DOCSLIB.ORG

Imidazoline Receptors in Insulin Signaling And

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Imidazoline Receptors in Insulin Signaling And IMIDAZOLINE RECEPTORS IN INSULIN SIGNALING AND METABOLIC REGULATION by Zheng Sun Submitted in partial fulfillment of the requirements for the Degree of Doctor of Philosophy Thesis Advisor: Paul Ernsberger, Ph.D. Department of Nutrition CASE WESTERN RESERVE UNIVERSITY January 2007 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the dissertation of ______________________________________________________ Zheng Sun candidate for the Ph.D. degree *. Henri Brunengraber (signed)_______________________________________________ (chair of the committee) Bryan Roth ________________________________________________ Laura Nagy ________________________________________________ Jonathan Whittaker ________________________________________________ Paul Ernsberger ________________________________________________ ________________________________________________ (date) _______________________09/07/2006 *We also certify that written approval has been obtained for any proprietary material contained therein. Table of Contents Table of Contents 1 List of Figures 4 Acknowledgements 6 Abbreviations Used 7 Abstract 8 Chapter 1. Literature review Imidazoline ligands 10 Imidazoline receptors 11 Identification of imidazoline receptor subtypes 12 Cellular mechanisms of I1-imidazoline receptors 14 Molecular identity of I1-imidazoline receptor 17 PC12 pheochromocytoma cells as a model system 30 I1-imidazoline receptor agonists as therapeutic agents for the insulin resistance syndrome 31 Insulin and Akt (PKB) cell signaling 33 Metabolic Syndrome X 37 SHROB as animal model for Metabolic Syndrome 40 Phenotypic features of the SHROB model 43 Obesity 43 Hypertension 44 Hyperlipidemia 45 Retinal abnormalities 47 1 Glucose metabolism 47 Insulin and insulin signaling 48 Conclusion 50 Summary 50 Chapter 2. Research design Introduction 52 Specific aims 53 Chapter 3. Materials and methods Materials 57 Plasma membrane isolation for binding assays 58 [125I]p-Iodoclonidine radioligand binding assays 58 Cell culture and transfection 59 Cell experiments 60 Akt activation assay in PC12 cells 62 Ruthenium red staining 63 Animals 63 Chronic drug treatment 64 Adipocyte isolation and insulin application 64 Western blot procedure 65 Glucose uptake assay 66 Statistical methods 68 Chapter 4. Manuscripts from the implementation of the research plan Manuscript 1. 69 2 Manuscript 2. 105 Chapter 5. Discussion and significance The significance of the present study on IRAS 133 Antisense and imidazoline binding studies 134 Antisense and I1-imidazoline cell signaling study 137 Possibility of IRAS as a subunit of imidazoline receptor 143 IRAS could also act as a scaffolding protein 145 Comparison of adipocyte glucose uptake results to previous studies 147 Impact of insulin concentration 147 SHR as control for SHROB 149 Insulin degradation in the experiments 151 SHROB as an animal model for human syndrome X 152 Akt activation studies 154 Chronic I1-R Activation 156 Acute I1R Activation 158 Clinical significance 159 Chapter 6. Future Studies 161 Bibliography 164 3 List of Figures Figure 1. Working model of the I1R signaling pathway 16 Figure 2. Functional domains illustration of human IRAS protein 21 Figure 3. Sequence alignment of EST106158 and human IRAS 28 Figure 4. Sequence alignment of EST106158 and predicted rat IRAS 29 Figure 5. A simplified illustration of Akt(PKB) cellular function 36 Figure 6. Domain map of the rat IRAS gene and sequence comparison to human and mouse 95 125 Figure 7. Saturation kinetics of [ I]-p-iodoclonidine binding to I1R in PC12 98 Figure 8. Effect of antisense treatment on IRAS protein expression 99 Figure 9. IRAS antisense inhibits I1R signaling 101 Figure 10. Effect of antisense treatment on basal activation of ERK1/2 103 Figure 11. Insulin induced