Effects of repeated administration of baclofen on transient lower esophageal sphincter relaxation in the dog.
The metabotropic gamma-aminobutyric acid (GABA) receptor (GABA(B) receptor) agonist baclofen inhibits transient lower esophageal sphincter relaxation in dogs, ferrets, and humans. Since transient lower esophageal sphincter relaxations are the major cause of gastroesophageal reflux, GABA(B) receptor agonists may have a therapeutic value in the treatment of gastroesophageal reflux disease. However, repeated stimulation of the GABA(B) receptor may induce receptor desensitization which, depending on the magnitude, would limit the therapeutic effect. The aim of the present study was to follow the effects of baclofen on transient lower esophageal sphincter relaxation in the dog after repeated administration. The effect of 7 micromol/kg baclofen b.i.d. (given intragastrically) on transient lower esophageal sphincter relaxation and related parameters was determined in four dogs. Transient lower esophageal sphincter relaxations stimulated by infusion of liquid nutrient and insufflation of air were quantified after placebo and then after the 1st, 13th, and 27th dose. Baclofen reduced the number of transient lower esophageal sphincter relaxations without affecting their duration, and the latency to the first transient lower esophageal sphincter relaxation was prolonged. Basal sphincter pressure was unaffected by baclofen, and the number of reflux episodes and esophageal acid exposure decreased. There was a statistically insignificant numerical decrease (approximately 30%) in the effect of baclofen on transient lower esophageal sphincter relaxation after the seventh dose but this was not further accentuated after the 27th dose. The effect on latency was also reduced with repeated dosing, but again, the effects after the 1st, 13th, and 27th doses were not statistically significant. The attenuation of acid exposure and reflux episodes was unaltered after repeated dosing. Three of the dogs greatly reduced their food intake within the first 2-3 days but this side effect was resolved subsequently. It is concluded that repeated dosing of baclofen leads to mild tolerance development in terms of the effects on transient lower esophageal sphincter relaxation, but that the tolerance is much less pronounced than that previously reported in other animal models.
Lehmann
A
A
Gastrointestinal Pharmacology, AstraZeneca R&D Mölndal, S-431 83, Mölndal, Sweden. anders.lehmann@astrazeneca.com
Hansson-Brändén
L
L
Kärrberg
L
L
D000818:Animals; D001418:Baclofen / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D004943:Esophagogastric Junction / Q000187:drug effects* / Q000502:physiology; D018755:GABA Agonists / Q000494:pharmacology*; D005764:Gastroesophageal Reflux; D009126:Muscle Relaxation / Q000187:drug effects*; D013997:Time Factors
D018755:GABA Agonists; D001418:Baclofen