Quantitation of the contractile response mediated by two receptors: M2 and M3 muscarinic receptor-mediated contractions of human gastroesophageal smooth muscle.
Although muscarinic receptors are known to mediate tonic contraction of human gastrointestinal tract smooth muscle, the receptor subtypes that mediate the tonic contractions are not entirely clear. Whole human stomachs with attached esophagus were procured from organ transplant donors. Cholinergic contractile responses of clasp, sling, lower esophageal circular (LEC), midesophageal circular (MEC), and midesophageal longitudinal (MEL) muscle strips were determined. Sling fibers contracted greater than the other fibers. Total, M(2) and M(3) muscarinic receptor density was determined for each of these dissections by immunoprecipitation. M(2) receptor density is greatest in the sling fibers, followed by clasp, LEC, MEC, and then MEL, whereas M(3) density is greatest in LEC, followed by MEL, MEC, sling, and then clasp. The potency of subtype-selective antagonists to inhibit bethanechol-induced contraction was calculated by Schild analysis to determine which muscarinic receptor subtypes contribute to contraction. The results suggest both M(2) and M(3) receptors mediate contraction in clasp and sling fibers. Thus, this type of analysis in which multiple receptors mediate the contractile response is inappropriate, and an analysis method relating dual occupation of M(2) and M(3) receptors to contraction is presented. Using this new method of analysis, it was found that the M(2) muscarinic receptor plays a greater role in mediating contraction of clasp and sling fibers than in LEC, MEC, and MEL muscles in which the M(3) receptor predominantly mediates contraction.
Braverman
Alan S
AS
Department of Urology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Miller
Larry S
LS
Vegesna
Anil K
AK
Tiwana
Mansoor I
MI
Tallarida
Ronald J
RJ
Ruggieri
Michael R
MR
D018723:Bethanechol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004943:Esophagogastric Junction / Q000187:drug effects*; D004947:Esophagus / Q000187:drug effects*; D006801:Humans; D047468:Immunoprecipitation; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000166:cytology* / Q000187:drug effects*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects*; D043585:Receptor, Muscarinic M2 / Q000187:drug effects*; D043587:Receptor, Muscarinic M3 / Q000187:drug effects*; D013270:Stomach / Q000187:drug effects*
D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D018723:Bethanechol