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Jesus A Garciasevilla - One of the best experts on this subject based on the ideXlab platform.
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a biomarker to differentiate between primary and cocaine induced major depression in cocaine use disorder the role of platelet iras nischarin i1 Imidazoline Receptor
Frontiers in Psychiatry, 2017Co-Authors: Benjamin Keller, Jesus A Garciasevilla, Joanignasi Mestrepinto, Maria Alvarobartolome, Diana Martinezsanvisens, Magi Farre, Julia M Garciafuster, Marta TorrensAbstract:The association of cocaine use disorder (CUD) and comorbid major depressive disorder (MDD; CUD/MDD) is characterized by high prevalence and poor treatment outcomes. CUD/MDD may be primary (primary MDD) or cocaine-induced (CUD-induced MDD). Specific biomarkers are needed to improve diagnoses and therapeutic approaches in this dual pathology. Platelet biomarkers [5-HT2A Receptor and Imidazoline Receptor antisera selected (IRAS)/nischarin] were assessed by Western blot in subjects with CUD and primary MDD (n = 16) or CUD-induced MDD (n = 9; antidepressant free, AD−; antidepressant treated, AD+) and controls (n = 10) at basal level and/or after acute tryptophan depletion (ATD). Basal platelet 5-HT2A Receptor (monomer) was reduced in comorbid CUD/MDD subjects (all patients: 43%) compared to healthy controls, and this down-regulation was independent of AD medication (decreases in AD−: 47%, and in AD+: 40%). No basal differences were found for IRAS/nischarin contents in AD+ and AD− comorbid CUD/MDD subjects. The comparison of IRAS/nischarin in the different subject groups during/after ATD showed opposite modulations (i.e., increases and decreases) in response to low plasma tryptophan levels with significant differences discriminating between the subgroups of CUD with primary MDD and CUD-induced MDD. These specific alterations suggested that platelet IRAS/nischarin might be useful as a biomarker to discriminate between primary and CUD-induced MDD in this dual pathology.
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upregulation of iras nischarin i1 Imidazoline Receptor a regulatory protein of μ opioid Receptor trafficking in postmortem prefrontal cortex of long term opiate and mixed opiate cocaine abusers
Neurochemistry International, 2017Co-Authors: Benjamin Keller, Romano La Harpe, Jesus A GarciasevillaAbstract:Imidazoline Receptor antisera-selected (IRAS)/nischarin, a putative I1-Imidazoline Receptor, has recently been shown to regulate μ-opioid Receptor (OR) trafficking and resensitisation. To study a possible involvement of this μ-OR regulator in opiate dependence, the present study assessed by Western blot analysis the contents of IRAS/nischarin and μ-OR in total homogenates and subcellular preparations of postmortem human prefrontal cortex (PFC/BA9) of long-term opiate and mixed opiate/cocaine abusers as well as of matched healthy control subjects. In the PFC/BA9 of long-term opiate/cocaine abusers (all subjects together) IRAS/nischarin content was increased (+67%, p < 0.01, n = 11) when compared with matched controls (n = 10). Similar increases were found for the subgroups of opiate (+72%, n = 6) and mixed opiate/cocaine (+61%, n = 5) abusers. IRAS/nischarin immunocontents were also found increased in subcellular membrane preparations (+61%, p < 0.05, n = 10) of PFC/BA9 from opiate addicts. In the same brain samples, the levels of μ-OR were not different to those in control subjects. Based on the increased contents in brains of opiate abusers and the reported function as μ-OR regulator, IRAS/nischarin could represent a new promising target for treatment of opiate use disorder.
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inhibitory effects of Imidazoline Receptor ligands on basal and kainic acid induced neurotoxic signalling in mice
Journal of Psychopharmacology, 2016Co-Authors: Benjamin Keller, Jesus A GarciasevillaAbstract:This in vivo study assessed the potential of the Imidazoline Receptor (IR) ligands moxonidine (selective I1-IR), BU224 (selective I2-IR) and LSL61122 (mixed I1/I2-IR) to dampen excitotoxic signalling induced by kainic acid (KA; 45 mg/kg) in the mouse brain (hippocampus and cerebral cortex). KA triggered a strong behavioural syndrome (seizures; maximal at 60-90 minutes) and sustained stimulation (at 72 hours with otherwise normal mouse behaviour) of pro-apoptotic c-Jun-N-terminal kinases (JNK) and calpain with increased cleavage of p35 into neurotoxic p25 (cyclin-dependent kinase 5 [Cdk5] activators) in mouse hippocampus. Pretreatment (five days) with LSL61122 (10 mg/kg), but not moxonidine (1 mg/kg) or BU224 (20 mg/kg), attenuated the KA-induced behavioural syndrome, and all three IR ligands inhibited JNK and calpain activation, as well as p35/p25 cleavage after KA in the hippocampus (effects also observed after acute IR drug treatments). Efaroxan (I1-IR, 10 mg/kg) and idazoxan (I2-IR, 10 mg/kg), postulated IR antagonists, did not antagonise the effects of moxonidine and LSL61122 on KA targets (these IR ligands showed agonistic properties inhibiting pro-apoptotic JNK). Brain subcellular preparations revealed reduced synaptosomal postsynaptic density-95 protein contents (a mediator of JNK activation) and indicated increased p35/Cdk5 complexes (with pro-survival functions) after treatment with moxonidine, BU224 and LSL61122. These results showed that I1- and I2-IR ligands (moxonidine and BU224), and especially the mixed I1/I2-IR ligand LSL61122, are partly neuroprotective against KA-induced excitotoxic signalling. These findings suggest a therapeutic potential of IR drugs in disorders associated with glutamate-mediated neurodegeneration.
