Thiazolidinedione and isoxazolidinedione insulin sensitizers activate peroxisome proliferator-activated receptor gamma (PPAR gamma). Some thiazolidinediones modify ion channels in smooth muscles; however, the mechanism by which their actions occur has not been clarified. We, thus, examined the effects of three thiazolidinediones (troglitazone, pioglitazone, and rosiglitazone) and isoxazolidinedione (JTT-501), as well as an intrinsic ligand for PPAR gamma, 15-deoxy-Delta(12,14) prostaglandin J(2) (prostaglandin J(2)), on voltage-operated Ca(2+) currents (I(Ca)), voltage-dependent K(+) currents (I(Kv)), and Ca(2+)-activated K(+) currents (I(Kca)), to clarify whether a thiazolidinedione structure or PPAR gamma activation is related to their actions on ion channels. The whole-cell patch clamp method was used to record currents in smooth muscle cells from guinea-pig mesenteric arteries. Thiazolidinediones inhibited I(Ca) in a dose-dependent manner (troglitazone>pioglitazone=rosiglitazone). Troglitazone (> or =1 microM) and rosiglitazone (100 microM), but not pioglitazone, inhibited I(Kv). Rosiglitazone (> or =10 microM) enhanced, troglitazone (> or =1 microM) inhibited, and pioglitazone did not affect I(Kca). A high concentration of JTT-501 (100 microM) inhibited I(Ca), I(Kv), and I(Kca) to a similar extent. Prostaglandin J(2) enhanced I(Kca), but affected neither I(Ca) nor I(Kv). In summary, the three thiazolidinediones and isoxazolidinedione act differently on Ca(2+) and K(+) channels in vascular smooth muscle. The action of thiazolidinediones on I(Ca) could be attributed to specific regions of the molecules and not to activation of PPAR gamma. Involvement of PPAR gamma activation in the stimulation of I(Kca) is possible but should be tested further.