Effects of antagonism of NMDA receptors on transient lower esophageal sphincter relaxations in the dog.
Transient lower esophageal sphincter relaxation is the major cause of gastroesophageal reflux. Mechanisms underlying transient lower esophageal sphincter relaxation are poorly understood although gastric mechanosensitive vagal afferent pathways play a central role. Glutamate is a key transmitter of vagal afferents acting partly on NMDA receptors. The aim of this work was to study the effects on transient lower esophageal sphincter relaxation in awake dogs (n=5) of the competitive NMDA receptor antagonist cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS 19755; 0.3 and 3 mg/kg i.v., the high dose was given at two separate occasions to each dog). Transient lower esophageal sphincter relaxations were evoked by intragastric infusion of a liquid meal followed by air insufflation and were scored during a 45-min period. Neither dose produced any significant effect on the group average number of transient lower esophageal sphincter relaxations. Synchronous contractions of the esophagus were commonly seen during transient lower esophageal sphincter relaxation and CGS 19755 at both doses greatly reduced their occurrence. The findings indicate that NMDA receptor antagonism selectively inhibits the esophageal component of transient lower esophageal sphincter relaxation although the rate of transient lower esophageal sphincter relaxations is not consistently affected.
Lehmann
A
A
Integrative Pharmacology, Gastrointestinal Biology, AstraZeneca R&D Mölndal, S-431 83 Mölndal, Sweden. Anders.Lehmann@astrazeneca.com
Brändén
L
L
D000818:Animals; D004285:Dogs; D004943:Esophagogastric Junction / Q000187:drug effects* / Q000502:physiology; D004946:Esophagostomy; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D005764:Gastroesophageal Reflux / Q000209:etiology / Q000503:physiopathology; D008297:Male; D009126:Muscle Relaxation; D009130:Muscle, Smooth / Q000187:drug effects; D010875:Pipecolic Acids / Q000494:pharmacology*; D011312:Pressure; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013997:Time Factors
D018691:Excitatory Amino Acid Antagonists; D010875:Pipecolic Acids; D016194:Receptors, N-Methyl-D-Aspartate; C053672:selfotel