by administration of endothelin-1 into rostral ventrolateral medulla in cats].
- Author
-
Yang XL, Fu WJ, and Xu SL
- Subjects
- Animals, Arrhythmias, Cardiac chemically induced, Cats, Endothelin-1 adverse effects, Medulla Oblongata drug effects, Arrhythmias, Cardiac prevention & control, Metoprolol pharmacology, gamma-Aminobutyric Acid pharmacology
- Published
- 2002
30. Endothelin-1 as a target for therapeutic intervention in prostate cancer.
- Author
-
Kopetz ES, Nelson JB, and Carducci MA
- Subjects
- Apoptosis, Endothelin Receptor Antagonists, Half-Life, Humans, Male, Neovascularization, Pathologic, Tissue Distribution, Endothelin-1 adverse effects, Endothelin-1 antagonists & inhibitors, Endothelin-1 biosynthesis, Prostatic Neoplasms blood supply, Prostatic Neoplasms drug therapy, Prostatic Neoplasms physiopathology, Receptors, Endothelin physiology
- Abstract
The endothelins, a family of potent vasoconstricting peptides, have been implicated in the pathophysiology of advanced prostate cancer. Two endothelin receptors, ET-A and ET-B are found in normal prostate tissue. Malignant prostate cells are notable for the loss of ET-B receptors and increased levels of endothelin-1 [ET-1]; this distortion of the endothelin system may be a significant factor in the progression of prostate cancer. Proposed roles for endothelin in prostate cancer include growth promotion, apoptosis inhibition, bone formation, and stimulation of nociceptive receptors. ET-1 can act alone as a mitogen, but its effects are greatest as a comitogen with a variety of growth factors, including basic fibroblast growth factor, insulin-like growth factors, and platelet derived growth factor. Although their exact functions are unclear, ET-1, in conjunction with vascular endothelial growth factor, appears to play a major role in tumor angiogenesis. By a variety of methods, ET-1 alters the balance of osteoblast and osteoclasts to the favor new bone formation that is characteristic of metastatic disease. Several studies indicate that the refractory pain of metastatic cancer is related to the direct nociceptive effects ET-1. These findings suggest that ET receptors are promising therapeutic targets for pharmacologic intervention. Early clinical trials indicate that the ET-A receptor antagonist used in prostate cancer is reasonably well tolerated with mild but pervasive symptoms related to ET-1's vasoconstrictive effects. Results of ongoing clinical trials are eagerly awaited in order to see if the hypothetical promise of ET antagonism will result in clinical success.
- Published
- 2002
- Full Text
- View/download PDF
31. Endothelin, nephropathy, and blood pressure.
- Author
-
Luft FC
- Subjects
- Animals, Endothelin-1 adverse effects, Endothelin-1 biosynthesis, Endothelin-1 genetics, Kidney Diseases etiology, Mice, Mice, Transgenic, Blood Pressure physiology, Endothelin-1 physiology, Heart physiopathology, Kidney Diseases blood, Kidney Diseases physiopathology
- Published
- 2002
- Full Text
- View/download PDF
32. Functional interactions between tumor and peripheral nerve: morphology, algogen identification, and behavioral characterization of a new murine model of cancer pain.
