Inflammation inhibits muscarinic signaling in in vivo canine colonic circular smooth muscle cells.
We investigated the effects of experimental colitis on the muscarinic signaling properties and contractile behavior of canine colonic circular smooth muscle. The hypotheses that inflammation 1) inhibits in vivo muscarinic receptor mediated contractions, and 2) alters receptor density or receptor-binding affinities were tested. Muscarine was infused close-intra-arterially in seven conscious dogs during normal and experimental colitis states. Colonic circular muscle contractions were recorded via surgically attached strain gauge transducers. Muscarine stimulated phasic contractions in a dose-dependent manner, whereas colitis was inhibited. The inhibitory concentration 50% dose of M(3) receptor inhibitor was several times lower than that of M(1), M(2), and M(4) inhibitors during normal and colitis. However, inflammation induced a significant leftward shift in the circular muscle inhibitory dose-response curve of M(2) inhibitor. Muscarinic receptor density and binding analyses in isolated circular muscle cells was done in normal and colitis states. Inflammation significantly decreased maximum binding from 4082 fmol/mg to 2708 fmol/mg, whereas affinity constant remained unaffected. The conclusions were that 1) spontaneous and muscarine-activated in vivo phasic contractile activity of colonic circular muscle cells is primarily mediated by M(3) receptors; 2) inflammation was associated with a shift in M(2) receptor potency, due chiefly to a decrease in receptor density; and 3) this inhibitory effect was seen in normal and inflamed states, suggesting the importance of M(2) receptor. These findings suggest that changes in muscarinic response during colitis may contribute to the abnormal motility seen with inflammatory bowel disease.
Jadcherla
Sudarshan Rao
SR
Section of Neonatology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, USA. jadcherlas@pediatrics.ohio-state.edu
D000818:Animals; D018678:Cholinergic Agents / Q000494:pharmacology; D003092:Colitis / Q000139:chemically induced / Q000503:physiopathology*; D004285:Dogs; D005260:Female; D005730:Ganglionic Blockers / Q000494:pharmacology; D018738:Hexamethonium / Q000494:pharmacology; D007261:Infusions, Intra-Arterial; D008297:Male; D009116:Muscarine / Q000008:administration & dosage / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000503:physiopathology*; D009195:Peroxidase / Q000032:analysis; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology
D018678:Cholinergic Agents; D005730:Ganglionic Blockers; D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; D018738:Hexamethonium; D013779:Tetrodotoxin; D009116:Muscarine; D009195:Peroxidase