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immunodetection and subcellular distribution of Imidazoline Receptor proteins with three antibodies in mouse and human brains effects of treatments with i1 and i2 Imidazoline drugs
Journal of Psychopharmacology, 2015Co-Authors: Benjamin Keller, Jesus A GarciasevillaAbstract:Various Imidazoline Receptor (IR) proteins have been proposed to mediate the effects of selective I1- and I2-IR drugs. However, the association of these IR-binding proteins with classic I1- and I2-radioligand binding sites remains somewhat controversial. In this study, three IR antibodies (anti-NISCH and anti-nischarin for I1-IRs; and anti-IRBP for I1/I2-IRs) were used to immunodetect, characterize and compare IR protein patterns in brain (mouse and human; total homogenate, subcellular fractionation, grey and white matter) and some cell systems (neurones, astrocytes, human platelets). Various immunoreactive IRs (specific molecular weight bands coincidently detected with the different antibodies) were related to I1-IR (167 kDa, 105/115 kDa and 85 kDa proteins) or I2-IR (66 kDa, 45 kDa and 30 kDa proteins) types. The biochemical characterization of cortical 167 kDa protein, localized in the membrane/cytosol but not in the nucleus, indicated that this I1-IR also forms part of higher order nischarin-related c...
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induction of reactive astrocytosis and prevention of motoneuron cell death by the i2 Imidazoline Receptor ligand lsl 60101
British Journal of Pharmacology, 2000Co-Authors: Anna Casanovas, Gabriel Olmos, Joan Ribera, Assumpcio M Boronat, Josep E Esquerda, Jesus A GarciasevillaAbstract:I2-Imidazoline Receptors are mainly expressed on glial cells in the rat brain. This study was designed to test the effect of treatment with the I2-Imidazoline selective Receptor ligand LSL 60101 [2-(2-benzofuranyl)imidazole] on the morphology of astrocytes in the neonate and adult rat brain, and to explore the putative neuroprotective effects of this glial response. Short-term (3 days) or chronic (7–10 days) treatment with LSL 60101 (1 mg kg−1, i.p. every 12 h) enhanced the area covered by astroglial cells in sections of facial motor nucleus from neonate rats processed for glial fibrillary acidic protein (GFAP) immunostaining. Facial motoneurons surrounded by positive glial cell processes were frequently observed in sections of LSL 60101-treated rats. A similar glial response was observed in the parietal cortex of adult rats after chronic (10 days) treatment with LSL 60101 (10 mg kg−1, i.p. every 12 h). Western-blot detection of the specific astroglial glutamate transporter GLT-1, indicated increased immunoreactivity after LSL 60101 treatment in the pons of neonate and in the parietoccipital cortex of adult rats. In the facial motor nucleus of neonate rats, the glial response after LSL 60101 treatment was associated to a redistribution of the immunofluorescence of the basic fibroblast growth factor (FGF-2) from the perinuclear area of motoneurons to cover most of their cytoplasm, suggesting a translocation of this mitogenic and neurotrophic factor towards secretion pathways. The neuroprotective potential of the above effects of LSL 60101 treatment was tested after neonatal axotomy of facial motor nucleus. Treatment with LSL 60101 (1 mg kg−1, i.p. every 12 h from day 0 to day 10 after birth) significantly reduced (38%) motoneuron death rate 7 days after facial nerve axotomy performed on day 3 after birth. It is concluded that treatment with the I2-Imidazoline selective Receptor ligand LSL 60101 provokes morphological/biochemical changes in astroglia that are neuroprotective after neonatal axotomy. British Journal of Pharmacology (2000) 130, 1767–1776; doi:10.1038/sj.bjp.0703485
Paul Ernsberger - One of the best experts on this subject based on the ideXlab platform.
