DOCSLIB.ORG

The Adrenergic Control of Lower Esophageal Sphincter Function: an EXPERIMENTAL MODEL of DENERVATION SUPERSENSITIVITY

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Adrenergic Control of Lower Esophageal Sphincter Function: an EXPERIMENTAL MODEL of DENERVATION SUPERSENSITIVITY The Adrenergic Control of Lower Esophageal Sphincter Function: AN EXPERIMENTAL MODEL OF DENERVATION SUPERSENSITIVITY Anthony J. DiMarino, Sidney Cohen J Clin Invest. 1973;52(9):2264-2271. https://doi.org/10.1172/JCI107413. To evaluate the adrenergic regulation of lower esophageal sphincter (LES) function, LES pressure, LES relaxation during swallowing, and blood pressure were measured in the anesthetized opossum, Didelphis virginiana, during intravenous administration of alpha and beta adrenergic agonists and antagonists. Studies were done in controls and animals adrenergically denervated with 6-hydroxydopamine. Alpha adrenergic agonists (norepinephrine, phenylephrine) increased LES pressure and blood pressure, whereas a beta adrenergic agonist (isoproterenol) decreased both pressures. Alpha adrenergic antagonism (phentolamine) reduced basal LES pressure by 38.3±3.8% (mean ±SEM) (P < 0.001). Beta adrenergic antagonism (propranolol) had no significant effect on either basal LES pressure or percent of LES relaxation with swallowing. After adrenergic denervation with 6-hydroxydopamine, basal LES pressure was reduced by 22.5±5.3% (P < 0.025) but LES relaxation during swallowing was unaltered. In denervated animals, both LES pressure and blood pressure dose response curves showed characteristics of denervation supersensitivity to alpha but not to beta adrenergic agonists. These studies suggest: (a) a significant portion of basal LES pressure is dependent upon alpha adrenergic stimulation; (b) LES relaxation during swallowing is not an adrenergically mediated response; c( ) the LES pressure response to alpha adrenergic agonists after 6-hydroxydopamine may serve as a model of denervation supersensitivity in the gastrointestinal tract. Find the latest version: https://jci.me/107413/pdf The Adrenergic Control of Lower Esophageal Sphincter Function AN EXPERIMENTAL MODEL OF DENERVATION SUPERSENSITIVITY ANTHoNY J. DIMANO and SmINEY COHEN From the Gastrointestinal Section, Department of Medicine, Hospital of the University of Pennsylvania, and Veterans Administration Hospital, Philadelphia, Pennsylvania 19104 A BSTRACT To evaluate the adrenergic regulation INTRODUCTION of lower esophageal sphincter (LES) function, LES The adrenergic innervation of the gastrointestinal tract pressure, LES relaxation during swallowing. and blood generally has an inhibitory effect on motor function pressure were measured in the anesthetized opossum, (1). Howev-er, the internal anial (2), choledochal (3, Didelph is virginiana, during intravenous administration 4), ileocecal (5, 6), and lower esophageal sphincters of alpha and beta adrenergic agonists and antagonists. (7-9) (LES) ' have been shown to have alpha adren- Studies were done in controls and animals adrenergi- ergic receptors, the stimulation of which produces an cally denervated with 6-hydroxydopamine. Alpha adren- excitatory effect. Beta adrenergic stimulation at these ergic agonists (norepinephrinie. phenylephrine) in- sphincters still produces an inhibitory response. It had creased LES pressure and blood pressure. whereas a been suggested through studies in vitro that the excita- beta adrenergic agonist (isoproterenol) decreased both tory response mediated through alpha adrenergic stimui- pressures. Alpha adrenergic antagonism (phentolamine) lation at the LES may be an important factor in the reduced basal LES pressure by 38.3+3.8% (mean genesis of sphincter pressure (7). Tn addition. it had +SEM) (P < 0.001). Beta adrenergic antagonism been proposed that the inhibitory response to beta (propranolol) had no significant effect on either basal adrenergic stimiiulation may represent the relaxation in LES pressure or percent of LES relaxation with LES pressure durinig swallowing (10). The purpose swallowing. After adrenergic denervation with 6-hy- of this study was to investigate the adrenergic responses droxydopamine, basal LES pressure was reduced by of the LES in the anesthetized opossum and to quantify 22.5+5.3% (P < 0.025) but LES relaxation during the role of the adrenergic neural system in the genesis swallowing was unaltered. In denervated animals, both of basal LES pressure and in the inhibitory response to LES pressure and blood pressure