PAC1 and VPAC receptors mediate colon distension-evoked slow depolarization in guinea pig inferior mesenteric ganglion neurons

Abstract

smooth muscle are associated with reductions in the calciumand calmodulin-dependent phosphorylation of the 2O-kD myosin light chains (MLCP). In this study, we identified cats in which clinical abnormalities were confined to the descending colon, and we have speculated that the pathogenesis of the generalized disorder may originate in the descending colon. Methods: Longitudinal and circular colonic smooth muscle strips from ascending, transverse, and descending colon of affected cats were attached to isometric force transducers at optimal muscle length. Peak active isometric stress (P,=; N = x 104/m z) and MLCP were determined following stimulation with ACh (10 .7 to 10 4 M), SP (10 -lO to 10 ~ M), or KCI (10 to 70 mM) in a 1.5 or 5.0 mM CaCI2 HEPES buffer solution, with or without 1 p.M bovine brain calmodulin. Results: Active isometric stress responses (ACh, SP, KCI) of descending colonic smooth muscle were significantly diminished (P,~ = 1.7-2.6 N) compared to responses observed in ascending and transverse colonic smooth muscle (P,= = 7.5-14.5 N). Diminished responses were observed in longitudinal and circular muscle layers of the descending colon. MLCP was diminished (20-25%) at all time points of contraction compared to ascending or transverse colon (MLCP = 57-62%). Raising the extracellular calcium concentration (5.0 mM), or incubating with 1 /~M calmodulin, did not induce further increases in P,r= or MLCP in the descending colon. Conclusions: 1) isometric stress output and MLCP are diminished in the descending colon of cats affected with severe constipation and idiopathic megacoion. 2) Ascending and transverse colonic smooth muscle function (P,,= and MLCP) is normal in some cats with constipation and severe dysfunction of the descending colon. 3) We speculate that the pathogenesis of this disorder may originate in the descending colon.