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Mechanisms of Antihyperglycemic Effects of Moxonidine in the Obese Spontaneously Hypertensive Koletsky Rat (SHROB)1
2016Co-Authors: Paul Ernsberger, Richard J Koletsky, Tatsuya Ishizuka, Sha Liu, Craig J. Farrell, David Bedol, Jacob E FriedmanAbstract:Increased activity of the sympathetic nervous system may be a critical factor in the development of impaired insulin secretion and insulin resistance. We studied the chronic effects of sym-pathetic inhibition with moxonidine on glucose metabolism in the spontaneously hypertensive genetically obese rat (SHROB). This unique animal model closely resembles human syndrome X, expressing insulin resistance, genetic obesity, spontaneous hypertension, and hyperlipoproteinemia. Moxonidine, a selec-tive Imidazoline Receptor agonist, was administered to lean spontaneous hypertensive rats (SHR) and SHROBs for 90 days in food at 8 mg/kg/day and significantly reduced mean blood pressure. Moxonidine treatment reduced fasting insulin levels by 71 % in SHROB and lowered plasma free fatty acids by 25%. In SHR, moxonidine treatment decreased free fatty acids b
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the i1 Imidazoline Receptor in pc12 pheochromocytoma cells activates protein kinases c extracellular signal regulated kinase erk and c jun n terminal kinase jnk
Journal of Neurochemistry, 2008Co-Authors: Lincoln Edwards, Daniel Fishman, Peleg M Horowitz, Nicole Bourbon, Mark Kester, Paul ErnsbergerAbstract:We sought to further elucidate signal transduction pathways for the I1-Imidazoline Receptor in PC12 cells by testing involvement of protein kinase C (PKC) isoforms (βII, e, ζ), and the mitogen-activated protein kinases (MAPK) ERK and JNK. Stimulation of I1-Imidazoline Receptor with moxonidine increased enzymatic activity of the classical βII isoform in membranes by about 75% and redistributed the atypical isoform into membranes (40% increase in membrane-bound activity), but the novel isoform of PKC was unaffected. Moxonidine and clonidine also increased by greater than two-fold the proportion of ERK-1 and ERK-2 in the phosphorylated active form. In addition, JNK enzymatic activity was increased by exposure to moxonidine. Activation of ERK and JNK followed similar time courses with peaks at 90 min. The action of moxonidine on ERK activation was blocked by the I1-Receptor antagonist efaroxan and by D609, an inhibitor of phosphatidylcholine-selective phospholipase C (PC-PLC), previously implicated as the initial event in I1-Receptor signaling. Inhibition or depletion of PKC blocked activation of ERK by moxonidine. Two-day treatment of PC12 cells with the I1/α2-agonist clonidine increased cell number by up to 50% in a dose related manner. These data suggest that ERK and JNK, along with PKC, are signaling components of the I1-Receptor pathway, and that this Receptor may play a role in cell growth.
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identification of iras nischarin as an i1 Imidazoline Receptor in pc12 rat pheochromocytoma cells
Journal of Neurochemistry, 2007Co-Authors: Chung Ho Chang, Paul ErnsbergerAbstract:The I1-Imidazoline Receptor (I1R) is a proposed target for drug action relevant to blood pressure and glucose control. The Imidazoline Receptor antisera-selected (IRAS) gene, also known as Nischarin, has several characteristics of an I1R. To test the contribution of IRAS to I1R binding capacity and cell-signaling function, an antisense probe targeting the initiating codon of rat IRAS gene was evaluated in PC12 rat pheochromocytoma cells, a well-established model for I1R action. The density of I1R was significantly reduced by antisense compared with control transfection (Bmax = 400 ± 16 vs. 691 ± 29 fmol/mg protein), without significantly affecting binding affinity (Kd = 0.30 ± 0.04 vs. 0.39 ± 0.05 nmol/L). Thus, IRAS expression is necessary for high-affinity binding to I1R. Western blots with polyclonal anti-IRAS showed reduced IRAS expression in the major 85-kDa band relative to an actin reference, paralleling the reduction in binding site density. To determine whether reduced IRAS expression attenuated I1R cell signaling, PC12 cells transfected with antisense or sense oligo-DNA were treated with moxonidine, an I1R agonist, then cell lysates were analyzed by western blot. Dose-dependent activation of extracellular signal-regulated kinase was attenuated without affecting the potency of the agonist. In contrast, extracellular signal-regulated kinase activation by insulin was unchanged. The IRAS gene is likely to encode an I1R or a functional subunit.
