DOCSLIB.ORG

Imidazoline Receptor System: the Past, the Present, and the Future

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Imidazoline Receptor System: the Past, the Present, and the Future 1521-0081/72/1/50–79$35.00 https://doi.org/10.1124/pr.118.016311 PHARMACOLOGICAL REVIEWS Pharmacol Rev 72:50–79, January 2020 Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics ASSOCIATE EDITOR: CHARLES P. FRANCE Imidazoline Receptor System: The Past, the Present, and the Future Pascal Bousquet, Alan Hudson, Jesús A. García-Sevilla, and Jun-Xu Li Faculty of Medicine, University of Strasbourg, Strasbourg, France (P.B.); Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada (A.H.); Laboratory of Neuropharmacology, University Research Institute on Health Sciences, University of the Balearic Islands, Palma de Malllorca, Spain (J.A.G.-S.); and Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, New York (J.-X.L.) Abstract .................................................................................... 51 I. Introduction . ...............................................................................51 II. History of Imidazoline Receptors .............................................................52 III. Endogenous Imidazoline Receptor Ligands . .................................................54 A. Clonidine-Displacing Substance . .......................................................54 B. Harmane . ...............................................................................55 C. Imidazole-4-Acetic Acid-Ribotide . .......................................................56 Downloaded from D. Agmatine . ...............................................................................57 IV. Imidazoline Subtype 1 Receptors.............................................................57 A. Definition. ...............................................................................57 B. Specific Binding Properties, Selective Ligands, and Tissue and Subcellular Localization..............................................................................58 by guest on September 23, 2021 1. Selective Ligands . ...................................................................58 2. Tissue Distribution ...................................................................58 3. Subcellular Distribution . .............................................................59 4. Second-Generation Imidazoline Subtype 1 Receptor Ligands . ..........................59 5. Selective Imidazoline Subtype 1 Receptor Ligands with High Affinity as Pharmacological Probes. .............................................................60 6. Receptor–Receptor Interactions .......................................................60 7. Transduction Mechanisms ............................................................61 8. Attempts to Clone Imidazoline Subtype 1 Receptors . ................................62 C. Cellular Effects . .........................................................................62 1. Imidazoline Subtype 1 Receptors and Apoptosis, Cell Viability, Growth, and Proliferation . .........................................................................62 2. Imidazoline Subtype 1 Receptors and Insulin and Adiponectin .........................62 3. Imidazoline Subtype 1 Receptors and Neurons . ......................................62 D. Imidazoline Subtype 1 Receptors and In Vivo Effects .....................................63 1. Effects on Blood Pressure and Heart Rate . ...........................................63 2. Antiarrhythmic Effects. .............................................................63 3. Effects in Congestive Heart Failure . .................................................63 4. Effects on Glucose and Lipid Metabolism and Interest in Metabolic Syndrome . ........63 V. Imidazoline Subtype 2 Receptors.............................................................64 A. Definition, Distribution, and Composition.................................................64 B. Synthetic Imidazoline Subtype 2 Receptor Ligands . ......................................65 C. Neuropharmacology of Imidazoline Subtype 2 Receptor Ligands. ..........................66 1. Pain. ...............................................................................66 Address correspondence to: Jun-Xu Li, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, 955 Main St., Buffalo, NY 14203. E-mail: [email protected] P.B. and A.H. contributed equally to this work. J.A.G.