In the present study, it was aimed to further indentify the intracellular action mechansm of cromakalim and levcromakalim in the porcine coronary artery. In intact porcine coronary arterial strips loaded with fura-2/AM, acetylcholine caused an increase in intracellular free Ca2⁢ ([Ca2⁢]i) in association with a contraction in a concentration-dependent manner. Cromakalim (1 ㄍM) caused a reduction in acetylcholine-induced increased [Ca2⁢]i not only in the mormal physiological salt solution (PSS) but also in Ca2⁢-free PSS (containing 1 mM EGTA). In the skinned strips prepared by exposure of tissue to 20 ㄍM ㄂-escin, inositol 1,4,5-trisphosphate (IP3) evoked an increase in [Ca2⁢]i, but it was without effect on the intact strips. The IP3-induced increase in [Ca2⁢]i was inhibited by cromakalim by 78% and levcromakalim by 59% (1 ㄍM, each). Pretreatment with glibenclamide (a blocker of ATP-sensitive K⁢ channels, 10 ㄍM) and apamin (a blocker of small conductance Ca2⁢-activated K⁢ channels, 1 ㄍM) strongly blocked the effect of cromakalim and levcromakalim. However, charybdotoxin (a blocker of large conductance Ca2⁢-activated K⁢ channels, 1 ㄍM) was without effect. In addition, cromakalim inhibited the GTP㄃S (100 ㄍM, nonhydrolysable analogue of GTP)-induced increase in [Ca2⁢]i. Based on these results, it is suggested that cromakalim and levcromakalim exert a potent vasorelaxation, in part, by acting on the K⁢ channels of the intracellular sites (e.g., sarcoplasmic reticulum membrane), thereby, resulting in decrease in release of Ca2⁢ from the intracellular storage site.