ERK activation in PC12 cells 104 Figure 12. Representative Western blot showing phosphorylated and total Akt immunoreactivity 125 Figure 13. Time course of insulin activation of Akt in lean SHR, SHROB and in SHROB treated with moxonidine for 21d in vivo 126 Figure 14. Dose response curves for insulin activation of Akt in lean SHR, SHROB and in SHROB treated with moxonidine for 21d in vivo 127 Figure 15. Basal Akt activation is not affected by phenotype or pharmacotherapy 128 4 Figure 16. Dose-response curve for insulin activation of [3H]-2-deoxy-D-glucose uptake 129 Figure 17. Treatment with moxonidine alone in vitro does not affect Akt activation 130 Figure 18. Representative blot showing the time course of Akt activation by insulin with and without moxonidine pretreatment 131 Figure 19. Effect of in vitro moxonidine treatment on insulin activation of Akt in adipocytes from SHR and SHROB 132 5 Acknowledgements Helpful Lab Colleagues • Paul Ernsberger, Ph.D (Advisor) • Janean Johnson • Anna Saal • Ryan Strachan Collaborators • Laura Nagy, Ph.D • Becky Sebastian • Chung-Ho Chang, Ph.D Thesis Committee • Henri Brunengraber, M.D. • Laura Nagy, Ph.D • Jonathan Whittaker, Ph.D. • Bryan Roth, M.D., Ph.D. • Paul Ernsberger, Ph.D Personal support • Jing Han, Ph.D. Candidate 6 Abbreviations Used 2-DG 2-deoxy-D-glucose α2AR alpha-2 adrenergic receptor ERK Extracellular Regulated Kinase I1-R I1-imidazoline receptor IRAS Imidazoline Receptor Antisera-Selected IRBP Imidazoline Receptor Binding Peptide IRS Insulin Receptor Substrate (4 subtypes) JNK cJun N-Terminal Kinase MEK MAPK Kinase (phosphorylates ERK) NGF Nerve Growth Factor PAK p21-activated Kinase PKB protein kinase B PI3-K phosphoinositol-3-kinase PIX PAK-interacting exchange factor Rac Rho-family protein SHR spontaneously hypertensive rat SHROB spontaneously hypertensive rat obese strain 7 Abstract The I1-imidazoline receptor is a novel target of drug development for hypertension and insulin resistance. This thesis focused on the molecular basis for I1-imidazoline binding and cell signaling and the mechanisms linking this signaling protein to regulation glucose metabolism. IRAS is a gene candidate for the I1-imidazoline receptor. To investigate the possibility that IRAS is the I1- imidazoline receptor, antisense oligo-nucleotides directly against the initiation site of IRAS sequence were designed and transfected into PC12 cells. Antisense transfection for 48h reduced specific imidazoline radioligand binding to plasma membrane fractions by about 50%, with parallel drops in IRAS protein expression as detected by Western blot. Furthermore, transfection with antisense caused functional impairment of I1-imidazoline receptor signaling. Imidazoline agonist induced ERK1/2 activation was significantly inhibited with antisense transfection without affecting basal ERK level or ERK activation by growth factors. These findings strongly suggested that IRAS encodes an I1-imidazoline receptor or at least an important subunit of it. The mechanism of insulin sensitizing effect from imidazolines was studied in the SHROB rat, an animal model for human metabolic syndrome. Insulin induced Akt activation was found to be severely impaired in isolated adipocytes from SHROB compared to their lean SHR littermates. In addition, insulin induced glucose uptake in these cells from SHROB were also similarly resistant to stimulation by insulin. Chronic treatment of SHROB with the imidazoline agonist moxonidine partially restored both Akt activation and glucose uptake stimulated 8 by insulin in isolated abdominal adipocytes without affecting basal Akt activation level. However, acute in vitro moxonidine administration did not yield similar effects, nor did moxonidine affect basal Akt level in adipocytes from either SHROB or SHR. These results implicate adipose tissue as a locus of insulin resistance in this model of metabolic syndrome, and impairment of insulin signaling through Akt may contribute to this defect. Chronic oral treatment with I1- imidazoline receptor agonists such as moxonidine significantly normalizes insulin resistance in adipose tissue of SHROB in both insulin cell signaling and glucose metabolism. These changes in adipose tissue very likely contribute to the overall insulin sensitizing effect of imidazoline ligands on SHROB. 