-S. and J.-X.L. contributed equally to this work. https://doi.org/10.1124/pr.118.016311. 50 A Review of Imidazoline Receptors 51 2. Discriminative Stimulus Effects.......................................................68 3. Neuroprotection . ...................................................................69 4. Body Temperature. ...................................................................70 D. Pharmacological and Neurobiological Mechanisms . ......................................70 VI. Imidazoline Subtype 3 Receptors.............................................................72 VII. Summary and Conclusions ...................................................................73 References...................................................................................73 Abstract——Imidazoline receptors historically re- receptors associate with several distinct proteins, but the ferred to a family of nonadrenergic binding sites that identities of these proteins remain elusive. I2 receptor recognize compounds with an imidazoline moiety, agonists have demonstrated various centrally mediated although this has proven to be an oversimplification. effects including antinociception and neuroprotection. A For example, none of the proposed endogenous new I2 receptor agonist, CR4056 [2-phenyl-6-(1H-imidazol- ligands for imidazoline receptors contain an imida- 1yl) quinazoline], demonstrated clear analgesic activity zoline moiety but they are diverse in their chemical in a recently completed phase II clinical trial and structure. Three receptor subtypes (I1,I2,andI3) holds great promise as a novel I2 receptor–based first- have been proposed and the understanding of each in-class nonopioid analgesic. The understanding of has seen differing progress over the decades. I1 I3 receptors is relatively limited. Existing data receptors partially mediate the central hypoten- suggest that I3 receptors may represent a binding sive effects of clonidine-like drugs. Moxonidine and site at the Kir6.2-subtype ATP-sensitive potassium rilmenidine have better therapeutic profiles (fewer side channels in pancreatic b-cells and may be involved effects) than clonidine as antihypertensive drugs, thought in insulin secretion. Despite the elusive nature of to be due to their higher I1/a2-adrenoceptor selectivity. their molecular identities, recent progress on drug Newer I1 receptor agonists such as LNP599 [3-chloro-2- discovery targeting imidazoline receptors (I1 and methyl-phenyl)-(4-methyl-4,5-dihydro-3H-pyrrol-2-yl)- I2) demonstrates the exciting potential of these amine hydrochloride] have little to no activity on compounds to elicit neuroprotection and to treat a2-adrenoceptors and demonstrate promising therapeutic various disorders such as hypertension, metabolic potential for hypertension and metabolic syndrome. I2 syndrome, and chronic pain. I. Introduction the fifth edition of the Guide to Receptors and Channels Although the imidazoline receptor concept was pro- (Alexander et al., 2011), imidazoline receptors are only posed decades ago and the field has been consistently briefly described under the entry on a2-adrenoceptors. evolving, many pharmacologists have not yet heard However, there has recently been renewed interest in about this receptor. This is not surprising because, to increasing understanding and pharmacological study of some extent, this concept has not received unanimous this system due to exciting new developments regarding acceptance in the biomedical community. For example, the therapeutic potential of imidazoline receptor ligands. in the 12th edition of Goodman & Gilman’s The Pharma- This review provides a comprehensive update on the cological Basis of Therapeutics (Brunton et al., 2011), there historical and current status of imidazoline receptor is only one sentence mentioning imidazoline receptors. In research and offers our perspective on future directions. ABBREVIATIONS: 2-BFI, 2-(2-benzofuranyl)-2-imidazoline; AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; AMPK, 59 adenosine monophosphate-activated protein kinase; BU216, 3-[4,5-dihydroimidaz-2-yl]-quinoline hydrochloride; BU224, 2-[4,5-dihy- droimidaz-2-yl]-quinoline hydrochloride; BU226, 2-[4,5-dihydroimidaz-2-yl]-isoquinoline hydrochloride; CCI, chronic constriction injury; CDS, clonidine-displacing substance; CFA, complete Freund’s adjuvant; CNS, central nervous