dose response curves swallowing. showed characteristics of denervation supersensitivity to alpha but not to beta adrenergic agonists. These METHODS studies suggest: (a) a significant portion of basal LES All studies were performed on the adult opossum, species pressure is dependent upoIn alpha adrenergic stimula- D)idelphis virginiana. Animals of both sexes weighing be- tioin; (b) LES relaxation during swallowing is tnot an tween 2.2 and 3.6 kg were anesthetized with 2.0% choralose adrenergically miiediated response; (c) the LES pres- (3.0 cm'/kg) and supplemented once with pentobarbital, 10.0 mg, during surgery anid tube insertion. After success- sure response to alpha adrenergic agonists after 6- ful anesthesia, a heparinized cannula was inserted into the hydroxydopamine may serve as a model of denervation femoral artery and connected to an external transducer supersensitivity in the gastrointestinal tract. (Statham Instruments, Inc., Oxnard, Calif.) for constant Received for publication 23 October 1972 and in revised 'Abbreviation utscd int this paper: LES, lower esophageal form 23 February 1973. sphincter. 2264 The Journal of Clinical Investigation Volume 52 September 1973 *2264-2271 Blood Pressure lw W-- -- -Nc t20_0r ~~~~~~~LESPressure 10_I Epinephrine -4J X - ~~~~~(6.0,gg /Kg) 2 4 6 8 10 Time (minutes) FIGURE 1 LES pressure and femoral arterial pressure after an intravenous bolus of epi- nephrine (6.0 jug/kg) in a single animal. After epinephrine, sphincter pressure declined by 38.4% of its initial level. Simultaneously, mean arterial pressure rose by 61.3%. blood pressure monitoring. A similar cannula was inserted Control values of LES pressure, percent of relaxation into the opposite femoral vein for drug administration. of the LES with swallowing, and blood pressure were ob- Patency of this cannula was maintained through a slow tained after insertion of the intravenous and intra-arterial infusion of 0.9%o saline. cannulas and before the instillation of drugs. A period of Intralumiaal pressures were measured through water- 30 min for stabili7ation to baseline levels was observed filled polyvinyl catheters, 1.4 mm ID, connected to external after the administration of each pharmacological agent. transducers (Statham P23BB) with a linear external cali- The following pharmacological agents were given intra- bration of 0-250 mm Hg. Recording tubes were arranged venously as 30-s boluses: norepinephrine (0.025 ,ug/kg- as a fixed unit with three side orifices, 1.2 mm in diameter, 72.0 /Ag/kg), isoproterenol (0.001 ,ug/kg-14.0 Ag/kg), phe- spaced 5 cm apart over the distal segment of the tube. Each nylephrine (55.0 ,ug/kg), and epinephrine (60 ,g/kg). The recording tube was constantly perfused with distilled water beta adrenergic antagonist, propranolol (0.2 mg/kg-2.0 mg/ by a Harvard infusion pump (Harvard Apparatus Co., Inc., kg) and the alpha adrenergic antagonist, phentolamine (0.5 Millis, Mass.) at 1.2 cm'/min. After insertion into the mg/kg-1.5 mg/kg) were also administered. The selections animal's stomach, the entire recording assembly was with- of doses of drugs were initially based on the recognized drawn at 0.5-cm intervals with measurements being recorded predictable effects on blood pressure and pulse rates of the at each level for 1 min. For changes in LES pressure in animals. Drugs were given in random order and at random response to drugs, the middle recording orifice was posi- doses with agonists and antagonists given on separate days. tioned in the sphincter with the proximal lumen in the Each drug was diluted in normal saline and administered as esophagus and the distal pressure orifice in the stomach. a 2.0-cm3 injection. Isoproterenol was diluted in 5% dex- The middle orifice was maintained at the zone of maximal trose and water and given at the same volume. LES pressure by the evaluation of a complete pull-through Sympathetic denervation was obtained with 6-hydroxy- at each 5-min interval. To evacuate the stomach, gastric dopamine at a dose of 100 mg/kg given intraperitoneally. aspiration was done through the distal orifice approximately The compound, 6-hydroxydopamine, had been shown to every 30 min. All intraluminal pressures, as well as blood cause destructicn of adrenergic nerves at several anatomic pressure, were graphed on a Beckman rectilinear, ink-writ- locations (11-14). Previous studies have shown that a ing recorder (Beckman Instruments, Inc., Fullerton, Calif.). single i.p. injection of 16.5 mg/kg of 6-hydroxydopamine LES