9 CHAPTER 1. LITERATURE REVIEW Imidazoline Ligands The discovery of imidazoline compounds greatly preceded the concept of imidazoline receptors and can be traced back to Switzerland in 1939 (Hartmann & Isler, 1939). The first two imidazoline drugs were tolazoline, an α-adrenoceptor antagonist possessing vasodilating properties, and naphazoline, an α2- adrenoceptor/I1-imidazoline receptor agonist, still in daily use as an over the counter medication for topical application to relieve nasal congestion. Another milestone in the history of imidazoline drugs was the discovery of clonidine in 1962, initially named St155, which was first developed as a nasal decongestant but serendipitously was found to lower blood pressure, and subsequently became the prototype for centrally acting antihypertensive drugs (Hoefke and Kobinger, 1966;Ernsberger et al., 1987). Clonidine is still in use, mainly in the form of a patch to be worn on the skin for continuous control of blood pressure (Klein et al., 1985). Clonidine is also widely used for certain psychiatric disorders (Hieble et al., 1991), including posttraumatic stress disorder (Harmon and Riggs, 1996), Tourette’s syndrome (Leckman et al., 1991), autism (Jaselskis et al., 1992;Posey and McDougle, 2001), attention deficit disorder (Olfson, 2004) and opiate withdrawal (Agren, 1986). Clonidine may also have cognitive enhancing actions (Jackson and Buccafusco, 1991). Clonidine has also been used
Load more

Recommended publications
  • Imidazoline Antihypertensive Drugs: Selective I1-Imidazoline Receptors Activation K
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by FarFar - Repository of the Faculty of Pharmacy, University of Belgrade REVIEW Imidazoline Antihypertensive Drugs: Selective I1-Imidazoline Receptors Activation K. Nikolic & D. Agbaba Faculty of Pharmacy, Institute of Pharmaceutical Chemistry, University of Belgrade, Vojvode Stepe, Belgrade, Serbia Keywords SUMMARY α2-Adrenergic receptors; Centrally acting antihypertensives; Clonidine; Hypertension; Involvement of imidazoline receptors (IR) in the regulation of vasomotor tone as well as in Imidazoline receptors; Rilmenidine. the mechanism of action of some centrally acting antihypertensives has received tremen- dous attention. To date, pharmacological studies have allowed the characterization of three Correspondence main imidazoline receptor classes, the I1-imidazoline receptor which is involved in central K. Nikolic, Faculty of Pharmacy, Institute of inhibition of sympathetic tone to lower blood pressure, the I2-imidazoline receptor which Pharmaceutical Chemistry, University of is an allosteric binding site of monoamine oxidase B (MAO-B), and the I3-imidazoline re- Belgrade, Vojvode Stepe 450, 11000 Belgrade, ceptor which regulates insulin secretion from pancreatic β-cells. All three imidazoline re- Serbia. ceptors represent important targets for cardiovascular research. The hypotensive effect of + Tel: 381-63-84-30-677; clonidine-like centrally acting antihypertensives was attributed both to α2-adrenergic re- + Fax: 381-11-3974-349; ceptors and nonadrenergic I1-imidazoline receptors, whereas their sedative action involves E-mail: [email protected] activation of only α2-adrenergic receptors located in the locus coeruleus. Since more selec- tive I1-imidazoline receptors ligands reduced incidence of typical side effects of other cen- trally acting antihypertensives, there is significant interest in developing new agents with higher selectivity and affinity for I1-imidazoline receptors.
