Morphological and physiological evidence for interstitial cell of Cajal‐like cells in the guinea pig gallbladder

Gallbladder smooth muscle (GBSM) exhibits spontaneous rhythmic electrical activity, but the origin and propagation of this activity are not understood. We used morphological and physiological approaches to determine whether interstitial cells of Cajal (ICC) are present in the guinea pig extrahepatic biliary tree. Light microscopic studies involving Kit tyrosine kinase immunohistochemistry and laser confocal imaging of Ca2+ transients revealed ICC‐like cells in the gallbladder. One type of ICC‐like cell had elongated cell bodies with one or two primary processes and was observed mainly along GBSM bundles and nerve fibres. The other type comprised multipolar cells that were located at the origin and intersection of muscle bundles. Electron microscopy revealed ICC‐like cells that were rich in mitochondria, caveolae and smooth endoplasmic reticulum and formed close appositions between themselves and with GBSM cells. Rhythmic Ca2+ flashes, which represent Ca2+ influx during action potentials, were synchronized in any given GBSM bundle and associated ICC‐like cells. Gap junction uncouplers (1‐octanol, carbenoxolone, 18β‐glycyrrhetinic acid and connexin mimetic peptide) eliminated or greatly reduced Ca2+ flashes in GBSM, but they persisted in ICC‐like cells, whereas the Kit tyrosine kinase inhibitor, imanitib mesylate, eliminated or reduced action potentials and Ca2+ flashes in both cell types, as well as associated tissue contractions. This study provides morphological and physiological evidence for the existence of ICC‐like cells in the gallbladder and presents data supporting electrical coupling between ICC‐like and GBSM cells. The results support a role for ICC‐like cells in the generation and propagation of spontaneous rhythmicity, and hence, the excitability of gallbladder.