pressure was recorded as millimeters of mercury produced adrenergic nerve destruction, which was maximal with gastric fundal pressure used as a zero reference. The at 24 h and lasted for several weeks (12). All studies were values were obtained as the midrespiratory value during a performed 24-96 h after i.p. injection. In eight animals, the 1-min interval from the portion of the sphincter demonstrat- mean LES pressure and the percent relaxation in LES ing the highest pressure. Mean LES pressure was obtained pressure during swallowing was noted both before and after by determining the stable pressure at a minimum of four 6-hydroxydopamine injection in the same animal. points during a 1-min period. Blood pressure was measured An evaluation of the extent of adrenergic nerve destruc- as the mean pressure
Load more

Recommended publications
  • Adrenergic Antagonist
    PHARMACOLOGY Adrenergic antagonist OBJECTIVES: • Describe the different classifications for drugs that can block sympathetic nervous system. •Describe the kinetics, dynamics, uses and side effects of alpha adrenergic drugs. • Identify Difference between selective and non selective alpha blockers. • Know the difference between tamsulosin and other selective alpha receptor blockers. •Identify the different classifications for beta receptors blockers. •Describe the kinetics, dynamics, uses and side effects of beta adrenergic drugs. •Know the preferable drug for diseases as hypertension, glaucoma, arrythmia, myocardial infarction, anxiety, migraine and ect…. • Important. • Extra notes It’s a recall, if you know it you can skip it! Adrenergic receptors Adrenergic receptors Dopaminergic adrenoceptors adrenoceptors α− β− receptors β3 α1 α2 β1 β2 e.g. D1 α1 β2 β1 β3 Post-synaptic excitatory in function (cause inhibitory in function excitatory in In adipose contraction) except in GIT. (cause relaxation) function, present tissue mainly in heart Present mainly in smooth muscles. Contraction of pregnant Relaxation of the uterus ↑ heart rate: ↑ lipolysis uterus. (Delay premature labor) + chronotropic ↑ free fatty effect, Vasoconstriction of skin & Relaxation of skeletal & acids. Tachycardia peripheral blood vessels coronary blood vessels →increased peripheral (vasodilatation) ↑ force of → resistance hypertension. contraction : Relaxation of GIT muscles & urinary bladder’s muscles. + inotropic effect Contraction of GIT sphincter (constipation) & urinary
    [Show full text]
  • M100907, a Serotonin 5-HT2A Receptor Antagonist and Putative Antipsychotic, Blocks Dizocilpine-Induced Prepulse Inhibition Defic
    M100907, a Serotonin 5-HT2A Receptor Antagonist and Putative Antipsychotic, Blocks Dizocilpine-Induced Prepulse Inhibition Deficits in Sprague–Dawley and Wistar Rats Geoffrey B. Varty, Ph.D., Vaishali P. Bakshi, Ph.D., and Mark A. Geyer, Ph.D. a In a recent study using Wistar rats, the serotonergic 5-HT2 1 receptor agonist cirazoline disrupts PPI. As risperidone a receptor antagonists ketanserin and risperidone reduced the and M100907 have affinity at the 1 receptor, a final study disruptive effects of the noncompetitive N-methyl-D- examined whether M100907 would block the effects of aspartate (NMDA) antagonist dizocilpine on prepulse cirazoline on PPI. Risperidone partially, but inhibition (PPI), suggesting that there is an interaction nonsignificantly, reduced the effects of dizocilpine in Wistar between serotonin and glutamate in the modulation of PPI. rats, although this effect was smaller than previously In contrast, studies using the noncompetitive NMDA reported. Consistent with previous studies, risperidone did antagonist phencyclidine (PCP) in Sprague–Dawley rats not alter the effects of dizocilpine in Sprague–Dawley rats. found no effect with 5-HT2 antagonists. To test the hypothesis Most importantly, M100907 pretreatment fully blocked the that strain differences might explain the discrepancy in effect of dizocilpine in both strains; whereas SDZ SER 082 these findings, risperidone was tested for its ability to had no effect. M100907 had no influence on PPI by itself reduce the PPI-disruptive effects of dizocilpine in Wistar and did not reduce the effects of cirazoline on PPI. These and Sprague–Dawley rats. Furthermore, to determine studies confirm the suggestion that serotonin and glutamate which serotonergic receptor subtype may mediate this effect, interact in modulating PPI and indicate that the 5-HT2A the 5-HT2A receptor antagonist M100907 (formerly MDL receptor subtype mediates this interaction.