    [Show full text]
  • )&F1y3x PHARMACEUTICAL APPENDIX to THE
    )&f1y3X PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE )&f1y3X PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 3 Table 1. This table enumerates products described by International Non-proprietary Names (INN) which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service (CAS) registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known. Product CAS No. Product CAS No. ABAMECTIN 65195-55-3 ACTODIGIN 36983-69-4 ABANOQUIL 90402-40-7 ADAFENOXATE 82168-26-1 ABCIXIMAB 143653-53-6 ADAMEXINE 54785-02-3 ABECARNIL 111841-85-1 ADAPALENE 106685-40-9 ABITESARTAN 137882-98-5 ADAPROLOL 101479-70-3 ABLUKAST 96566-25-5 ADATANSERIN 127266-56-2 ABUNIDAZOLE 91017-58-2 ADEFOVIR 106941-25-7 ACADESINE 2627-69-2 ADELMIDROL 1675-66-7 ACAMPROSATE 77337-76-9 ADEMETIONINE 17176-17-9 ACAPRAZINE 55485-20-6 ADENOSINE PHOSPHATE 61-19-8 ACARBOSE 56180-94-0 ADIBENDAN 100510-33-6 ACEBROCHOL 514-50-1 ADICILLIN 525-94-0 ACEBURIC ACID 26976-72-7 ADIMOLOL 78459-19-5 ACEBUTOLOL 37517-30-9 ADINAZOLAM 37115-32-5 ACECAINIDE 32795-44-1 ADIPHENINE 64-95-9 ACECARBROMAL 77-66-7 ADIPIODONE 606-17-7 ACECLIDINE 827-61-2 ADITEREN 56066-19-4 ACECLOFENAC 89796-99-6 ADITOPRIM 56066-63-8 ACEDAPSONE 77-46-3 ADOSOPINE 88124-26-9 ACEDIASULFONE SODIUM 127-60-6 ADOZELESIN 110314-48-2 ACEDOBEN 556-08-1 ADRAFINIL 63547-13-7 ACEFLURANOL 80595-73-9 ADRENALONE
    [Show full text]
  • Master.Pmd 2
    The Effects of Idazoxan and Efaroxan Improves Memory and Cognitive Functions in Rats Experimental research GABRIELA RUSU-ZOTA1, DANIEL VASILE TIMOFTE2*, ELENA ALBU1, PETRONELA NECHITA3, VICTORITA SORODOC4 1 Grigore T. Popa University of Medicine and Pharmacy, Department of Pharmacology, Clinical Pharmacology and Algesiology, 16 Universitatii Str., 700115, Iasi, Romania 2 Grigore T. Popa University of Medicine and Pharmacy, Department of Surgery, 16 Universitatii Str., 700115, Iasi, Romania 3 Institutul de psihiatrie Socola, Soseaua Bucium, nr 36, 700282, Iasi, Romania 4 Grigore T. Popa University of Medicine and Pharmacy, Department of Internal Medicine, 16 Universitatii Str., 700115, Iasi, Romania Investigating the effects of idazoxan and efaroxan imidazoline receptor antagonists on cognitive functions with the rat Y-maze test; an internationally recognized experimental pattern of behavior, is to be used in order to evaluate the effects of test substances on the simple spatial memory of the laboratory animals. Our experimental evaluation tested the influence induced by idazoxan and efaroxan on the short-term memory on rats. In the experiment were used eighteen (18) male Wistar rats which were randomly divided into three groups (I - Control, II - IDZ and III - EFR) comprising of 6 animals each, treated intraperitoneally according to the following protocol: group I (Control): distilled water 0.5 mL/100 g body weight; group II (IDZ): idazoxan 3 mg/kg body weight; group III (EFR): efaroxan 1 mg/kg body weight. The purpose of this research was to assess the eligibility using the Y-maze test, involving: latency of the first arm visited, the number of arms visited, and the time spent into the arms, the number of returns of the experimental animals in the same arm, the number of alternations, percentage of spontaneous alternation.
