Sodium-, chloride-, and mibefradil-sensitive calcium channels in intestinal pacing in wild-type and W/WV mice.
Pacing of intestinal smooth muscle is driven by a network of cells found in the myenteric plexus called the interstitial cells of Cajal (ICC-MP), which produce a rhythmic pacemaker current. Using intact segments of circular (CM) and longitudinal (LM) muscle from wild-type and W/WV mice, we found that sodium-, chloride-, and mibefradil-sensitive ion channel currents are required for normal pacing to occur. Application of 30 micromol/L and 300 micromol/L lidocaine, 1 mmol/L 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), 50 nmol/L and 500 nmol/L mibefradil, or low sodium Krebs significantly reduced pacing frequency in LM and CM. However, simultaneously applying DIDS and lidocaine or low sodium Krebs solution did not completely block pacing nor did it have an additive effect. Lidocaine and low sodium Krebs solution also abolished the gradient of pacing frequencies (higher proximally) found throughout the intestine, resulting in a uniform contraction frequency of 30-40/min. In W/WV mice, which lack ICC-MP, application of DIDS and lidocaine had no effect on the robust pacing in LM segments. In conclusion we found that sodium-, chloride-, and mibefradil-sensitive channel activities were required for normal pacing and to maintain the pacing gradient found throughout the intestines in wild-type but not W/WV mice.
Boddy
Geoffrey
G
Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
Willis
A
A
Galante
G
G
Daniel
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EE
D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000493:pharmacokinetics; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020747:Calcium Channels, T-Type / Q000502:physiology*; D018118:Chloride Channels / Q000037:antagonists & inhibitors / Q000502:physiology*; D005769:Gastrointestinal Motility / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism*; D008012:Lidocaine / Q000494:pharmacology; D008297:Male; D020748:Mibefradil / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009132:Muscles / Q000187:drug effects / Q000502:physiology; D012964:Sodium / Q000493:pharmacokinetics; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020747:Calcium Channels, T-Type; D018118:Chloride Channels; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D020748:Mibefradil; D013779:Tetrodotoxin; D008012:Lidocaine; D012964:Sodium; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; D002118:Calcium