    [Show full text]
  • Guanfacine Extended Release for ADHD
    Out of the Pipeline p Guanfacine extended release for ADHD Floyd R. Sallee, MD, PhD uanfacine extended release (GXR)— Table 1 α Once-daily a selective -2 adrenergic agonist Guanfacine extended release: GFDA-approved for the treatment formulation may of attention-defi cit/hyperactivity disor- Fast facts improve adherence der (ADHD)—has demonstrated effi cacy Brand name: Intuniv and control for inattentive and hyperactive/impulsive Indication: Attention-defi cit/hyperactivity symptoms across disorder symptom domains in 2 large trials lasting® Dowden Health Media a full day 8 and 9 weeks.1,2 GXR’s once-daily formu- Approval date: September 3, 2009 lation may increase adherence and deliver Availability date: November 2009 consistent control of symptomsCopyright across a For personalManufacturer: use Shire only full day (Table 1). Dosing forms: 1-mg, 2-mg, 3-mg, and 4-mg extended-release tablets Recommended dosage: 0.05 to 0.12 mg/kg Clinical implications once daily GXR exhibits enhancement of noradren- ergic pathways through selective direct receptor action in the prefrontal cortex.3 brain believed to play a major role in at- This mechanism of action is different from tentional and organizational functions that that of other FDA-approved ADHD medi- preclinical research has linked to ADHD.3 cations. GXR can be used alone or in com- The postsynaptic α-2A receptor is bination with stimulants or atomoxetine thought to play a central role in the opti- for treating complex ADHD, such as cases mal functioning of the PFC as illustrated accompanied by oppositional features and by the “inverted U hypothesis of PFC ac- emotional dysregulation or characterized tivation.”4 In this model, cyclic adenos- by partial stimulant response.
    [Show full text]
  • Covalent Agonists for Studying G Protein-Coupled Receptor Activation
    Covalent agonists for studying G protein-coupled receptor activation Dietmar Weicherta, Andrew C. Kruseb, Aashish Manglikb, Christine Hillera, Cheng Zhangb, Harald Hübnera, Brian K. Kobilkab,1, and Peter Gmeinera,1 aDepartment of Chemistry and Pharmacy, Friedrich Alexander University, 91052 Erlangen, Germany; and bDepartment of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305 Contributed by Brian K. Kobilka, June 6, 2014 (sent for review April 21, 2014) Structural studies on G protein-coupled receptors (GPCRs) provide Disulfide-based cross-linking approaches (17, 18) offer important insights into the architecture and function of these the advantage that the covalent binding of disulfide-containing important drug targets. However, the crystallization of GPCRs in compounds is chemoselective for cysteine and enforced by the active states is particularly challenging, requiring the formation of affinity of the ligand-pharmacophore rather than by the elec- stable and conformationally homogeneous ligand-receptor com- trophilicity of the cross-linking function (19). We refer to the plexes. Native hormones, neurotransmitters, and synthetic ago- described ligands as covalent rather than irreversible agonists nists that bind with low affinity are ineffective at stabilizing an because cleavage may be promoted by reducing agents and the active state for crystallogenesis. To promote structural studies on disulfide transfer process is a reversible chemical reaction the pharmacologically highly relevant class
    [Show full text]
  • The Importance of Serotonergic and Adrenergic Receptors for the Induction and Expression of One-Trial Cocaine-Induced Behavioral Sensitization" (2016)
