Effects of KC 2450 on the lower esophageal sphincter in vivo and in vitro.
The effect of KC 2450 (racemic 3,5-cis-3-methylamino-2,3,4,5-tetrahydro-1-benzoxepine-5-ol hydrochloride) on lower esophageal sphincter pressure in pentobarbital-anesthetized dogs was determined and compared to the effect of metoclopramide. The ED20 value (i.e. the dose that increased lower esophageal sphincter pressure 20 mm Hg) was 0.72 (0.45-1.04) mg/kg i.v. for KC 2450, significantly different from 2.18 (1.30-3.42) mg/kg i.v. for metoclopramide (P less than 0.01). The superior potency of KC 2450 over metoclopramide also was demonstrated at a dose of 2 mg/kg i.v.; KC 2450 produced an increase in sphincter pressure of 43.2 +/- 4.4 mm Hg and metoclopramide produced an increase in sphincter pressure of only 28.5 +/- 5.4 mm Hg (P less than 0.05). Intraduodenally administered KC 2450 increased lower esophageal sphincter pressure at a threshold dose of 2 mg/kg with 10 mg/kg producing an increase in pressure of 53.2 +/- 9.9 mm Hg. KC 2450-induced increases in sphincter pressure were not affected by bilateral cervical vagotomy or ketanserin, but were eliminated by atropine and reduced by neuronal blockade using tetrodotoxin (TTX). KC 2450 effects also were determined in isolated circular strips of lower esophageal sphincter muscle. KC 2450 produced a concentration-related increase in canine (EC50 = 27 microM) and opossum (EC50 = 199 microM) sphincter muscle strip tension. The KC 2450 concentration-response curve was antagonized by atropine in canine and opossum sphincter muscle strips. Neuronal blockade of canine sphincter muscle with TTX antagonized the KC 2450 concentration-response curve in a non-competitive manner.(ABSTRACT TRUNCATED AT 250 WORDS)
Fowler
P J
PJ
Department of Pharmacology, Smith Kline & French Laboratories, Philadelphia, PA 19101.
Nelson
A H
AH
Price
W J
WJ
Sarau
H M
HM
Grous
M
M
Lombardi
D M
DM
Barone
F C
FC
Ormsbee
H S
HS
D000818:Animals; D001584:Benzoxepins / Q000378:metabolism / Q000494:pharmacology*; D001667:Binding, Competitive; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004943:Esophagogastric Junction / Q000187:drug effects*; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D009893:Opossums; D011312:Pressure; D011976:Receptors, Muscarinic / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism
D001584:Benzoxepins; D011976:Receptors, Muscarinic; D011985:Receptors, Serotonin; C045026:exepanol