- Author
-
Wacnik PW, Eikmeier LJ, Ruggles TR, Ramnaraine ML, Walcheck BK, Beitz AJ, and Wilcox GL
- Subjects
- Animals, Behavior, Animal, Calcaneus pathology, Calcaneus surgery, Crosses, Genetic, Endothelin-1 adverse effects, Endothelin-1 biosynthesis, Endothelin-1 metabolism, Fibrosarcoma complications, Fibrosarcoma pathology, Hindlimb pathology, Hindlimb physiopathology, Hyperalgesia diagnosis, Hyperalgesia etiology, Hyperalgesia physiopathology, Melanoma, Experimental complications, Melanoma, Experimental pathology, Mice, Mice, Inbred C3H, Mice, Inbred C57BL, Neoplasm Transplantation, Neoplasms, Experimental complications, Neoplasms, Experimental pathology, Pain diagnosis, Pain etiology, Pain Measurement drug effects, Peripheral Nerves pathology, Physical Stimulation, Tumor Cells, Cultured, Disease Models, Animal, Fibrosarcoma physiopathology, Melanoma, Experimental physiopathology, Neoplasms, Experimental physiopathology, Pain physiopathology, Peripheral Nerves physiopathology
- Abstract
This paper describes a model of tumor-induced bone destruction and hyperalgesia produced by implantation of fibrosarcoma cells into the mouse calcaneus bone. Histological examination indicates that tumor cells adhere to the bone edge as early as post-implantation day (PID) 3, but osteolysis does not begin until PID 6, correlating with the development of hyperalgesia. C3H/He mice exhibit a reproducible hyperalgesia to mechanical and cold stimuli between PID 6 and 16. These behaviors are present but significantly reduced with subcutaneous implantation that does not involve bone. Systemic administration of morphine (ED(50) 9.0 mg/kg) dose-dependently attenuated the mechanical hyperalgesia. In contrast, bone destruction and hypersensitivity were not evident in mice implanted with melanoma tumors or a paraffin mass of similar size. A novel microperfusion technique was used to identify elevated levels of the putative algogen endothelin (ET) in perfusates collected from the tumor sites of hyperalgesic mice between PID 7 and 12. Increased ET was evident in microperfusates from fibrosarcoma tumor-implanted mice but not from melanoma tumor-implanted mice, which are not hyperalgesic. Intraplantar injection of ET-1 in naive and, to a greater extent, fibrosarcoma tumor-bearing mice produced spontaneous pain behaviors, suggesting that ET-1 activates primary afferent fibers. Intraplantar but not systemic injection of the ET-A receptor antagonist BQ-123 partially blocked tumor-associated mechanical hyperalgesia, indicating that ET-1 contributes to tumor-induced nociception. This model provides a unique approach for quantifying the behavioral, biochemical, and electrophysiological consequences of tumor-nerve interactions.
- Published
- 2001
33. A serial MR study of cerebral blood flow changes and lesion development following endothelin-1-induced ischemia in rats.
- Author
-
Biernaskie J, Corbett D, Peeling J, Wells J, and Lei H
- Subjects
- Animals, Brain Ischemia chemically induced, Endothelin-1 adverse effects, Male, Rats, Rats, Sprague-Dawley, Brain Ischemia pathology, Brain Ischemia physiopathology, Cerebrovascular Circulation, Magnetic Resonance Imaging
- Abstract
The vasoconstrictive peptide endothelin-1 (ET-1) has been used previously to transiently occlude the middle cerebral artery (MCA) in rats. However, the duration of the resulting reduction in cerebral blood flow (CBF) and the reperfusion characteristics are poorly understood. In this study perfusion and T(2)-weighted MRI were used together with histology to characterize the cerebral perfusion dynamics and lesion development following ET-1 injection. Twenty-two rats received an intracerebral injection of ET-1 adjacent to the MCA. CBF was reduced to 30-50% of control levels, and a significant reduction persisted for 16 h in the cortex and 7 h in the striatum. The lesion size measured by T(2)-weighted imaging at 48 h correlated with the final infarct size measured by histology at 7 d. The sustained reduction in CBF and the gradual development of the ischemic lesion resemble human stroke evolution, suggesting that this model may be useful for evaluating therapeutic agents, particularly when treatment is delayed., (Copyright 2001 Wiley-Liss, Inc.)