    California State University, San Bernardino CSUSB ScholarWorks Electronic Theses, Projects, and Dissertations Office of aduateGr Studies 12-2016 THE IMPORTANCE OF SEROTONERGIC AND ADRENERGIC RECEPTORS FOR THE INDUCTION AND EXPRESSION OF ONE- TRIAL COCAINE-INDUCED BEHAVIORAL SENSITIZATION Krista N. Rudberg California State University - San Bernardino Follow this and additional works at: https://scholarworks.lib.csusb.edu/etd Part of the Biological Psychology Commons, and the Pharmacology Commons Recommended Citation Rudberg, Krista N., "THE IMPORTANCE OF SEROTONERGIC AND ADRENERGIC RECEPTORS FOR THE INDUCTION AND EXPRESSION OF ONE-TRIAL COCAINE-INDUCED BEHAVIORAL SENSITIZATION" (2016). Electronic Theses, Projects, and Dissertations. 420. https://scholarworks.lib.csusb.edu/etd/420 This Thesis is brought to you for free and open access by the Office of aduateGr Studies at CSUSB ScholarWorks. It has been accepted for inclusion in Electronic Theses, Projects, and Dissertations by an authorized administrator of CSUSB ScholarWorks. For more information, please contact [email protected]. THE IMPORTANCE OF SEROTONERGIC AND ADRENERGIC RECEPTORS FOR THE INDUCTION AND EXPRESSION OF ONE-TRIAL COCAINE- INDUCED BEHAVIORAL SENSITIZATION A Thesis Presented to the Faculty of California State University, San Bernardino In Partial Fulfillment of the Requirements for the Degree Master of Arts in General/Experimental Psychology by Krista Nicole Rudberg December 2016 THE IMPORTANCE OF SEROTONERGIC AND ADRENERGIC RECEPTORS FOR THE INDUCTION AND EXPRESSION OF ONE-TRIAL COCAINE- INDUCED BEHAVIORAL SENSITIZATION A Thesis Presented to the Faculty of California State University, San Bernardino by Krista Nicole Rudberg December 2016 Approved by: Sanders McDougall, Committee Chair, Psychology Cynthia Crawford, Committee Member Matthew Riggs, Committee Member © 2016 Krista Nicole Rudberg ABSTRACT Addiction is a complex process in which behavioral sensitization may be an important component.
    [Show full text]
  • Pharmacological Approach to Sleep Disturbances in Autism Spectrum Disorders with Psychiatric Comorbidities: a Literature Review
    medical sciences Review Pharmacological Approach to Sleep Disturbances in Autism Spectrum Disorders with Psychiatric Comorbidities: A Literature Review Sachin Relia 1,* and Vijayabharathi Ekambaram 2,* 1 Department of Psychiatry, University of Tennessee Health Sciences Center, 920, Madison Avenue, Suite 200, Memphis, TN 38105, USA 2 Department of Psychiatry, University of Oklahoma Health Sciences Center, 920, Stanton L Young Blvd, Oklahoma City, OK 73104, USA * Correspondence: [email protected] (S.R.); [email protected] (V.E.); Tel.: +1-901-448-4266 (S.R.); +1-405-271-5251 (V.E.); Fax: +1-901-297-6337 (S.R.); +1-405-271-3808 (V.E.) Received: 15 August 2018; Accepted: 17 October 2018; Published: 25 October 2018 Abstract: Autism is a developmental disability that can cause significant emotional, social and behavioral dysfunction. Sleep disorders co-occur in approximately half of the patients with autism spectrum disorder (ASD). Sleep problems in individuals with ASD have also been associated with poor social interaction, increased stereotypy, problems in communication, and overall autistic behavior. Behavioral interventions are considered a primary modality of treatment. There is limited evidence for psychopharmacological treatments in autism; however, these are frequently prescribed. Melatonin, antipsychotics, antidepressants, and α agonists have generally been used with melatonin, having a relatively large body of evidence. Further research and information are needed to guide and individualize treatment for this population group. Keywords: autism spectrum disorder; sleep disorders in ASD; medications for sleep disorders in ASD; comorbidities in ASD 1. Introduction Autism is a developmental disability that can cause significant emotional, social, and behavioral dysfunction. According to the Diagnostic and Statistical Manual (DSM-V) classification [1], autism spectrum disorder (ASD) is characterized by persistent deficits in domains of social communication, social interaction, restricted and repetitive patterns of behavior, interests, or activities.
