Comparative actions of insulin sensitizers on ion channels in vascular smooth muscle

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 Ca2+ currents (I-Ca), voltage-dependent K+ currents (I-Kv), and Ca2+-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 (greater than or equal to 1 muM) and rosiglitazone (100 muM), but not pioglitazone, inhibited I-Kv. Rosiglitazone (greater than or equal to 10 muM) enhanced, troglitazone (greater than or equal to 1 muM) inhibited, and pioglitazone did not affect I-Kca. A high concentration of JTT-501 (100 muM) inhibited I-Ca, I-Kv, and I-Kca to a similar extent. Prostaglandin J2 enhanced IKca, but affected neither I-Ca nor I-Kv. In summary, the three thiazolidinediones and isoxazolidinedione act differently on Ca2+ 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-Kcu is possible but should be tested further. (C) 2001 Elsevier Science B.V. All rights reserved.