    [Show full text]
  • Original Article Dexmedetomidine Inhibits Epileptiform Activity in Rat Hippocampal Slices
    Int J Clin Exp Med 2017;10(4):6704-6711 www.ijcem.com /ISSN:1940-5901/IJCEM0046980 Original Article Dexmedetomidine inhibits epileptiform activity in rat hippocampal slices Atsushi Kurosawa, Yasumitsu Sato, Tomoki Sasakawa, Takayuki Kunisawa, Hiroshi Iwasaki Department of Anesthesiology and Critical Care Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan Received December 20, 2016; Accepted January 23, 2017; Epub April 15, 2017; Published April 30, 2017 Abstract: Purpose: Our study aimed to investigate the effects of dexmedetomidine on basal synaptic transmission in the rat hippocampus. We also examined dexmedetomidine in an animal epilepsy model, with further investigation into the role of specific antagonists on the alpha-2 adrenoceptors and the imidazoline receptors. Methods: All of the experiments used the CA1 region of hippocampal brain slices prepared from Sprague-Dawley rats. Epileptiform discharges were induced by perfusing Mg2+-free artificial cerebrospinal fluid (ACSF). We first investigated the ef- fects of dexmedetomidine on population spike (PS) amplitudes and field excitatory postsynaptic potentials (fEPSP) amplitudes in normal ACSF. We then investigated the effects of dexmedetomidine on the amplitudes of the first three PSs and the discharge duration in Mg2+-free ACSF or in normal ACSF containing 10 μM bicuculline. Results: Dexmedetomidine depressed PS amplitudes and fEPSP without affecting the paired-pulse inhibition in normal ACSF. Dexmedetomidine inhibited the epileptiform activity produced by Mg2+-free ACSF in a dose-dependent manner. Dexmedetomidine completely abolished the epileptiform activity induced by bicuculline. In the presence of yohim- bine, dexmedetomidine had no significant effect on epileptiform activity. In the presence of efaroxan and idazoxan, dexmedetomidine significantly (P < 0.05) increased and slightly attenuated the amplitude of the epileptiform activ- ity, respectively.
    [Show full text]
  • 4 Supplementary File
    Supplemental Material for High-throughput screening discovers anti-fibrotic properties of Haloperidol by hindering myofibroblast activation Michael Rehman1, Simone Vodret1, Luca Braga2, Corrado Guarnaccia3, Fulvio Celsi4, Giulia Rossetti5, Valentina Martinelli2, Tiziana Battini1, Carlin Long2, Kristina Vukusic1, Tea Kocijan1, Chiara Collesi2,6, Nadja Ring1, Natasa Skoko3, Mauro Giacca2,6, Giannino Del Sal7,8, Marco Confalonieri6, Marcello Raspa9, Alessandro Marcello10, Michael P. Myers11, Sergio Crovella3, Paolo Carloni5, Serena Zacchigna1,6 1Cardiovascular Biology, 2Molecular Medicine, 3Biotechnology Development, 10Molecular Virology, and 11Protein Networks Laboratories, International Centre for Genetic Engineering and Biotechnology (ICGEB), Padriciano, 34149, Trieste, Italy 4Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy 5Computational Biomedicine Section, Institute of Advanced Simulation IAS-5 and Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich GmbH, 52425, Jülich, Germany 6Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy 7National Laboratory CIB, Area Science Park Padriciano, Trieste, 34149, Italy 8Department of Life Sciences, University of Trieste, Trieste, 34127, Italy 9Consiglio Nazionale delle Ricerche (IBCN), CNR-Campus International Development (EMMA- INFRAFRONTIER-IMPC), Rome, Italy This PDF file includes: Supplementary Methods Supplementary References Supplementary Figures with legends 1 – 18 Supplementary Tables with legends 1 – 5 Supplementary Movie legends 1, 2 Supplementary Methods Cell culture Primary murine fibroblasts were isolated from skin, lung, kidney and hearts of adult CD1, C57BL/6 or aSMA-RFP/COLL-EGFP mice (1) by mechanical and enzymatic tissue digestion. Briefly, tissue was chopped in small chunks that were digested using a mixture of enzymes (Miltenyi Biotec, 130- 098-305) for 1 hour at 37°C with mechanical dissociation followed by filtration through a 70 µm cell strainer and centrifugation.