    [Show full text]
  • F3-Adrenergic Antagonist (Receptors/Cyclic AMP/Aminobenzylpropranolol/Iodohydroxybenzylpindolol/Isoproterenol) WESLEY L
    Proc. Natl. Acad. Sci. USA Vol. 76, No. 12, pp. 6401-6405, December 1979 Cell Biology Quantitative relationship between 3-adrenergic receptor number and physiologic responses as studied with a long-lasting f3-adrenergic antagonist (receptors/cyclic AMP/aminobenzylpropranolol/iodohydroxybenzylpindolol/isoproterenol) WESLEY L. TERASAKI, JOEL LINDEN, AND GARY BROOKER* Department of Pharmacology, School of Medicine, University of Virginia, Charlottesville, Virginia 22908 Communicated by Paul Greengard, August 20, 1979 ABSTRACT The aminobenzyl analog of propranolol, atrium when f3-adrenergic receptor number is selectively de- 1- (p-amino-a,a-dimethylphenethylamino)-3(1-naphthoxy)2- creased. To investigate this problem, a new propanol, was synthesized and found tobe a potent B-adrenergic f3-adrenergic blocking agent. The fl-adrenergic receptors of cultured rat C6 blocking agent, 1-(p-amino-a,a-dimethylphenethylamino- glioma cells (2B clone) as assessed by [' 51]iodohydroxybenzyl- 3-(1-naphthoxy)-2-propanol (aminobenzylpropranolol), was pindolol binding were decreased 50 and >95% afterpretreat- synthesized. It was found to be a selective agent for the elimi- ment with 8 nM and 1 ,M aminobenzylpropranolol, respec- nation of cellular /3-adrenergic receptors. tively. Unlike propranolol, aminobenzylpropranolol displayed a prolonged blockade of receptors that was maintained during several hours of washing. [121s]Iodohydroxybenzylpindolol MATERIALS AND METHODS saturation binding experiments in cells exposed to aminoben- Tissue Culture. C6 rat glioma cells, 2B subclone (7), were zylpropranolol and subsequently washed indicated that the compound effectively diminished receptor number with no grown in monolayer cultures as described (1) in 16-mm plastic change in the affinity of the remaining receptors for iodohy- cluster dishes. In all experiments, the cells were changed from droxybenzylpindolol.
    [Show full text]
  • Mutation of the 2A-Adrenoceptor Impairs Working Memory Performance and Annuls Cognitive Enhancement by Guanfacine
    The Journal of Neuroscience, October 1, 2002, 22(19):8771–8777 ␣ Mutation of the 2A-Adrenoceptor Impairs Working Memory Performance and Annuls Cognitive Enhancement by Guanfacine Jenna S. Franowicz,1 Lynn E. Kessler,1 Catherine M. Dailey Borja,1 Brian K. Kobilka,2 Lee E. Limbird,3 and Amy F. T. Arnsten1 1Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06510, 2Howard Hughes Medical Institute and Departments of Medicine and Molecular and Cellular Physiology, Stanford University, Palo Alto, California 94305, and 3Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 Norepinephrine strengthens the working memory, behavioral cortical damage or a spatial discrimination control task with inhibition, and attentional functions of the prefrontal cortex similar motor and motivational demands but no dependence on ␣ ␣ through actions at postsynaptic 2-adrenoceptors ( 2-AR). The prefrontal cortex. The effects of guanfacine on performance of ␣ 2-AR agonist guanfacine enhances prefrontal cortical func- the delayed alternation task were assessed in additional groups ␣ tions in rats, monkeys, and human beings and ameliorates of wild-type versus 2A-AR mutant mice. We observed that ␣ prefrontal cortical deficits in patients with attention deficit hy- functional loss of the 2A-AR subtype, unlike knock-out of the ␣ peractivity disorder. The present study examined the subtype of 2C-AR subtype, weakened performance of the prefrontal cor- ␣ 2-AR underlying these beneficial effects. Because there are no tical task without affecting learning and resulted in loss of the ␣ ␣ ␣ selective 2A-AR, 2B-AR, or 2C-AR agonists or antagonists, beneficial response to guanfacine. These data demonstrate the ␣ genetically altered mice were used to identify the molecular importance of 2A-AR subtype stimulation for the cognitive target of the action of guanfacine.
