We recently showed that endothelin-1 (ET-1) increases cell Ca²⁺ in the mouse cortical collecting duct. To clarify the cellular action and target cell of ET-1, electrophysiologic techniques and cell Ca²⁺ measurement were applied to rabbit cortical collecting ducts perfused in vitro. When 10⁻⁸ mol/L ET-1 was added to the bath, a transient increase followed by a sustained increase in cell Ca²⁺ was observed. A sustained increase in cell Ca²⁺ lasted 10 to 20 minutes and was associated with a decrease in lumen-negative transepithelial voltage. To confirm the target cell type of ET-1, confocal laser microscopy was used. An increase in cell Ca²⁺ was observed in the same cell, which also showed an increase in cell Ca²⁺ in response to arginine vasopressin (AVP), which indicated that the principal cell has ET-1 receptors in the basolateral membrane. When ET-1 was applied to the bath, total cellular membrane resistance (Ri) decreased initially and then gradually increased because of inhibition of the luminal Na⁺ channel. An initial decrease in Ri was considered an influx of Ca²⁺ from the basolateral membrane. To further determine the source of an increase in cell Ca²⁺, the effect of ET-1 was tested in the absence of external Ca²⁺ and in the presence of a Ca²⁺ channel blocker in the bath. Cell Ca²⁺ did not respond to ET-1 in the absence of external Ca²⁺, a condition in which an AVP-stimulated increase in cell Ca²⁺ was preserved. A dihydropyridine-type Ca²⁺ channel blocker, manidipine, in the bath caused a decrease in cell Ca²⁺ in a dose-dependent manner, indicating that the principal cell has a dihydropyridine-type Ca²⁺ channel in the basolateral membrane. In the presence of 10⁻⁷ mol/L manidipine, cell Ca²⁺ response to ET-1 disappeared, but AVP response was preserved. This indicated the ET-1-stimulated extracellular influx of Ca²⁺ through the dihydropyridine-sensitive Ca²⁺ channel. Furthermore, ET-1 specifically increases cell Ca²⁺ in the principal cell, but not in the intercalated cell in confocal laser microscopy. These data show that ET-1 causes an influx of Ca²⁺ through the dihydropyridine-sensitive Ca²⁺ channel in the basolateral membrane of the principal cell of the cortical collecting duct, which leads to the inhibition of the luminal Na⁺ channel. This action of ET-1 may be responsible, at least in part, for the natriuresis induced by this peptide.