    [Show full text]
  • Convergent Pharmacological Mechanisms in Impulsivity And
    British Journal of DOI:10.1111/bph.12787 www.brjpharmacol.org BJP Pharmacology Themed Section: Animal Models in Psychiatry Research Correspondence Jeffrey W Dalley, Department of Psychology, University of REVIEW Cambridge, Downing St, Cambridge CB2 3EB, UK. E-mail: [email protected] Convergent ---------------------------------------------------------------- Received 20 February 2014 pharmacological Revised 2 May 2014 Accepted mechanisms in impulsivity 12 May 2014 and addiction: insights from rodent models B Jupp1,2 and J W Dalley1,3 1Behavioural and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Cambridge, UK, 2Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Australia, and 3Department of Psychiatry, University of Cambridge, Cambridge, UK Research over the last two decades has widely demonstrated that impulsivity, in its various forms, is antecedent to the development of drug addiction and an important behavioural trait underlying the inability of addicts to refrain from continued drug use. Impulsivity describes a variety of rapidly and prematurely expressed behaviours that span several domains from impaired response inhibition to an intolerance of delayed rewards, and is a core symptom of attention deficit hyperactivity disorder (ADHD) and other brain disorders. Various theories have been advanced to explain how impulsivity interacts with addiction both causally and as a consequence of chronic drug abuse; these acknowledge the strong overlaps in neural circuitry and mechanisms between impulsivity and addiction and the seemingly paradoxical treatment of ADHD with stimulant drugs with high abuse potential. Recent years have witnessed unprecedented progress in the elucidation of pharmacological mechanisms underpinning impulsivity. Collectively, this work has significantly improved the prospect for new therapies in ADHD as well as our understanding of the neural mechanisms underlying the shift from recreational drug use to addiction.
    [Show full text]
  • Monoamine Depletion in Psychiatric and Healthy Populations
    Molecular Psychiatry (2003) 8, 951–973 & 2003 Nature Publishing Group All rights reserved 1359-4184/03 $25.00 www.nature.com/mp FEATURE REVIEW Monoamine depletion in psychiatric and healthy populations: review L Booij1, AJW Van der Does1,2 and WJ Riedel3,4,5 1Department of Psychology, Leiden University, Leiden 2333 AK, The Netherlands; 2Department of Psychiatry, Leiden University, Leiden 2333 AK, The Netherlands; 3GlaxoSmithKline, Translational Medicine & Technology, Cambridge, UK; 4Department of Psychiatry, University of Cambridge, UK; 5Faculty of Psychology, Maastricht University, The Netherlands A number of techniques temporarily lower the functioning of monoamines: acute tryptophan depletion (ATD), alpha-methyl-para-tyrosine (AMPT) and acute phenylalanine/tyrosine deple- tion (APTD). This paper reviews the results of monoamine depletion studies in humans for the period 1966 until December 2002. The evidence suggests that all three interventions are specific, in terms of their short-term effects on one or two neurotransmitter systems, rather than on brain protein metabolism in general. The AMPT procedure is somewhat less specific, affecting both the dopamine and norepinephrine systems. The behavioral effects of ATD and AMPT are remarkably similar. Neither procedure has an immediate effect on the symptoms of depressed patients; however, both induce transient depressive symptoms in some remitted depressed patients. The magnitude of the effects, response rate and quality of response are also comparable. APTD has not been studied in recovered major depressive patients. Despite the similarities, the effects are distinctive in that ATD affects a subgroup of recently remitted patients treated with serotonergic medications, whereas AMPT affects recently remitted patients treated with noradrenergic medications.
    [Show full text]
  • The Effects of Clonidine and Idazoxan on Cerebral Blood Flow in Rats Studied by Arterial Spin Labeling Magnetic Resonance Perfusion Imaging
    The Effects of Clonidine and Idazoxan on Cerebral Blood Flow in Rats Studied by Arterial Spin Labeling Magnetic Resonance Perfusion Imaging X. Du1, H. Lei1 1State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Institute of Physics & Mathematics, Chinese Academy of Sciences, Wuhan, Hubei, China, People's Republic of Introduction Agonists of α2-adrenoceptors are known to produce many central and peripheral effects. For example, xylazine, a selective α2-adrenoceptors agonist, has been shown to cause region-dependent CBF decreases in rat [1]. Clonidine, an agonist for both α2-adrenergic receptor and imidazoline receptor, is a widely used drug for treating hypertension. Its effect on CBF, however, is not well understood. In this study, continuous arterial labeling (CASL) MR perfusion imaging was used to investigate the effects of clonidine and idazoxan, an antagonist for α2-adrenergic and imidazoline receptors, on CBF in rats. Materials and Methods Twelve male Sprague-Dawley rats, weighting 250-320 g, were used. After intubation, the rats were anesthetized by 1.0-1.5% isoflurane in a 70:30 N2O/O2 gas mixture. For each rat, bilateral femoral arteries and the right femoral vein were catheterized for monitoring blood gases and blood pressure, and for delivering drugs. Rectal temperature was maintained at 37.0-37.5 oC using a warm water pad. After measuring baseline CBF, the rats were divided into two groups. In the first group (n=7), clonidine (10 µg/kg, i.v.) was injected first, followed by idazoxan injection (300 µg/kg, i.v.) at 30 minutes later. Perfusion maps were obtained after administration of each drug.