    [Show full text]
  • Synergistic Action of 5-HT2A Antagonists and Selective Serotonin Reuptake Inhibitors in Neuropsychiatric Disorders
    Neuropsychopharmacology (2003) 28, 402–412 & 2003 Nature Publishing Group All rights reserved 0893-133X/03 $25.00 www.neuropsychopharmacology.org Synergistic Action of 5-HT2A Antagonists and Selective Serotonin Reuptake Inhibitors in Neuropsychiatric Disorders ,1 2 3 2 Gerard J Marek* , Linda L Carpenter , Christopher J McDougle and Lawrence H Price 1Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA; 2Department of Psychiatry and Human, Brown Medical School, Mood 3 Disorders Program, Behavior, Butler Hospital, Providence, RI, USA; Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA Recently, the addition of drugs with prominent 5-HT2 receptor antagonist properties (risperidone, olanzapine, mirtazapine, and mianserin) to selective serotonin reuptake inhibitors (SSRIs) has been shown to enhance therapeutic responses in patients with major depression and treatment-refractory obsessive–compulsive disorder (OCD). These 5-HT antagonists may also be effective in 2 ameliorating some symptoms associated with autism and other pervasive developmental disorders (PDDs). At the doses used, these drugs would be expected to saturate 5-HT2A receptors. These findings suggest that the simultaneous blockade of 5-HT2A receptors and activation of an unknown constellation of other 5-HT receptors indirectly as a result of 5-HT uptake inhibition might have greater therapeutic efficacy than either action alone. Animal studies have suggested that activation of 5-HT1A and 5-HT2C receptors may counteract the effects of activating 5-HT2A receptors. Additional 5-HT receptors, such as the 5-HT1B/1D/5/7 receptors, may similarly counteract the effects of 5-HT receptor activation. These clinical and preclinical observations suggest that the combination of highly 2A selective 5-HT antagonists and SSRIs, as well as strategies to combine high-potency 5-HT receptor and 5-HT transporter blockade in 2A 2A a single compound, offer the potential for therapeutic advances in a number of neuropsychiatric disorders.
    [Show full text]
  • Study of Methyl Dopa Versus Labetalol in Management of Preeclampsia and Gestational Hypertension
    logy & Ob o st ec e tr n i y c s G Dharwadkar et al., Gynecol Obstet (Sunnyvale) 2014, 4:9 Gynecology & Obstetrics DOI; 10.4172/2161-0932.1000242 ISSN: 2161-0932 Research Article Open Access Study of Methyl Dopa Versus Labetalol in Management of Preeclampsia and Gestational Hypertension Dharwadkar MN1, Kanakamma MK1, Dharwadkar SN2*, Rajagopal K1, Gopakumar C3, Divya James Fenn J4 and Balachandar V3,5 1Department of Obstetrics and Gynaecology, Yenepoya Medical College and teaching Hospital, Yenepoya University, Deralakatte, Mangalore, Karnataka 575022, India 2Department of Zoology, K.L.E’s. S. Nijalingappa College, KLE Medical University (Health), Bangalore, Karnataka 560010, India 3Department of Human Genetics Molecular Biology, Bharathiar University, Coimbatore, India 4Post Graduate Student, Department of Obstetrics and Gynaecology, Sree Balaji Medical College and Hospital, Chennai 600044, Tamil Nadu, India 5Human Molecular Genetics Laboratory, Department of Zoology, Bharathiar University, Coimbatore, India Abstract Objective: To assess the efficacy and safety of labetalol compared with methyldopa in the management of mild and moderate cases of pregnancy-induced hypertension (PIH). Methods: Eighty patients with PIH were randomly allocated to receive either labetalol (group A) or methyldopa (group B). Administration of drugs with respect to Age, Gravid Status, Blood Pressure, Urine albumin Levels, Side Effects, Drug dosage, Additional Treatment, Prolongation of Pregnancy, New born Screening Test (NST), mode of termination, Indication of caesarean section, Perinatal safety and APGAR scores were studied. The statistical level of significance was taken at P<0.05. Results: A labetalol has been very effective in control as well as earlier onset of action in patients with methyl dopa.