system; CR4056, 2-phenyl-6-(1H-imidazol-1yl) qui- nazoline; DSP-4, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine; ERK, extracellular signal-regulated kinase; HPLC, high-performance liquid chromatography; IAA-RP, imidazole-4-acetic acid-ribotide; IRAS, imidazoline receptor antisera-selected; KATP, ATP-sensitive potassium; KU14-R, 2-(2-ethyl-2,3-dihydro-2-benzofuranyl)-1H-imidazole; LNP509, cis-/trans-dicyclopropylmethyl-(4,5-dimethyl-4,5-dihydro-3H-pyrrol- 2-yl)-amine; LNP599, 3-chloro-2-methyl-phenyl)-(4-methyl-4,5-dihydro-3H-pyrrol-2-yl)-amine hydrochloride; LNP630, (2,6-dichloro-phenyl)- (4-methyl-4,5-dihydro-1H-imidazol-2-yl)-amine; LNP906, 2-(5-azido-2-chloro-4-iodo-phenylamino)-5-methyl-pyrroline; LNP911, (2-(2-chloro-4-
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]
  • 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]
  • 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]
  • Estonian Statistics on Medicines 2016 1/41
    Estonian Statistics on Medicines 2016 ATC code ATC group / Active substance (rout of admin.) Quantity sold Unit DDD Unit DDD/1000/ day A ALIMENTARY TRACT AND METABOLISM 167,8985 A01 STOMATOLOGICAL PREPARATIONS 0,0738 A01A STOMATOLOGICAL PREPARATIONS 0,0738 A01AB Antiinfectives and antiseptics for local oral treatment 0,0738 A01AB09 Miconazole (O) 7088 g 0,2 g 0,0738 A01AB12 Hexetidine (O) 1951200 ml A01AB81 Neomycin+ Benzocaine (dental) 30200 pieces A01AB82 Demeclocycline+ Triamcinolone (dental) 680 g A01AC Corticosteroids for local oral treatment A01AC81 Dexamethasone+ Thymol (dental) 3094 ml A01AD Other agents for local oral treatment A01AD80 Lidocaine+ Cetylpyridinium chloride (gingival) 227150 g A01AD81 Lidocaine+ Cetrimide (O) 30900 g A01AD82 Choline salicylate (O) 864720 pieces A01AD83 Lidocaine+ Chamomille extract (O) 370080 g A01AD90 Lidocaine+ Paraformaldehyde (dental) 405 g A02 DRUGS FOR ACID RELATED DISORDERS 47,1312 A02A ANTACIDS 1,0133 Combinations and complexes of aluminium, calcium and A02AD 1,0133 magnesium compounds A02AD81 Aluminium hydroxide+ Magnesium hydroxide (O) 811120 pieces 10 pieces 0,1689 A02AD81 Aluminium hydroxide+ Magnesium hydroxide (O) 3101974 ml 50 ml 0,1292 A02AD83 Calcium carbonate+ Magnesium carbonate (O) 3434232 pieces 10 pieces 0,7152 DRUGS FOR PEPTIC ULCER AND GASTRO- A02B 46,1179 OESOPHAGEAL REFLUX DISEASE (GORD) A02BA H2-receptor antagonists 2,3855 A02BA02 Ranitidine (O) 340327,5 g 0,3 g 2,3624 A02BA02 Ranitidine (P) 3318,25 g 0,3 g 0,0230 A02BC Proton pump inhibitors 43,7324 A02BC01 Omeprazole
    [Show full text]
  • Harmine Augments Electrically Evoked Dopamine Efflux in the Nucleus Accumbens Shell
    JOP27110.1177/0269881112463125Journal of PsychopharmacologyBrierley and Davidson 4631252013 Original Paper Harmine augments electrically evoked dopamine efflux in the nucleus accumbens shell Journal of Psychopharmacology 27(1) 98 –108 © The Author(s) 2013 Reprints and permission: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0269881112463125 Daniel I Brierley and Colin Davidson jop.sagepub.com Abstract Harmine is a β-carboline alkaloid and major component of ayahuasca, a traditional South American psychoactive tea with anecdotal efficacy for treatment of cocaine dependence. Harmine is an inhibitor of monoamine oxidase A (MAO-A) and interacts in vitro with several pharmacological targets which modulate dopamine (DA) neurotransmission. In vivo studies have demonstrated dopaminergic effects of harmine, attributed to monoamine oxidase inhibitor (MAOI) activity, however none have directly demonstrated a pharmacological mechanism. This study investigated the acute effects, and pharmacological mechanism(s), of harmine on electrically evoked DA efflux parameters in the nucleus accumbens both in the absence and presence of cocaine. Fast cyclic voltammetry in rat brain slices was used to measure electrically evoked DA efflux in accumbens core and shell. Harmine (300 nM) significantly augmented DA efflux (148±8% of baseline) in the accumbens shell. Cocaine augmented efflux in shell additive to harmine (260±35%). Harmine had no effect on efflux in the accumbens core or on reuptake in either sub-region. The effect of harmine in the shell was attenuated by the 5-HT2A/2C antagonist ketanserin. The MAOI moclobemide (10 µM) had no effect on DA efflux. These data suggest that harmine augments DA efflux via a novel, shell-specific, presynaptic 5-HT2A receptor-dependent mechanism, independent of MAOI activity.