    [Show full text]
  • Autonomic Nervous System Activity Changes in Patients with Hypertension and Overweight: Role and Therapeutic Implications Paul Valensi*
    Valensi Cardiovasc Diabetol (2021) 20:170 https://doi.org/10.1186/s12933-021-01356-w Cardiovascular Diabetology REVIEW Open Access Autonomic nervous system activity changes in patients with hypertension and overweight: role and therapeutic implications Paul Valensi* Abstract The incidence and prevalence of hypertension is increasing worldwide, with approximately 1.13 billion of people currently afected by the disease, often in association with other diseases such as diabetes mellitus, chronic kidney disease, dyslipidemia/hypercholesterolemia, and obesity. The autonomic nervous system has been implicated in the pathophysiology of hypertension, and treatments targeting the sympathetic nervous system (SNS), a key component of the autonomic nervous system, have been developed; however, current recommendations provide little guid‑ ance on their use. This review discusses the etiology of hypertension, and more specifcally the role of the SNS in the pathophysiology of hypertension and its associated disorders. In addition, the efects of current antihypertensive management strategies, including pharmacotherapies, on the SNS are examined, with a focus on imidazoline recep‑ tor agonists. Keywords: Autonomic nervous system, Hypertension, Obesity, Type 2 diabetes, Selective imidazoline receptor agonists Introduction 6]. Te prevalence of hypertension is higher in low- and Hypertension is one of the leading causes of premature middle-income countries [5] and increases with age [1]. death worldwide with 1.13 billion people having hyper- Te autonomic nervous system has been implicated tension. It is associated with an increased risk of cardio- in the pathophysiology of hypertension [7, 8] and treat- vascular diseases (CVD; e.g., stroke, angina, myocardial ments targeting the sympathetic nervous system (SNS) infarction, heart failure, peripheral artery disease, and have been developed [9, 10] although largely forgotten or abdominal aortic aneurysm) as well as end-stage renal ruled out in international recommendations [1, 2].
    [Show full text]
  • Download Product Insert (PDF)
    PRODUCT INFORMATION Guanfacine (hydrochloride) Item No. 22907 CAS Registry No.: 29110-48-3 Formal Name: N-(aminoiminomethyl)-2,6-dichloro- Cl H benzeneacetamide, monohydrochloride N NH2 MF: C9H9Cl2N3O • HCl FW: 282.6 O NH Purity: ≥98% Supplied as: A crystalline solid Cl • HCl Storage: -20°C Stability: ≥2 years Information represents the product specifications. Batch specific analytical results are provided on each certificate of analysis. Laboratory Procedures Guanfacine (hydrochloride) is supplied as a crystalline solid. A stock solution may be made by dissolving the guanfacine (hydrochloride) in the solvent of choice. Guanfacine (hydrochloride) is soluble in organic solvents such as ethanol, DMSO, and dimethyl formamide (DMF), which should be purged with an inert gas. The solubility of guanfacine (hydrochloride) in ethanol is approximately 25 mg/ml and approximately 30 mg/ml in DMSO and DMF. Further dilutions of the stock solution into aqueous buffers or isotonic saline should be made prior to performing biological experiments. Ensure that the residual amount of organic solvent is insignificant, since organic solvents may have physiological effects at low concentrations. Organic solvent-free aqueous solutions of guanfacine (hydrochloride) can be prepared by directly dissolving the crystalline solid in aqueous buffers. The solubility of guanfacine (hydrochloride) in PBS, pH 7.2, is approximately 10 mg/ml. We do not recommend storing the aqueous solution for more than one day. Description Guanfacine is an α2-adrenergic receptor (α2-AR) agonist with Ki values of 93, 1,380, and 3,890 nM for α2A-, 1 α2B-, and α2C-ARs, respectively, in a radioligand binding assay. It has EC50 values of 52, 288, and 602 nM for 35 α2A-, α2B-, and α2C-ARs, respectively, for stimulated [ S]GTPγS binding.