- Published
- 2001
- Full Text
- View/download PDF
34. New strategies in the prevention of restenosis.
- Author
-
Angerio AD and Fink DA
- Subjects
- Angioplasty, Balloon, Coronary methods, Coronary Stenosis diagnosis, Coronary Stenosis therapy, Endothelin-1 adverse effects, Humans, Prognosis, Risk Assessment, Secondary Prevention, Stents adverse effects, Angioplasty, Balloon, Coronary adverse effects, Coronary Stenosis prevention & control, Endothelial Growth Factors antagonists & inhibitors, Endothelial Growth Factors metabolism, Endothelin-1 metabolism, Endothelium, Vascular metabolism, Primary Prevention methods
- Abstract
Restenosis is a common and serious complication following angioplasty and stent implantation in patients with arterial vascular disease. Restenosis is a form of intimal hyperplasia. Endothelin-1 (ET-1) and vascular endothelial growth factor (VEGF) stimulate intimal hyperplasia and may play a role in restenosis. ET-1 and VEGF may act in concert in promoting restenosis following mechanical injury to the vessel wall in angioplasty and stent implantation. An understanding of their mechanism of action may lead to more effective methods for preventing restenosis. ET-1 receptor antagonists may play a prominent role in prophylaxis.
- Published
- 2001
- Full Text
- View/download PDF
35. Arrhythmogenic action of endothelin-1.
- Author
-
Merkely B, Kiss O, Vágó H, Zima E, Szabó T, and Gellér L
- Subjects
- Animals, Arrhythmias, Cardiac drug therapy, Dogs, Drug Administration Schedule, Endothelin Receptor Antagonists, Myocardial Ischemia chemically induced, Phenylpropionates therapeutic use, Pyrimidines therapeutic use, Receptor, Endothelin A, Arrhythmias, Cardiac chemically induced, Endothelin-1 adverse effects
- Published
- 2000
- Full Text
- View/download PDF
36. Re: 'Ventricular arrhythmias induced by endothelin-1 or by acute ischemia: a comparative analysis using three dimensional mapping' (Cardiovasc Res 2000;45:310-320).
- Author
-
Duru F, Barton M, and Candinas R
- Subjects
- Animals, Arrhythmias, Cardiac chemically induced, Dogs, Heart Ventricles, Arrhythmias, Cardiac etiology, Endothelin-1 adverse effects, Myocardial Ischemia complications
- Published
- 2000
- Full Text
- View/download PDF
37. Endothelial dysfunction in diabetes mellitus.
- Author
-
Schiekofer S, Balletshofer B, Andrassy M, Bierhaus A, and Nawroth PP
- Subjects
- Diabetes Mellitus physiopathology, Endothelin-1 adverse effects, Endothelin-1 metabolism, Endothelium, Vascular metabolism, Glucose Intolerance blood, Glucose Intolerance pathology, Humans, Vascular Diseases blood, Vascular Diseases etiology, Diabetes Mellitus blood, Endothelium, Vascular physiopathology
- Abstract
Diabetes mellitus and impaired glucose tolerance are linked to increased cardiovascular morbidity and mortality. Vascular disease is directly associated with plasma glucose levels, and reduction of these levels forestalls to a certain extent the vascular complications of diabetes, such as myocardial infarction, nephropathies, and retinopathies. In addition to hyperglycemia, there are other risk factors that play a prominent role, such as hypertension, hyperlipidemia, and genetic factors. Endothelial dysfunction is one of the major factors in the development of cardiovascular disease. The vascular endothelium regulates the blood flow by tightly controlling the coagulation system, cell-cell interaction, and vascular tone. These functions are disturbed in diabetic patients. In diabetics, endothelin-1 levels are increased, leading to vasoconstriction. Endothelin levels are directly related to plasma glucose levels. In addition, the endothelial cell-NO axis is disturbed. NO release and function are impaired. This seems to be dependent upon hyperglycemia and genetic factors. Impaired NO function also results in vasoconstriction. Furthermore, enhanced vascular permeability is seen in diabetics. This appears to be related to impaired endothelial cell relaxation and reactive oxygen species as well as advanced glycosylated end products (AGEs). The complex changes seen in diabetes and even prediabetes are therefore related to numerous derailments related to endothelial dysfunction, and no single therapeutic approach is likely to solve the problem of vascular complications.
- Published
- 2000
- Full Text
- View/download PDF
38. [Pathological action of endothelin-1 on the heart: coronary spasm and arrhythmia].