    [Show full text]
  • Estonian Statistics on Medicines 2013 1/44
    Estonian Statistics on Medicines 2013 DDD/1000/ ATC code ATC group / INN (rout of admin.) Quantity sold Unit DDD Unit day A ALIMENTARY TRACT AND METABOLISM 146,8152 A01 STOMATOLOGICAL PREPARATIONS 0,0760 A01A STOMATOLOGICAL PREPARATIONS 0,0760 A01AB Antiinfectives and antiseptics for local oral treatment 0,0760 A01AB09 Miconazole(O) 7139,2 g 0,2 g 0,0760 A01AB12 Hexetidine(O) 1541120 ml A01AB81 Neomycin+Benzocaine(C) 23900 pieces A01AC Corticosteroids for local oral treatment A01AC81 Dexamethasone+Thymol(dental) 2639 ml A01AD Other agents for local oral treatment A01AD80 Lidocaine+Cetylpyridinium chloride(gingival) 179340 g A01AD81 Lidocaine+Cetrimide(O) 23565 g A01AD82 Choline salicylate(O) 824240 pieces A01AD83 Lidocaine+Chamomille extract(O) 317140 g A01AD86 Lidocaine+Eugenol(gingival) 1128 g A02 DRUGS FOR ACID RELATED DISORDERS 35,6598 A02A ANTACIDS 0,9596 Combinations and complexes of aluminium, calcium and A02AD 0,9596 magnesium compounds A02AD81 Aluminium hydroxide+Magnesium hydroxide(O) 591680 pieces 10 pieces 0,1261 A02AD81 Aluminium hydroxide+Magnesium hydroxide(O) 1998558 ml 50 ml 0,0852 A02AD82 Aluminium aminoacetate+Magnesium oxide(O) 463540 pieces 10 pieces 0,0988 A02AD83 Calcium carbonate+Magnesium carbonate(O) 3049560 pieces 10 pieces 0,6497 A02AF Antacids with antiflatulents Aluminium hydroxide+Magnesium A02AF80 1000790 ml hydroxide+Simeticone(O) DRUGS FOR PEPTIC ULCER AND GASTRO- A02B 34,7001 OESOPHAGEAL REFLUX DISEASE (GORD) A02BA H2-receptor antagonists 3,5364 A02BA02 Ranitidine(O) 494352,3 g 0,3 g 3,5106 A02BA02 Ranitidine(P)
    [Show full text]
  • Moxonidine: Clinical Profile
    Journal of Clinical and Basic Cardiology An Independent International Scientific Journal Journal of Clinical and Basic Cardiology 2001; 4 (3), 197-200 Moxonidine: Clinical Profile Farsang C Homepage: www.kup.at/jcbc Online Data Base Search for Authors and Keywords Indexed in Chemical Abstracts EMBASE/Excerpta Medica Krause & Pachernegg GmbH · VERLAG für MEDIZIN und WIRTSCHAFT · A-3003 Gablitz/Austria FOCUS ON SYMPATHETIC TONE Moxonidine: Clinical Profile J Clin Basic Cardiol 2001; 4: 197 Moxonidine: Clinical Profile C. Farsang Several haemodynamic, humoral, and metabolic changes develop in patients with hypertension. Antihypertensive drugs inhibiting or reversing these alterations are of clinical value in the therapy of hypertension. Among these agents, most recently the imidazoline I1 receptor agonists can also be considered as the first therapeutic option. Moxonidine is a selective I1 receptor agonist with a pharmacokinetic profile that enables it to be used once daily. It inhibits the consequences of the increased sym- pathetic tone, it increases natriuresis, and therefore effectively decreases blood pressure in a wide variety of hypertensive pa- tients. The particular advantage of moxonidine is that it can increase the insulin sensitivity of those patients where it is de- creased, therefore it is useful in hypertensive patients with insulin resistance. Moxonidine can be combined with many other antihypertensive drugs such as thiazides, ACE-inhibitors, calcium antagonists, but it can be potentially useful in combinations with alpha1-blockers, angiotensin AT1 blockers, and, in a particular group of patients, with beta-blockers (patients with exagger- ated sympathetic tone, or in those with hyperthyroidism). J Clin Basic Cardiol 2001; 4: 197–200.