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the i1 Imidazoline Receptor in pc12 pheochromocytoma cells reverses ngf induced erk activation and induces mkp 2 phosphatase
Brain Research, 2003Co-Authors: Lincoln Edwards, Paul ErnsbergerAbstract:Abstract We sought to further elucidate signal transduction pathways for the I1-Imidazoline Receptor in PC12 cells and their interaction with the well-characterized signaling events triggered by nerve growth factor (NGF) in these cells. Stimulation of the I1-Imidazoline Receptor with moxonidine, a centrally acting antihypertensive, increased by greater than two-fold the proportion of ERK-1 and ERK-2 in the phosphorylated active form. Similarly, NGF elicited a five-fold increase in activated ERKs. Surprisingly, treatment of NGF-treated cells with moxonidine completely reversed activation of ERK. Moxonidine-induced inhibition of ERK activation in NGF-treated cells was dose-dependent, followed a limited time course and could be blocked by the I1-antagonist efaroxan. These data suggested possible deactivation of ERK by specific phosphatases. Therefore, we assayed levels of MKP-2, a dual specificity phosphatase whose substrates include ERK. Moxonidine and NGF both increased levels of MKP-2 by three-fold. These effects were additive, as both agents together increased MKP-2 by a total of six-fold. Moxonidine-induced induction of MKP-2 was time- and dose-dependent and could be blocked by the I1-antagonist efaroxan or by D609, an inhibitor of phosphatidylcholine-selective phospholipase C known to block downstream signaling events coupled to I1-Receptors. Thus, I1-Receptors can abrogate the primary signaling cascade activated by NGF, most likely by increasing levels of a specific phosphatase to return dually phosphorylated ERK to its unphosphorylated state.
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regulation of phenylethanolamine n methyltransferase gene expression by Imidazoline Receptors in adrenal chromaffin cells
Journal of Neurochemistry, 2002Co-Authors: Marian J Evinger, Paul Ernsberger, Soundararajan Regunathan, Donald J ReisAbstract:As adrenal medullary chromaffin cells express Imidazoline binding sites in the absence of alpha 2-adrenergic Receptors, these cells provide an ideal system in which to determine whether Imidazolines can influence catecholamine gene expression through nonadrenergic Receptors. This study evaluates the ability of clonidine and related drugs to regulate expression of the gene for the epinephrine-synthesizing enzyme phenylethanolamine N-methyltransferase (PNMT) in the rat adrenal gland and in bovine adrenal chromaffin cell cultures. In vivo, PNMT and tyrosine hydroxylase (TH) mRNA levels increase in rat adrenal medulla after a single injection of clonidine. Clonidine also dose-dependently stimulates PNMT mRNA expression in vitro in primary cultures of bovine chromaffin cells, with a threshold dose of 0.1 microM. Other putative Imidazoline Receptor agonists, including cimetidine, rilmenidine, and imidazole-4-acetic acid, likewise enhance PNMT mRNA production showing relative potencies that correlate with their binding affinities at chromaffin cell I1-Imidazoline binding sites. The effects of clonidine on PNMT mRNA appear to be distinct from and additive with those exerted by nicotine. Moreover, neither nicotinic antagonists nor calcium channel blockers, which attenuate nicotine's influence on PNMT mRNA production, diminish clonidine's effects on PNMT mRNA. Although 100 microM clonidine diminishes nicotine-stimulated release of epinephrine and norepinephrine in chromaffin cells, this effect appears unrelated to stimulation of Imidazoline Receptor subtypes. This is the first report to link Imidazoline Receptors to neurotransmitter gene expression.
Benjamin Keller - One of the best experts on this subject based on the ideXlab platform.
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a biomarker to differentiate between primary and cocaine induced major depression in cocaine use disorder the role of platelet iras nischarin i1 Imidazoline Receptor
Frontiers in Psychiatry, 2017Co-Authors: Benjamin Keller, Jesus A Garciasevilla, Joanignasi Mestrepinto, Maria Alvarobartolome, Diana Martinezsanvisens, Magi Farre, Julia M Garciafuster, Marta TorrensAbstract:The association of cocaine use disorder (CUD) and comorbid major depressive disorder (MDD; CUD/MDD) is characterized by high prevalence and poor treatment outcomes. CUD/MDD may be primary (primary MDD) or cocaine-induced (CUD-induced MDD). Specific biomarkers are needed to improve diagnoses and therapeutic approaches in this dual pathology. Platelet biomarkers [5-HT2A Receptor and Imidazoline Receptor antisera selected (IRAS)/nischarin] were assessed by Western blot in subjects with CUD and primary MDD (n = 16) or CUD-induced MDD (n = 9; antidepressant free, AD−; antidepressant treated, AD+) and controls (n = 10) at basal level and/or after acute tryptophan depletion (ATD). Basal platelet 5-HT2A Receptor (monomer) was reduced in comorbid CUD/MDD subjects (all patients: 43%) compared to healthy controls, and this down-regulation was independent of AD medication (decreases in AD−: 47%, and in AD+: 40%). No basal differences were found for IRAS/nischarin contents in AD+ and AD− comorbid CUD/MDD subjects. The comparison of IRAS/nischarin in the different subject groups during/after ATD showed opposite modulations (i.e., increases and decreases) in response to low plasma tryptophan levels with significant differences discriminating between the subgroups of CUD with primary MDD and CUD-induced MDD. These specific alterations suggested that platelet IRAS/nischarin might be useful as a biomarker to discriminate between primary and CUD-induced MDD in this dual pathology.