- Author
-
Juhász-Nagy S
- Subjects
- Humans, Arrhythmias, Cardiac chemically induced, Coronary Disease chemically induced, Endothelin-1 adverse effects, Heart drug effects
- Abstract
Endothelin-1 (ET-1), the member of a newly discovered family of vasoactive peptides is the most aggressive endogenous vasoconstrictor agent known to science. This paper summarizes the recent work of a Hungarian research group related to the regulatory role of ET-1 in the mammalian heart. The results highlighted the unique pathophysiological and clinical features of the ET-1 action in the coronary vascular bed suggesting the potential role of the peptide in precipitating coronary spasm as well as its outstanding capacity for inducing cardiac arrhythmias. Contrary to the classical tenets of homeostasis, such effects do not reduce but increase variability and inhomogeneity (both in myocardial blood flow distribution and generation of electrical impulses), indicating the involvement of new types of regulatory principles in the cardiovascular system.
- Published
- 1999
39. [Effect of endothelin-1 injected into rostral ventrolateral medulla on cardiovascular responses in cats].
- Author
-
Yang XL, Fu WJ, Hou GX, and Chen JG
- Subjects
- Animals, Cats, Endothelin-1 adverse effects, Female, Male, Microinjections, Phentolamine pharmacology, Sympathetic Nervous System drug effects, Sympatholytics pharmacology, Vagotomy, Blood Pressure drug effects, Endothelin-1 pharmacology, Heart Rate drug effects, Medulla Oblongata physiology
- Abstract
Aim: To study the effect of endothelin-1 (ET-1) in the rostral ventrolateral medulla (rVLM) on cardiovascular responses in cats., Methods: The stereotatic technique and microinjection method were used., Results: ET-1 (4 mumol.L-1 0.5 microL) microinjected into rVLM induced mean arterial pressure (MAP) increasing (3.7 +/- 1.3) kPa, heart rate (HR) accelerating (29 +/- 7) beats.min-1, and renal nerve activity (RNA) intensifying 45% +/- 10%. The effects were dose-dependent. Before and after bilateral vagotomy, there was no significant difference in the reaction of MAP, HR, and RNA. After intravenous injection with phentolamine (5 mg.kg-1, alpha-blocker), ET-1 did not induce significant change of MAP. ET-1 raised the content of peripheral plasma argipressin (Arg) from (12.4 +/- 6.5) to (70.3 +/- 24.2) ng.L-1 with radioimmunoassay, and showed a correlation with MAP changes. ET-1 induced heart rhythm disorder (HRhD) in acute myocardiac ischemia, the occur time of HRhD was (4.8 +/- 2.9) min, and the score was 4.4 +/- 1.6, and it was significantly different from control., Conclusion: ET-1 microinjected into rVLM could involve with control regulation of cardiovascular and sympathetic nerve activity.
- Published
- 1999
40. ET-1 infusion increases systemic vascular resistance and depresses cardiac output in patients with chronic hypoxaemia and pulmonary hypertension.
- Author
-
Franco-Cereceda A, Holm P, Brodin LA, Liska J, and Larsen FF
- Subjects
- Abdominal Pain chemically induced, Aged, Carbon Dioxide blood, Case-Control Studies, Endothelin-1 adverse effects, Endothelin-1 blood, Female, Humans, Hypertension, Pulmonary drug therapy, Hypoxia drug therapy, Male, Middle Aged, Oxygen blood, Partial Pressure, Vasoconstriction drug effects, Cardiac Output drug effects, Endothelin-1 pharmacology, Hypertension, Pulmonary physiopathology, Hypoxia physiopathology, Vascular Resistance drug effects
- Abstract
The pulmonary vascular effects of the endothelium-derived peptide endothelin (ET) vary depending on the existing vascular tone, modes of administration and species studied; ET can cause both pulmonary vasodilatation and vasoconstriction. Increased plasma levels of ET have been reported in hypoxic pulmonary hypertension, although it is unclear whether ET is a mediator or a marker of hypoxia-induced increase in pulmonary vascular resistance (PVR). In our study, the plasma levels of ET-1 and the functional effects of ET-1 infusion in patients (n = 4) with chronic hypoxaemia and elevated PVR were evaluated. At rest, the arterial and venous ET-1-levels (13 +/- 2 and 12 +/- 1 fmol/ml, respectively) were significantly higher than those detected in venous plasma of an age-matched healthy control group (7 +/- 1 fmol/ml). Consecutive 10 min infusions of ET-1 at 1, 5, 10 and 15 ng/kg/min into the pulmonary artery decreased cardiac output (by 32%) and stroke volume (by 33%) and increased the systemic vascular resistance (by 62%) and arteriovenous oxygen difference (by 83%) at the highest dose. No deleterious effect was observed in the pulmonary circulation. The present study therefore suggests that intra-pulmonarily administered ET does not attenuate the increased PVR associated with chronic hypoxaemia.