    [Show full text]
  • Centrally Acting Antihypertensives: a Renaissance of Tinterest: Mechanisms and Haemodynamics Van Zwieten, P.A
    UvA-DARE (Digital Academic Repository) Centrally acting antihypertensives: a renaissance of tinterest: mechanisms and haemodynamics van Zwieten, P.A. Publication date 1997 Published in Journal of hypertension Link to publication Citation for published version (APA): van Zwieten, P. A. (1997). Centrally acting antihypertensives: a renaissance of tinterest: mechanisms and haemodynamics. Journal of hypertension, 15(Suppl.1), S3-S8. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) Download date:24 Sep 2021 New centrally acting antihypertensives van ZwietenReview S3 Centrally acting antihypertensives: a renaissance of interest. Mechanisms and haemodynamics Pieter A. van Zwieten Background Classic centrally acting antihypertensives are receptors, located in the nucleus reticularis lateralis will trig- α known to stimulate 2-adrenoceptors located in the ponto- ger peripheral sympathoinhibition, following similar path- α medullary region, in the vicinity of the nucleus tractus solitarii, ways as involved in the effects of the classic 2-adrenoceptor vasomotor centre, vagal nucleus and the various intercon- stimulants.
    [Show full text]
  • Constructing the Ecstasy of MDMA from Its Component Mental Organs: Proposing the Primer/Probe Method Q ⇑ Thomas S
    Medical Hypotheses 87 (2016) 48–60 Contents lists available at ScienceDirect Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy Constructing the ecstasy of MDMA from its component mental organs: Proposing the primer/probe method q ⇑ Thomas S. Ray Department of Biology, University of Oklahoma, Norman, OK 73069, United States article info abstract Article history: The drug MDMA, commonly known as ecstasy, produces a specific and distinct open hearted mental Received 4 October 2015 state, which led to the creation of a new pharmacological class, ‘‘entactogens”. Extensive literature on Accepted 17 December 2015 its mechanisms of action has come to characterize MDMA as a ‘‘messy” drug with multiple mechanisms, but the consensus is that the distinctive entactogenic effects arise from the release of neurotransmitters, primarily serotonin. I propose an alternative hypothesis: The entactogenic mental state is due to the simultaneous direct activation of imidazoline-1 (I1) and serotonin-2 (5-HT2) receptors by MDMA. This hypothesis emerges from ‘‘mental organ” theory, which embodies many hypotheses, the most relevant of which are: ‘‘Mental organs” are populations of neurons that all express their defining metabotropic receptor, and each mental organ plays a distinct role in the mind, a role shaped by evolution as mental organs evolve by duplication and divergence. Mental organs are the mechanism by which evolution sculpts the mind. Mental organs can be in or out of consciousness. In order for a mental organ to enter consciousness, three things must happen: s The mental organ must be activated directly at its defining receptor. s 5-HT2 must be simultaneously activated.
