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NEUROREGULATION AND MOTILITY

Decrease in activity of smooth muscle L-type Ca²⁺ channels and its reversal by NF-B inhibitors in Crohn's colitis model

Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, University of Tokyo, Tokyo 113-8657, Japan

Submitted 22 January 2003 ; accepted in final form 14 March 2003

We investigated the mechanisms of dysmotility of the colonic circular muscle of the Crohn's disease rat model. Contractions induced by KCl, carbachol, and Bay K 8644 were decreased in circular smooth muscles isolated from 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis rat colon. However, the absolute force and Ca²⁺ sensitivity of contractile proteins were not affected as assessed in -toxin permeabilized smooth muscle. The current density of the L-type Ca²⁺ channel in circular smooth muscle cells was significantly decreased in the TNBS-treated colonic cells. However, expressions of the L-type Ca²⁺ channel mRNA and protein did not differ between control and TNBS-treated preparations. Pretreatment with the NF-B inhibitors pyrrolidinedithiocarbamate and sulfasalazine partially recovered the decreased contractility and current density of the L-type Ca²⁺ channel by TNBS treatment. These results suggest that the decrease in the contraction of circular smooth muscle isolated from TNBS-induced colitis rat colon, which may be related to gut dysmotility in Crohn's disease, is attributable to the decreased activity of the L-type Ca²⁺ channel. The dysfunction of the L-type Ca²⁺ channel may be mediated by NF-B-dependent pathways.

2,4,6-trinitrobenzenesulfonic acid; rat colon; circular smooth muscle contractility; pyrrolidinedithiocarbamate; sulfasalazine; Crohn's disease

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