- Published
- 1999
- Full Text
- View/download PDF
41. Endothelin-1 and bronchial hyperresponsiveness in the rabbit.
- Author
-
D'Agostino B, Filippelli A, Falciani M, Rossi F, and Rossi F
- Subjects
- Airway Resistance drug effects, Animals, Bronchial Hyperreactivity etiology, Bronchoalveolar Lavage, Bronchoalveolar Lavage Fluid cytology, Capsaicin pharmacology, Dose-Response Relationship, Drug, Endothelin-1 adverse effects, Eosinophils cytology, Eosinophils drug effects, Female, Histamine pharmacology, Leukocyte Count drug effects, Leukocytes, Mononuclear cytology, Leukocytes, Mononuclear drug effects, Lung drug effects, Lung physiology, Lung physiopathology, Male, Neutrophils cytology, Neutrophils drug effects, Rabbits, Bronchial Hyperreactivity physiopathology, Endothelin-1 pharmacology
- Abstract
Endothelins (ETs) are a family of peptide mediators that have a number of biological properties, including the ability to act as potent bronchoconstrictors of isolated human airways. Moreover, elevated concentrations of ET-1 in the bronchoalveolar lavage fluid from patients with symptomatic asthma have also been detected. We investigated the possible contribution of ET-1 in the development of bronchial hyperresponsiveness and the role of inflammatory cell accumulation in rabbit lungs. Our data show that ET-1 challenge to rabbits does not modify basal lung function but results in an increased airway responsiveness to inhaled histamine. Endothelin-treated rabbits were 3-fold (P<0.01) more responsive to inhaled histamine when compared with vehicle-treated rabbits. This hyperresponsiveness was not associated with an alteration in either total or differential inflammatory cell numbers as assessed by bronchoalveolar lavage (BAL). Pre-treatment with capsaicin (80 mg/kg s.c.) did not alter basal lung function or basal responsiveness to inhaled histamine. While capsaicin had no significant effect on the acute bronchoconstriction induced by endothelin-1, this dose was sufficient to significantly inhibit the increase in airway responsiveness to inhaled histamine, achieved 24 h following endothelin-1 challenge. These results indicate that ET-1 may play a role in the development of bronchial hyperresponsiveness to inhaled histamine and that the maintenance of this state is unrelated to a detectable alteration in cellular infiltration within the airway lumen, but probably via the involvement of capsaicin-sensitive nerves.
- Published
- 1998
- Full Text
- View/download PDF
42. Effects of KRN4884 (a novel K+ channel opener), levcromakalim, nilvadipine and propranolol on endothelin-1-induced heart disorders in anesthetized rats.