    [Show full text]
  • Pharmaceuticals Appendix
    )&f1y3X PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE )&f1y3X PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 3 Table 1. This table enumerates products described by International Non-proprietary Names (INN) which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service (CAS) registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known. Product CAS No. Product CAS No. ABAMECTIN 65195-55-3 ADAPALENE 106685-40-9 ABANOQUIL 90402-40-7 ADAPROLOL 101479-70-3 ABECARNIL 111841-85-1 ADEMETIONINE 17176-17-9 ABLUKAST 96566-25-5 ADENOSINE PHOSPHATE 61-19-8 ABUNIDAZOLE 91017-58-2 ADIBENDAN 100510-33-6 ACADESINE 2627-69-2 ADICILLIN 525-94-0 ACAMPROSATE 77337-76-9 ADIMOLOL 78459-19-5 ACAPRAZINE 55485-20-6 ADINAZOLAM 37115-32-5 ACARBOSE 56180-94-0 ADIPHENINE 64-95-9 ACEBROCHOL 514-50-1 ADIPIODONE 606-17-7 ACEBURIC ACID 26976-72-7 ADITEREN 56066-19-4 ACEBUTOLOL 37517-30-9 ADITOPRIME 56066-63-8 ACECAINIDE 32795-44-1 ADOSOPINE 88124-26-9 ACECARBROMAL 77-66-7 ADOZELESIN 110314-48-2 ACECLIDINE 827-61-2 ADRAFINIL 63547-13-7 ACECLOFENAC 89796-99-6 ADRENALONE 99-45-6 ACEDAPSONE 77-46-3 AFALANINE 2901-75-9 ACEDIASULFONE SODIUM 127-60-6 AFLOQUALONE 56287-74-2 ACEDOBEN 556-08-1 AFUROLOL 65776-67-2 ACEFLURANOL 80595-73-9 AGANODINE 86696-87-9 ACEFURTIAMINE 10072-48-7 AKLOMIDE 3011-89-0 ACEFYLLINE CLOFIBROL 70788-27-1
    [Show full text]
  • Dopamine D2 Receptors in the Cerebral Cortex
    Proc. Nati. Acad. Sci. USA Vol. 86, pp. 6412-6416, August 1989 Neurobiology Dopamine D2 receptors in the cerebral cortex: Distribution and pharmacological characterization with [3Hlraclopride (raclopride binding/neostriatum/rat/monkey) MICHAEL S. LIDOW*t, PATRICIA S. GOLDMAN-RAKIC*, PASKO RAKIC*, AND ROBERT B. INNIS*f Section of *Neuroanatomy and tDepartment of Psychiatry, Yale University, School of Medicine, New Haven, CT 06510 Contributed by Pasko Rakic, May 17, 1989 ABSTRACT An apparent involvement of dopamine in the MATERIALS AND METHODS regulation of cognitive functions and the recognition of a widespread dopaminergic innervation of the cortex have fo- Tissue was obtained from three adult rhesus monkeys cused attention on the identity of cortical dopamine receptors. (Macaca mulatta): one male and two females. The animals However, only the presence and distribution of dopamine DI were anesthesized with sodium pentobarbital (40 mg/kg) and receptors in the cortex have been well documented. Compa- perfused with ice-cold phosphate-buffered saline followed by rable information on cortical D2 sites is lacking. We report here 0.1% paraformaldehyde (9; 15). The cerebral cortex and the results of binding studies in the cortex and neostriatum of neostriatum were rapidly removed and immersed in isopen- rat and monkey using the D2 selective antagonist [3H]raclo- tane at -700C for 5 min before storing at -800C until use. For pride. In both structures [3H]raclopride bound in a sodium- competition studies tissue was pooled from several neocor- dependent and saturable manner to a single population of sites tical areas. However, saturation studies were conducted on with pharmacological profiles of dopamine D2 receptors.
    [Show full text]