In guinea-pig stomach, the effect of increased intracellular cAMP induced by forskolin, 8-Br-cAMP, or isobuthyl-methylxanthine (IBMX) on K current was studied in whole-cell currents. In enzymatically dispersed single cells, agents elevating [cAMP]in showed quite different effects on the IK depending on the recording conditions. Though using the same recording pipette containing 0.1 mM EGTA, agents elevating [cAMP]in reduced IK(Ca) recorded at various membrane potentials, while forskolin increased the spontaneous transient outward currents (STOCs) recorded at fixed holding potential, 0 mV. Such a reduction of K currents was not observed in the cells dialysed with heparin contained in the recording pipette. These results suggested the possibility that the cAMP modulate the internal Ca(2+)-store. To assess the effect of cAMP on the internal Ca2+ store, carbachol or caffeine was used to mobilize intracellular Ca2+ store. Using the carbachol- or caffeine-induced IK(Ca), the effects of forskolin on [Ca2+]in was investigated. Forskolin inhibited the carbachol-induced K current, while the caffeine-induced current was not affected. From the above results, it might be suggested that increased intracellular cAMP might modulate the release of Ca2+ from IP3-sensitive Ca2+ store to- reduce the Ca(2+)-activated K currents.