Inflammatory modulation of muscarinic receptor activation in canine ileal circular muscle cells

Background & Aims: Spontaneous in vivo phasic contractions are suppressed during ileal inflammation. The aim of this study was to test the hypothesis that modulation of the contractile response to muscarinic receptor activation contributes to this inhibition. Methods: Muscarine, methacholine, and arecaidine propargyl ester were infused close-intra-arterially in the normal and inflamed ileum of conscious dogs. Concurrent studies were performed on in vitro muscle strips. Results: Prior close-intra-arterial infusions of tetrodotoxin or hexamethonium had no significant effect on the contractile response to any agonist, indicating that they acted primarily on smooth muscle muscarinic receptors. The contractile response to each agonist was suppressed significantly during inflammation. The median inhibitory dose of 4-diphenylacetoxy-N-methyl-piperidine methiodide (4-DAMP) was 57-244-fold smaller than that of pirenzepine, methoctramine, and tropicamide to inhibit the contractile response to muscarine. Inflammation induced a significant leftward shift in the inhibitory dose-response curve to methoctramine but not to 4-DAMP, pirenzepine, or tropicamide. The data from in vitro muscle strips were similar to those in conscious dogs. Conclusions: Inflammation suppresses the phasic contractile response to muscarinic receptor activation in circular smooth muscle cells. The spontaneous and muscarinic agonist-stimulated in vivo phasic contractions of ileal circular smooth muscle cells are mediated primarily by M(3) receptors.