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

Abstract

Thiazolidinedione and isoxazolidinedione insulin sensitizers activate peroxisome proliferator-activated receptor γ (PPARγ). 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 PPARγ, 15-deoxy-Δ 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 PPARγ 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 (≥1 μM) and rosiglitazone (100 μM), but not pioglitazone, inhibited I Kv. Rosiglitazone (≥10 μM) enhanced, troglitazone (≥1 μM) inhibited, and pioglitazone did not affect I Kca. A high concentration of JTT-501 (100 μM) 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 PPARγ. Involvement of PPARγ activation in the stimulation of I Kca is possible but should be tested further.