    [Show full text]
  • Oral Phentolamine: an Alpha-1, Alpha-2 Adrenergic Antagonist for the Treatment of Erectile Dysfunction
    International Journal of Impotence Research (2000) 12, Suppl 1, S75±S80 ß 2000 Macmillan Publishers Ltd All rights reserved 0955-9930/00 $15.00 www.nature.com/ijir Oral phentolamine: an alpha-1, alpha-2 adrenergic antagonist for the treatment of erectile dysfunction I Goldstein1 1Department of Urology, Boston University School of Medicine, Boston, MA, USA Phentolamine mesylate is an alpha-1 and alpha-2 selective adrenergic receptor antagonist which has undergone clinical trials for erectile dysfunction treatment. Biochemical and physiological studies in human erectile tissue have revealed a high af®nity of phentolamine for alpha-1 and alpha-2 adrenergic receptors. Based on pharmacokinetic studies, it is suggested that 30±40 min following oral ingestion of 40 or 80 mg of phentolamine (Vasomax), the mean plasma phentolamine concentrations are suf®cient to occupy the alpha-1 and -2 adrenergic receptors in erectile tissue and thereby result in inhibition of adrenergic-mediated physiologic activity. In large multi-center, placebo-controlled pivotal phase III clinical trials, the mean change in the erectile function domain of the International Index of Erectile Function scores (Questions 1±5 and 15) from screening to the end of treatment was signi®cantly higher following use of active drug (40 mg and 80 mg) compared to placebo. Three to four times as many patients receiving phentolamine reported being satis®ed or very satis®ed compared with those receiving placebo. At doses of 40 mg and 80 mg respectively, 55% and 59% of men were able to achieve vaginal penetration with 51% and 53% achieving penetration on 75% of attempts.
    [Show full text]
  • α2-Adrenoceptor and 5-Ht3 Serotonin Receptor
    Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2012 α2-ADRENOCEPTOR AND 5-HT3 SEROTONIN RECEPTOR LIGANDS AS POTENTIAL ANALGESIC ADJUVANTS Genevieve Alley Virginia Commonwealth University Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Pharmacy and Pharmaceutical Sciences Commons © The Author Downloaded from https://scholarscompass.vcu.edu/etd/2867 This Dissertation is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. © Genevieve Sirles Alley 2012 All Rights Reserved i α2-ADRENOCEPTOR AND 5-HT3 SEROTONIN RECEPTOR LIGANDS AS POTENTIAL ANALGESIC ADJUVANTS A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University. by Genevieve Sirles Alley Bachelor of Science in Biology, Virginia Commonwealth University 2005 Director: Małgorzata Dukat, Ph.D. Associate Professor, Department of Medicinal Chemistry Virginia Commonwealth University Richmond, Virginia August 2012 ii ACKNOWLEDGMENT First, I would like to thank Dr. Małgorzata Dukat for her continued assistance and advice throughout my studies. This guidance has helped me better understand and appreciate medicinal chemistry. Also, a special thanks is given to both Dr. Dukat and Dr. Richard A. Glennon for their constant quizzing during group meetings, which not only helped me recongnize what I did not already understand, but also, improved my ability to devise potential solutions for future research problems. Furthermore, I could not have successfully completed this dissertation work without the help of Dr.
    [Show full text]