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upregulation of iras nischarin i1 Imidazoline Receptor a regulatory protein of μ opioid Receptor trafficking in postmortem prefrontal cortex of long term opiate and mixed opiate cocaine abusers
Neurochemistry International, 2017Co-Authors: Benjamin Keller, Romano La Harpe, Jesus A GarciasevillaAbstract:Imidazoline Receptor antisera-selected (IRAS)/nischarin, a putative I1-Imidazoline Receptor, has recently been shown to regulate μ-opioid Receptor (OR) trafficking and resensitisation. To study a possible involvement of this μ-OR regulator in opiate dependence, the present study assessed by Western blot analysis the contents of IRAS/nischarin and μ-OR in total homogenates and subcellular preparations of postmortem human prefrontal cortex (PFC/BA9) of long-term opiate and mixed opiate/cocaine abusers as well as of matched healthy control subjects. In the PFC/BA9 of long-term opiate/cocaine abusers (all subjects together) IRAS/nischarin content was increased (+67%, p < 0.01, n = 11) when compared with matched controls (n = 10). Similar increases were found for the subgroups of opiate (+72%, n = 6) and mixed opiate/cocaine (+61%, n = 5) abusers. IRAS/nischarin immunocontents were also found increased in subcellular membrane preparations (+61%, p < 0.05, n = 10) of PFC/BA9 from opiate addicts. In the same brain samples, the levels of μ-OR were not different to those in control subjects. Based on the increased contents in brains of opiate abusers and the reported function as μ-OR regulator, IRAS/nischarin could represent a new promising target for treatment of opiate use disorder.
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inhibitory effects of Imidazoline Receptor ligands on basal and kainic acid induced neurotoxic signalling in mice
Journal of Psychopharmacology, 2016Co-Authors: Benjamin Keller, Jesus A GarciasevillaAbstract:This in vivo study assessed the potential of the Imidazoline Receptor (IR) ligands moxonidine (selective I1-IR), BU224 (selective I2-IR) and LSL61122 (mixed I1/I2-IR) to dampen excitotoxic signalling induced by kainic acid (KA; 45 mg/kg) in the mouse brain (hippocampus and cerebral cortex). KA triggered a strong behavioural syndrome (seizures; maximal at 60-90 minutes) and sustained stimulation (at 72 hours with otherwise normal mouse behaviour) of pro-apoptotic c-Jun-N-terminal kinases (JNK) and calpain with increased cleavage of p35 into neurotoxic p25 (cyclin-dependent kinase 5 [Cdk5] activators) in mouse hippocampus. Pretreatment (five days) with LSL61122 (10 mg/kg), but not moxonidine (1 mg/kg) or BU224 (20 mg/kg), attenuated the KA-induced behavioural syndrome, and all three IR ligands inhibited JNK and calpain activation, as well as p35/p25 cleavage after KA in the hippocampus (effects also observed after acute IR drug treatments). Efaroxan (I1-IR, 10 mg/kg) and idazoxan (I2-IR, 10 mg/kg), postulated IR antagonists, did not antagonise the effects of moxonidine and LSL61122 on KA targets (these IR ligands showed agonistic properties inhibiting pro-apoptotic JNK). Brain subcellular preparations revealed reduced synaptosomal postsynaptic density-95 protein contents (a mediator of JNK activation) and indicated increased p35/Cdk5 complexes (with pro-survival functions) after treatment with moxonidine, BU224 and LSL61122. These results showed that I1- and I2-IR ligands (moxonidine and BU224), and especially the mixed I1/I2-IR ligand LSL61122, are partly neuroprotective against KA-induced excitotoxic signalling. These findings suggest a therapeutic potential of IR drugs in disorders associated with glutamate-mediated neurodegeneration.
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immunodetection and subcellular distribution of Imidazoline Receptor proteins with three antibodies in mouse and human brains effects of treatments with i1 and i2 Imidazoline drugs
Journal of Psychopharmacology, 2015Co-Authors: Benjamin Keller, Jesus A GarciasevillaAbstract:Various Imidazoline Receptor (IR) proteins have been proposed to mediate the effects of selective I1- and I2-IR drugs. However, the association of these IR-binding proteins with classic I1- and I2-radioligand binding sites remains somewhat controversial. In this study, three IR antibodies (anti-NISCH and anti-nischarin for I1-IRs; and anti-IRBP for I1/I2-IRs) were used to immunodetect, characterize and compare IR protein patterns in brain (mouse and human; total homogenate, subcellular fractionation, grey and white matter) and some cell systems (neurones, astrocytes, human platelets). Various immunoreactive IRs (specific molecular weight bands coincidently detected with the different antibodies) were related to I1-IR (167 kDa, 105/115 kDa and 85 kDa proteins) or I2-IR (66 kDa, 45 kDa and 30 kDa proteins) types. The biochemical characterization of cortical 167 kDa protein, localized in the membrane/cytosol but not in the nucleus, indicated that this I1-IR also forms part of higher order nischarin-related c...
Donald D Smyth - One of the best experts on this subject based on the ideXlab platform.