    [Show full text]
  • Statistical Analysis Plan: GEM-301 10 July 2017
    Title: A 12-Week, Phase 2 Randomized, Placebo-Controlled, Double-Blind Study to Assess the Efficacy, Safety, and Tolerability of Gemcabene in Subjects with Hypercholesterolemia Not Adequately Controlled on High-Intensity or Moderate-Intensity Stable Statin Therapy (ROYAL-1) NCT ID: NCT02634151 Approval Date: 10-Jul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onfidentiality Statement 7KLVGRFXPHQWFRQWDLQVFRQILGHQWLDODQGSURSULHWDU\LQIRUPDWLRQDQGLVQRWWR EHGLVWULEXWHGWRDQ\WKLUGSDUW\ &RQILGHQWLDO 3DJHRI Gemcabene Gemphire Therapeutics Inc. Statistical Analysis Plan: GEM-301 10 July 2017 1 TABLE OF CONTENTS 1 TABLE OF CONTENTS ...................................................................................................2 LIST OF TABLES .....................................................................................................................3 LIST OF APPENDICES ............................................................................................................3
    [Show full text]
  • Protocol Use of Antidepressants and Risk of Hip/Femur Fracture
    WP2 Framework for pharmacoepidemiological studies WG1 Databases Study Protocol Use of Antidepressants and risk of hip/femur fracture. A methodological comparison across data sources and epidemiological design. Version: Final Nov 14, 2011 with Amendment 5 22 Jan , 2014 PROTECT WP2_ Final protocol_ Antidep_Hip 14Nov2011_Amend5_22Jan2014 Page 1 of 80 WG1 Drug AE group Name Role Gardarsdottir, Helga 1,2 Protocol lead Marieke De Bruin 1 Protocol backup Liset van Dijk 1,3 Protocol reviewer Montserrat Miret 4 Protocol reviewer Frank de Vries 1 Protocol reviewer Marietta Rottenkolber 5 Database 1 (Bavaria) lead Joerg Hasford 5 Database 1 (Bavaria) backup Consuelo Huerta 6 Database 2 (Bifap) lead Miguel Gil 6 Database 2 (Bifap) backup Ulrik Hesse7 Database 3 (DKMA) lead Frank de Vries1 Database 3 (DKMA) backup Edmond Ng /Jenny Campbell78 Database 4 (CPRD) lead/backup Olaf Klungel 1 Database 5 (Mondriaan) lead Liset van Dijk 1, 2 Database 5 (Mondriaan) backup Yolanda Alvarez 9 Database 6 (THIN) lead Ana Ruigomez 10 Database 6 (THIN) backup 1 Universiteit Utrecht, Utrecht, The Netherlands (UU) 2 University Medical Center Utrecht, Utrecht, The Netherlands (UU) 3 Netherlands Institute for Healthcare Research, Utrecht, The Netherlands (NIVEL) 4 Merck KGaA, Geneva, Switzerland (ME) 5 Ludwig-Maximilians-Universität-München, Munich, Germany (LMU- Muenchen) 6 Agencia Espanola de Medicamentos y Productos Sanitarios, Madrid, Spain (AEMPS) 7 Lægemiddelstyrelsen (Danish Medicines Agency), Copenhagen, Denmark (DKMA) 8 Clinical Practice Research Datalink, London, United Kingdom (CPRD) 9 European Medicines Agency, London, United Kingdom (EMA) 10 Fundación Centro Español de Investigación Farmacoepidemiológica, Madrid, Spain (CEIFE) PROTECT WP2_ Final protocol_ Antidep_Hip 14Nov2011_Amend5_22Jan2014 Page 2 of 80 Content 1 Context of the studies and objective ...........................................................................................................
    [Show full text]