5-Hydroxytryptamine (5-HT) and SK&F 103829 contract canine lower esophageal sphincter smooth muscle by stimulating 5-HT2 receptors.
Addition of 5-HT or SK&F 103829 (2,3,4,5 tetrahydro-8[methyl-sulfonyl]-1 H-3-benzazepin-7-ol hydrobromide) contracts isolated strips of canine lower esophageal sphincter (LES) circular smooth muscle. 5-HT acts directly on the smooth muscle, since pretreatment with the neurotoxin TTX does not inhibit this contraction. Depletion of extracellular calcium or pretreatment with nifedipine inhibited the contraction to both 5-HT and SK&F 103829. Therefore, in this smooth muscle, the contraction produced by both 5-HT and SK&F 103829 requires extracellular calcium and is sensitive to inhibition by a voltage-dependent Ca2+ channel antagonist. In addition, with respect to 5-HT, SK&F 103829 appeared to act as a partial agonist. Receptor alkylation studies using phenoxybenzamine demonstrated no receptor reserve for the contractile response to 5-HT. Nonsurmountable antagonism of the contraction induced by 5-HT and SK&F 103289 was observed with several 5-HT2 antagonists, i.e., methysergide, ketanserin, cyproheptadine, and LY 53857. Using a method established for pseudoirreversible antagonism, the Ki values for these 5-HT2 receptor antagonists were estimated. Results suggested that both 5-HT and SK&F 103829 contract the canine LES by interacting at the same receptor site and that this receptor site has characteristics of the 5-HT2 receptor. Finally, neither bulbocapnine, domperidone, nor prazosin significantly alters the response to 5-HT or SK&F 103829. Thus, isolated strips of canine LES contain a contractile 5-HT2 receptor, and SK&F 103829 behaves as a partial agonist at this site.
Barnette
M S
MS
Department of Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406.
Grous
M
M
Manning
C D
CD
Price
W J
WJ
Nelson
A H
AH
Bondinell
W E
WE
Barone
F C
FC
Ormsbee
H S
HS
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D004285:Dogs; D004943:Esophagogastric Junction / Q000187:drug effects* / Q000502:physiology; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009543:Nifedipine / Q000494:pharmacology; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000502:physiology; D012701:Serotonin / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
D001552:Benzazepines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C078977:SK&F 103829; D012701:Serotonin; D009543:Nifedipine