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renal denervation altered the hemodynamic and renal effects following intracerebroventricular administration of the i1 Imidazoline Receptor agonist rilmenidine in pentobarbital anaesthetized rats
Neurochemistry International, 1997Co-Authors: Brian S Penner, Donald D SmythAbstract:Abstract Previous studies have reported on the effects of intracerebroventricular (icv) administration of the I1-Imidazoline Receptor agonist moxonidine. In the present study, the relationship between increasing doses of the I1-agonist rilmenidine (administered icv) with blood pressure and renal function has been determined. Moreover, the importance of the renal nerves in this response have also been assessed. In pentobarbitone anesthetized rats, icv rilmenidine (30, 100, 300 nmol in 5μl) produced a dose related decrease in blood pressure and heart rate. Urine flow was not altered at the lower doses although at the highest dose (300 nmol) the increase approached significance (p = 0.06). Sodium excretion and osmolar clearance were not altered. Free water clearance was increased at 100 and 300 nmol rilmenidine (p
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clonidine induced increase in osmolar clearance and free water clearance via activation of two distinct α2 adrenoceptor sites
British Journal of Pharmacology, 1996Co-Authors: H D Intengan, Donald D SmythAbstract:1. Clonidine, an alpha 2-adrenoceptor agonist, will increase urine flow rate in the anaesthetized rat by increasing both free water and osmolar clearance. In the present study, we investigated whether these effects of clonidine were mediated at two sites which could be distinguished pharmacologically in uninephrectomized male Sprague-Dawley rats. 2. Clonidine (1.0 nmol kg-1 min-1) infused into the renal artery increased osmolar and free water clearance. Following pretreatment with prazosin (0.15 mg kg-1, i.v.), an antagonist with reported selectivity for the alpha 2b-adrenoceptor subtype, the increase in free water but not osmolar clearance was decreased. Pretreatment with the opioid Receptor antagonist, naltrexone (3.0 mg kg-1, i.v.) attenuated the increase in osmolar but not free water clearance. This disparate antagonism of clonidine by prazosin and naltrexone was consistent with two distinct sites. 3. We submit the hypothesis that the alpha 2a- and alpha 2b-adrenoceptor subtypes mediated the clonidine-induced osmolar and free water clearance. The blockade in free water clearance by prazosin indicated a possible role of the alpha 2b-adrenoceptor subtype whereas the alpha 2a-adrenoceptor subtype was considered as the site mediating the clonidine-induced increase in osmolar clearance. UK-14,304 (1.0 nmol kg-1 min-1), a mixed alpha 2-adrenoceptor/Imidazoline Receptor agonist with selectivity for the alpha 2a-subtype increased only osmolar clearance. This increase was blocked by naltrexone but not prazosin pretreatment. The Imidazoline Receptor was not involved, as naltrexone failed to alter the moxonidine (3.0 nmol kg-1-min-1) induced increase in osmolar clearance. These data suggested to us that the alpha 2a-/alpha 26-subtype hypothesis should be investigated more closely in future studies. 4. These findings indicate that the increase in osmolar and free water clearance following clonidine can be distinguished pharmacologically indicating that two sites were involved. Furthermore, we propose the hypothesis that the alpha 2a-adrenoceptor subtype mediated osmolar clearance whereas the alpha 2b-subtype mediated free water clearance. The prazosin-sensitive increase in free water clearance following clonidine suggested a possible role for the alpha 2b-subtype. The naltrexone-sensitive increase in osmolar clearance following clonidine and UK-14,304 (but not moxonidine) suggested a possible role of the alpha 2a-subtype. Clearly, this postulate requires further study.
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effects of the selective i1 Imidazoline Receptor agonist moxonidine on gastric secretion and gastric mucosal injury in rats
British Journal of Pharmacology, 1995Co-Authors: Gary B. Glavin, Donald D SmythAbstract:1 Previous reports of the effects of α2-adrenoceptor stimulation on gastric secretion are inconsistent because it was not clear whether the compounds were activating α2-adrenoceptors and/or newly described Imidazoline Receptors. In the present experiments, the effects of moxonidine, an I1-Imidazoline Receptor agonist and antihypertensive agent, on gastric secretion and on experimental gastric mucosal injury were examined. 2 Moxonidine (0.01, 0.1 and 1.0 mg kg−1, i.p.) potently inhibited basal (non-stimulated) gastric acid secretion in conscious rats with an ED50 of 0.04 mg kg−1. Two hours following administration of the highest dose of moxonidine (1.0 mg kg−1), gastric acid output was completely suppressed. Moxonidine also significantly increased intragastric pH, at the two highest doses. 3 The α2-adrenoceptor agonist, clonidine (0.01, 0.1 and 1.0 mg kg−1, i.p.) decreased basal acid secretion at the lowest dose (37%) and at the highest dose (46%), while the intermediate dose did not affect gastric acid output. 4 In an ethanol-induced model of gastric mucosal injury, moxonidine decreased the length of lesions at the lowest and highest doses (0.01 and 1.0 mg kg−1) as well as the number of the lesions, at the highest dose (1.0 mg kg−1). 5 In pylorus-ligated rats, moxonidine significantly decreased acid secretion (all doses), total secretory volume (1.0 mg kg−1) as well as pepsin output (1.0 mg kg−1). 6 In comparison to clonidine, moxonidine appears to be a more potent anti-secretory and gastric-protective compound. These data indicate a potential role for Imidazoline Receptor agonists in the management of gastroduodenal diseases associated with hypertension. The relative contribution of the central and peripheral effects of moxonidine to these gastrointestinal actions remains to be determined.
