In our study of the effects of hyposmotic swelling on the Ca²⁺-activated potassium currents [I_K(Ca)] and its mechanism, we employed the whole-cell patch clamp technique using the gastric antral circular myocytes of the guinea-pig. Hyposmotic swelling efficiently increased I_K(Ca), and the extent of changes in I_K(Ca) was sharply dependent on the osmolarity of the perfusion solutions. When the calcium-free solution (EGTA 10 μM added in calcium-free solution) was superfused, I_K(Ca) was not increased by the hyposmotic swelling. Gadolinium (Gd³⁺) 100 nM, a blocker of the stretch-activated nonselective cation channel, blocked the activation of I_K(Ca) induced by hyposmotic swelling, but nicardipine 5 μM (the L-type calcium channel blocker) did not. Heparin 3 mg/ml, a potent inhibitor of inositol triphosphate receptor (InsP₃R), did not inhibit the response, and caffeine 1 mM (the agonist for calcium-induced calcium release [CICR]) imitated the effect of hyposmotic swelling. Ryanodine (15 μM), markedly inhibited the effect. These results suggest that hyposmotic swelling activates I_K(Ca), and the activation is associated with CICR, which is triggered by extracellular calcium influx through the stretch-activated channel (SA channel).