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NEUROREGULATION AND MOTILITY

Role of L-Ca²⁺ channels in intestinal pacing in wild-type and W/W^V mice

Faculty of Medicine and Dentistry, Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada

Submitted 27 July 2004 ; accepted in final form 7 October 2004

Rhythmic contractions generating transit in the digestive tract are paced by a network of cells called interstitial cells of Cajal (ICC) found in the myenteric plexus (MP). ICC generate cyclic depolarizations termed "slow waves" that are passively transmitted to the smooth muscle to initiate contractions. The opening of L-Ca²⁺ channels are believed to be primarily responsible for the influx of calcium generating a contraction in smooth muscle. However, L-Ca²⁺ channels are not thought to be important in generating the pacing current found in ICC. Using intact segments of circular (CM) and longitudinal (LM) muscle from wild-type mice and mice lacking c-kit kinase (W/W^V), we found that L-Ca²⁺ channel currents are required for pacing at normal frequencies to occur. Application of 1 µM nicardipine caused a significant decrease in contraction amplitude and frequency in LM and CM that was successfully blocked with BAY K 8644. Nicardipine also abolished the pacing gradient found throughout the intestines, resulting in a uniform contraction frequency of 30–40/minute. Stimulating L-Ca²⁺ channels with BAY K 8644 neither removed nor recovered the pacing gradient. W/W^V mice, which lack ICC-MP, also exhibited a pacing gradient in LM. Application of nicardipine to LM segments of W/W^V mouse intestine did not reduce pacing frequency, and in jejunum, resulted in a slight increase. BAY K 8644 did not affect pacing frequency in W/W^V tissue. In conclusion, we found that L-Ca²⁺ channel activity was required for normal pacing frequencies and to maintain the pacing frequency gradient found throughout the intestines in wild-type but not in W/W^V mouse intestine.

interstitial cells of Cajal; gradient of pacing frequency; nicardipine