Transient lower esophageal sphincter relaxations in dogs are inhibited by a metabotropic glutamate receptor 5 antagonist.
Transient lower esophageal sphincter relaxation is the major mechanism for gastroesophageal reflux. The present study was initiated to investigate the potential effect of the metabotropic glutamate 5 (mGlu5) receptor antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), on transient lower esophageal sphincter relaxations in the conscious dog. MPEP (1.4-8.7 micromol/kg i.v.) produced a dose-dependent inhibition of transient lower esophageal sphincter relaxations (59+/-11% inhibition at 8.7 micromol/kg). In addition, there was a reduction of the number of reflux episodes and an increase in latency time to the occurrence of the first transient lower esophageal sphincter relaxation. No effect was seen on basal lower esophageal sphincter pressure or on swallowing. It is concluded that the mGlu5 receptor antagonist MPEP potently inhibits transient lower esophageal sphincter relaxations and that the mGlu5 receptor is a potential target for treatment of gastroesophageal reflux disease.
Jensen
Jörgen
J
AstraZeneca R&D Mölndal, S-431 83 Mölndal, Sweden. jorgen.m.jensen@astrazeneca.com
Lehmann
Anders
A
Uvebrant
Anna
A
Carlsson
Anita
A
Jerndal
Gunilla
G
Nilsson
Karolina
K
Frisby
Claudine
C
Blackshaw
L Ashley
LA
Mattsson
Jan P
JP
D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D049630:Esophageal Sphincter, Lower / Q000187:drug effects* / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D005764:Gastroesophageal Reflux / Q000503:physiopathology / Q000517:prevention & control; D007275:Injections, Intravenous; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects*; D011725:Pyridines / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014316:Tritium
D018691:Excitatory Amino Acid Antagonists; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D014316:Tritium; C121465:6-methyl-2-(phenylethynyl)pyridine