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sodium excretion following central administration of an i1 Imidazoline Receptor agonist moxonidine
British Journal of Pharmacology, 1994Co-Authors: Brian S Penner, Donald D SmythAbstract:Abstract 1. Previously we have shown that an intrarenal infusion of moxonidine, an I1-Imidazoline Receptor agonist, resulted in a natriuresis which was inhibited by intravenous idazoxan, a selective Imidazoline Receptor antagonist. Therefore we examined the effects of renal function of intracerebroventricular (i.c.v.) administration of moxonidine with or without i.c.v. idazoxan. 2. Seven days after unilateral nephrectomy, Sprague-Dawley rats had i.c.v. cannulae implanted. Three days later the rats were anaesthetized (pentobarbitone), followed by cannulation of the jugular vein (fluid and drug administration), carotid artery (blood pressure) and the ureter (urine collection). 3. After a 45 min stabilization period, the effect of moxonidine was investigated by the i.c.v. administration of either isotonic saline or moxonidine (0.1, 0.3 or 1 nmol in isotonic saline) administered in 5 microliters over 1 min. All doses of moxonidine resulted in an increase in urine flow with a concomitant increase in sodium excretion without affecting blood pressure. The highest dose of moxonidine (1 nmol) also increased free water clearance. 4. In a second series of experiments, the effects of idazoxan on the natriuretic response to i.c.v. moxonidine were determined. Moxonidine (0.3 nmol) again increased sodium and water excretion as compared to the i.c.v. saline control animals. Pretreatment with i.c.v. idazoxan (0.3 nmol), at a dose which alone failed to alter sodium and water excretion, completely attenuated the renal response to moxonidine. These results are consistent with central I1-Imidazoline Receptors mediating a moxonidine-induced increase in sodium and water excretion at doses that do not alter blood pressure.
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attenuated renal response to moxonidine and rilmenidine in one kidney one clip hypertensive rats
British Journal of Pharmacology, 1994Co-Authors: S B Penner, Donald D SmythAbstract:1. I1 non-adrenoceptor, Imidazoline Receptor agonists, such as moxonidine, increase urine flow rate and sodium excretion following infusion into the renal artery. The functions of these agonists in genetic and acquired models of hypertension have not been determined. 2. We therefore studied the renal effects of two known non-adrenoceptor, Imidazoline Receptor agonists, rilmenidine and moxonidine, in 1K-1C hypertensive and 1K-sham normotensive rats. Rilmenidine (0, 3, 10, 30 nmol kg-1 min-1) or moxonidine (0, 1, 3, 10 nmol kg-1 min-1) was infused directly into the renal artery (30 gauge needle) of 1K-sham normotensive and 1K-1C hypertensive rats. 3. In 1K-sham normotensive rats, rilmenidine and moxonidine produced dose related increases in urine flow rate, sodium excretion and osmolar clearance. Both rilmenidine and moxonidine failed to increase urine flow rate, sodium excretion and osmolar clearance in 1K-1C hypertensive rats to the same extent as in 1K-sham animals. At comparable doses, rilmenidine had no effect, while moxonidine (3 and 10 nmol kg-1 min-1) did result in a small increase in urine volume and osmolar clearance which was less than that observed in the 1K sham control animals. 4. These studies indicate that the renal effects of non-adrenoceptor, Imidazoline Receptor stimulation are diminished in 1K-1C hypertensive rats compared with 1K-sham normotensive rats. Whether this decrease in activity of the natriuretic non-adrenoceptor, Imidazoline Receptors contributes to the increase in blood pressure in the 1K-1C acquired model of hypertension remains to be determined.
Adam Ahmed Abdelrahman - One of the best experts on this subject based on the ideXlab platform.