- Author
-
Harada K, Kawahara J, Okada Y, Uzumaki H, Kusaka M, and Tokiwa T
- Subjects
- Anesthesia, Animals, Antihypertensive Agents therapeutic use, Blood Pressure drug effects, Bronchoconstrictor Agents pharmacology, Cromakalim pharmacology, Cromakalim therapeutic use, Electrocardiography drug effects, Endothelin-1 pharmacology, Heart Diseases chemically induced, Heart Rate drug effects, Injections, Intra-Arterial, Male, Methacholine Chloride pharmacology, Nifedipine analogs & derivatives, Nifedipine pharmacology, Nifedipine therapeutic use, Potassium Channels drug effects, Propranolol pharmacology, Propranolol therapeutic use, Pyridines pharmacology, Pyridines therapeutic use, Rats, Rats, Wistar, Antihypertensive Agents pharmacology, Endothelin-1 adverse effects, Heart Diseases prevention & control
- Abstract
The effects of KRN4884 (5-amino-N-[2-(2-chrolophenyl)ethyl]-N'-cyano-3-pyridinecarboxa midine), a novel K+ channel opener, on the electrocardiogram changes caused by the intracoronary administration of endothelin-1 (ET-1) were studied in anesthetized rats and compared with the effects of levcromakalim, a K+ channel opener; nilvadipine, a Ca2+ antagonist; and propranolol, a beta-adrenoceptor antagonist. KRN4884 (50 microg/kg, i.v.) and levcromakalim (300 microg/kg, i.v.) inhibited the ST segment elevation and the development of arrhythmias induced by ET-1 (5 microg, i.c.) and decreased the incidence of death. Nilvadipine (300 microg/kg, i.v.) and propranolol (1000 and 3000 microg/kg, i.v.) each prevented the ST segment elevation, but the suppressions of the occurrence of arrhythmias produced by nilvadipine and propranolol were less than that shown by KRN4884. KRN4884 (30 and 50 microg/kg, i.v.), levcromakalim (100 and 300 microg/kg, i.v.) and nilvadipine (100 and 300 microg/kg, i.v.) significantly decreased the mean blood pressure in a dose-dependent manner, but propranolol did not. The heart rate was decreased by nilvadipine (100 and 300 microg/kg, i.v.) and propranolol (1000 and 3000 microg/kg, i.v.), but was not affected by KRN4884 (30 and 50 microg/kg, i.v.) or levcromakalim (100 and 300 microg/kg, i.v.). These results suggest that pretreatments with KRN4884 and levcromakalim are more effective on ET-1-induced electrocardiogram changes than those with nilvadipine and propranolol.
- Published
- 1998
- Full Text
- View/download PDF
43. Augmentation of both hemolysate-induced contraction and activation of protein kinase C by submaximum activation in canine cerebral arteries in vitro.
- Author
-
Kawamata T, Peterson JW, Bun T, and Zervas NT
- Subjects
- Animals, Cell Membrane metabolism, Chronic Disease, Cytosol drug effects, Cytosol enzymology, Dogs, Endothelin-1 adverse effects, Enzyme Activation, Enzyme Inhibitors adverse effects, Ischemic Attack, Transient enzymology, Ischemic Attack, Transient etiology, Membrane Potentials drug effects, Muscle, Smooth, Vascular drug effects, Naphthalenes adverse effects, Phorbol 12,13-Dibutyrate adverse effects, Potassium pharmacology, Protein Binding drug effects, Protein Kinase C antagonists & inhibitors, Protein Kinase C metabolism, Stress, Mechanical, Subarachnoid Hemorrhage complications, Subarachnoid Hemorrhage metabolism, Vasoconstriction drug effects, Vasoconstriction physiology, Cerebral Arteries drug effects, Hemolysis, Ischemic Attack, Transient chemically induced, Phorbol Esters adverse effects, Protein Kinase C drug effects, Vasoconstrictor Agents adverse effects
- Abstract
Although phorbol esters, synthetic activators of protein kinase C (PKC), can stimulate large increases in the binding of cytosolic PKC to form membrane-bound PKC (PKCm, an indicator of PKC activation), the authors report that even small increases in PKCm induced by phorbol esters (8-12% of total PKC content) can be associated with significant PKC-mediated contractions in vitro (50-85% of maximum) in normal canine cerebral arteries. Increases in PKCm of similarly small magnitude were found in vitro when control artery segments were exposed to hemolysate, but only if the arterial smooth-muscle cells were first slightly depolarized by increased extracellular potassium to values of membrane potential similar to those observed in canine cerebral arteries during chronic cerebral vasospasm. These increases in PKCm (6-8% of total PKC content) coincided with a greatly augmented contractile response to hemolysate. These results show that the previous observation of only a small increase in PKCm (approximately 7% of total PKC content) after experimental subarachnoid hemorrhage in the canine model does not preclude a potentially important role for PKC-mediated contraction in the pathogenesis of cerebral vasospasm.
