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

Am J Physiol Gastrointest Liver Physiol. 2003 Sep;285(3):G483-93. doi: 10.1152/ajpgi.00038.2003. Epub 2003 Mar 19.

Abstract

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 alpha-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-kappaB 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-kappaB-dependent pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium Channels, L-Type / drug effects
  • Calcium Channels, L-Type / metabolism*
  • Colitis / metabolism
  • Crohn Disease / metabolism*
  • Crohn Disease / physiopathology
  • Electric Conductivity
  • Enzyme Inhibitors / pharmacology*
  • Gastrointestinal Motility
  • Intestinal Mucosa / metabolism*
  • Intestines / physiopathology
  • Male
  • Muscle, Smooth / metabolism*
  • Muscle, Smooth / physiopathology
  • NF-kappa B / antagonists & inhibitors*
  • Proline / analogs & derivatives*
  • Proline / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Sulfasalazine / pharmacology
  • Thiocarbamates / pharmacology

Substances

  • Calcium Channels, L-Type
  • Enzyme Inhibitors
  • NF-kappa B
  • Thiocarbamates
  • prolinedithiocarbamate
  • Sulfasalazine
  • Proline