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nischarin as a functional Imidazoline i1 Receptor
FEBS Letters, 2006Co-Authors: Adam Ahmed AbdelrahmanAbstract:Gene matching shows that Nischarin is a mouse homologue of human Imidazoline Receptor antisera-selective (IRAS) protein, a viable candidate of the Imidazoline (I1) Receptor. Nischarin and IRAS share the functions of enhancing cell survival, growth and migration. Bioinformatics modeling indicates that the IRAS and Nischarin may be transmembrane proteins and the convergence information raises the interesting possibility that Nischarin might serve as the I1-Receptor. To test this hypothesis, we developed antibodies against the Nischarin protein, and conducted signal transduction (functional) studies with the I1-Receptor agonist rilmenidine in the presence and absence of Nischarin antisense oligodeoxynucleotides (ODNs). NIH3T3 cells transfected with the Nischarin cDNA and incubated with the newly synthesized antibody expressed a 190 kD band. The antibody identified endogenous Nischarin in differentiated PC12 cells around 210 kD, which is consistent with reported findings in other cells of neuronal origin. The immunoflourescence findings showed the targeted protein to be associated with the cell membrane in PC12 cells. Nischarin ODNs abolished the expression of Nischarin in PC12 cells. Equally important, the Nischarin ODNs eliminated the production of MAPKp42/44, a recognized signal transduction product generated by I1-Receptor activation in differentiated PC12 cells. Together, the present findings suggest that Nischarin may serve as the functional I1-Receptor or at least share a common signaling pathway in the differentiated PC12 cells.
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mitogen activated protein kinase phosphorylation in the rostral ventrolateral medulla plays a key role in Imidazoline i1 Receptor mediated hypotension
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Adam Ahmed AbdelrahmanAbstract:Our previous study showed that rilmenidine, a selective I 1 -Imidazoline Receptor agonist, enhanced the phosphorylation of mitogen-activated protein kinase (MAPK) p42/44 , via the phosphatidylcholine-specific phospholipase C pathway in the pheochromocytoma cell line (PC12). In the present study, we tested the hypothesis that enhancement of MAPK phosphorylation in the rostral ventrolateral medulla (RVLM) contributes to the hypotensive response elicited by I 1 -Receptor activation in vivo. Systemic rilmenidine (600 μg/kg i.v.) elicited hypotension and bradycardia along with significant elevation in MAPK p42/44 , detected by immunohistochemistry, in RVLM neurons. To obtain conclusive evidence that the latter response was I 1 -Receptor-mediated, similar hypotensive responses were elicited by intracisternal (i.c.) rilmenidine (25 μg/rat) or the highly selective α 2 -agonist α-methylnorepinephrine (4 μg/rat). An increase in RVLM MAPK p42/44 occurred only after rilmenidine. Furthermore, pretreatment with efaroxan (0.15 μg/rat i.c.), a selective I 1 -Imidazoline Receptor antagonist, or with PD98059 (2′-amino-3′-methoxyflavone) (5 μg/rat i.c.), a selective extracellular signal-regulated kinase 1/2 inhibitor, significantly attenuated the hypotensive response and the elevation in RVLM MAPK p42/44 elicited by i.c. rilmenidine. The findings suggest that MAPK phosphorylation in the RVLM contributes to the hypotensive response induced by I 1 -Receptor activation and presents in vivo evidence that distinguishes the neuronal responses triggered by the I 1 -Receptor from those triggered by the α 2 -adrenergic Receptor.
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differential modulation by estrogen of α2 adrenergic and i1 Imidazoline Receptor mediated hypotension in female rats
Journal of Applied Physiology, 2004Co-Authors: Mahmoud M Elmas, Adam Ahmed AbdelrahmanAbstract:We have recently shown that estrogen negatively modulates the hypotensive effect of clonidine (mixed α2-/I1-Receptor agonist) in female rats and implicates the cardiovascular autonomic control in this interaction. The present study investigated whether this effect of estrogen involves interaction with α2- and/or I1-Receptors. Changes evoked by a single intraperitoneal injection of rilmenidine (600 μg/kg) or α-methyldopa (100 mg/kg), selective I1- and α2-Receptor agonists, respectively, in blood pressure, hemodynamic variability, and locomotor activity were assessed in radiotelemetered sham-operated and ovariectomized (Ovx) Sprague-Dawley female rats with or without 12-wk estrogen replacement. Three time domain indexes of hemodynamic variability were employed: the standard deviation of mean arterial pressure as a measure of blood pressure variability and the standard deviation of beat-to-beat intervals (SDRR) and the root mean square of successive differences in R-wave-to-R-wave intervals as measures of heart rate variability. In sham-operated rats, rilmenidine or α-methyldopa elicited similar hypotension that lasted at least 5 h and was associated with reductions in standard deviation of mean arterial pressure. SDRR was reduced only by α-methyldopa. Ovx significantly enhanced the hypotensive response to α-methyldopa, in contrast to no effect on rilmenidine hypotension. The enhanced α-methyldopa hypotension in Ovx rats was paralleled with further reduction in SDRR and a reduced locomotor activity. Estrogen replacement (17β-estradiol subcutaneous pellet, 14.2 μg/day, 12 wk) of Ovx rats restored the hemodynamic and locomotor effects of α-methyldopa to sham-operated levels. These findings suggest that estrogen downregulates α2- but not I1-Receptor-mediated hypotension and highlight a role for the cardiac autonomic control in α-methyldopa-estrogen interaction.