- Published
- 1997
- Full Text
- View/download PDF
44. Involvement of endothelin (ET)A and ETB receptors in the hypertrophic effects of ET-1 in rabbit ventricular cardiomyocytes.
- Author
-
Mullan DM, Bell D, Kelso EJ, and McDermott BJ
- Subjects
- Animals, Carbon Radioisotopes, Cardiomegaly physiopathology, Cells, Cultured, Contractile Proteins, Cycloheximide pharmacology, Endothelin Receptor Antagonists, Endothelin-1 pharmacology, Heart Ventricles cytology, Heart Ventricles drug effects, Heart Ventricles metabolism, In Vitro Techniques, Male, Muscle Proteins analysis, Muscle Proteins biosynthesis, Myocardium metabolism, Peptides, Cyclic pharmacology, Phenylalanine metabolism, Rabbits, Radioactive Tracers, Receptor, Endothelin A, Receptor, Endothelin B, Receptors, Endothelin drug effects, Uridine metabolism, Cardiomegaly chemically induced, Endothelin-1 adverse effects, Myocardium cytology, Receptors, Endothelin physiology
- Abstract
The question was addressed whether endothelin-1 (ET-1) exerts hypertrophic effects in cardiomyocytes isolated from ventricles of adult rabbits and maintained in short-term (24 h) serum-free primary culture providing mechanical quiescence. ET-1 (> or =100 pM) increased significantly total mass of cellular protein and incorporation of L-U-[(14)C]phenylalanine and 2-[(14)C]uridine into cellular protein and RNA, respectively. Cycloheximide (35 microM), an inhibitor of protein synthesis, significantly reduced the incorporation of L-U-[(14)C]phenylalanine and 2-[(14)C]uridine into cellular protein and RNA, respectively, under control conditions and in response to ET-1. Actinomycin D (5 microM), a selective inhibitor of transcription, abolished the incorporation of 2-[(14)C]uridine into cellular RNA and significantly reduced the incorporation of L-U-[(14)C]phenylalanine into cellular protein under control conditions and in response to ET-1. The selective antagonists at the ET(A) receptor [BQ123 (100 nM) and PD155080 (100 nM)] and the selective antagonist at the ET(B) receptor [BQ788 (100 nM)] significantly reduced the incorporation of L-U-[(14)C]phenylalanine into cellular protein in response to ET-1 (10 nM). The selective inhibitor of protein kinase C (PKC), bisindolylmaleimide (BIM) (5 microM), reduced markedly the incorporation of 2-[(14)C]uridine into cellular RNA and, to a lesser degree, the incorporation of L-U-[(14)C]phenylalanine into cellular protein in response to ET-1 (100 pM to 10 nM). ET-1 exerts hypertrophic effects directly in vitro in ventricular cardiomyocytes isolated from the hearts of adult rabbits. These effects are (a) due to de novo synthesis since total mass of cellular protein and incorporation of L-U-[(14)C]phenylalanine and 2-[(14)C]uridine into cellular protein and RNA, respectively, were increased; (b) mediated by both the ET(A) and ET(B) receptor subtypes; and (c) may be associated, at least partly, with the activation of PKC.
- Published
- 1997
- Full Text
- View/download PDF
45. [The clinical significance of endothelin].
- Author
-
Fyhrquist F and Saijonmaa O
- Subjects
- Animals, Arteriosclerosis physiopathology, Endothelin-1 adverse effects, Endothelin-1 biosynthesis, Endothelin-2 adverse effects, Endothelin-2 biosynthesis, Endothelin-3 adverse effects, Endothelin-3 biosynthesis, Endothelins adverse effects, Endothelins biosynthesis, Heart Failure physiopathology, Humans, Hypertension, Pulmonary physiopathology, Primary Prevention methods, Prognosis, Vasoconstriction, Arteriosclerosis drug therapy, Endothelins antagonists & inhibitors, Heart Failure drug therapy, Hypertension, Pulmonary drug therapy
- Published
- 1997
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.