First published August 9, 2001; 10.1152/ajprenal.00031.2001.Cytosolic calcium oscillations may permit cells to respond to information provided by increases in intracellular Ca²⁺ concentration ([Ca²⁺]_i ) while avoiding prolonged exposure to constantly elevated [Ca²⁺]_i. In this study, we demonstrated that agonists could induce Ca²⁺ oscillations in human bladder epithelial cells. Application of 10 µM acetylcholine or 200 nM bradykinin triggered an initial Ca²⁺ transient that was followed by periodic [Ca²⁺]_i oscillations. The oscillations did not depend on extracellular Ca²⁺. 8-Bromoguanosine 3',5'-cyclic monophosphate abolished acetylcholine- or bradykinin-induced oscillations. Elevation of cellular cGMP by dipyridamole, an inhibitor of cGMP-specific phosphodiesterase, also terminated the [Ca²⁺]_i oscillations. The inhibitory effect of cGMP could be reversed by KT-5823, a highly specific inhibitor of protein kinase G (PKG), suggesting that the action of cGMP was mediated by PKG. Comparison of the effect of cGMP with that of xestospongin C, an inhibitor of the inositol 1,4,5-trisphosphate (IP₃) receptor, revealed similarities between the action of cGMP and xestospongin C. Therefore, it is likely that cGMP and PKG may target a signal transduction step(s) linked to IP₃ receptor-mediated Ca²⁺ release.