Decrease in activity of smooth muscle L-type Ca2+ channels and its reversal by NF-kappaB inhibitors in Crohn's colitis model.
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.
Kinoshita
Kazuya
K
Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, University of Tokyo, Tokyo 113-8657, Japan.
Sato
Koichi
K
Hori
Masatoshi
M
Ozaki
Hiroshi
H
Karaki
Hideaki
H
D000818:Animals; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism*; D003092:Colitis / Q000378:metabolism; D003424:Crohn Disease / Q000378:metabolism* / Q000503:physiopathology; D004553:Electric Conductivity; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005769:Gastrointestinal Motility; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000503:physiopathology; D008297:Male; D009130:Muscle, Smooth / Q000378:metabolism* / Q000503:physiopathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012460:Sulfasalazine / Q000494:pharmacology; D013859:Thiocarbamates / Q000494:pharmacology
D020746:Calcium Channels, L-Type; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D013859:Thiocarbamates; C066229:prolinedithiocarbamate; D012460:Sulfasalazine; D011392:Proline