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

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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
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    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.