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

Eur J Pharmacol. 2001 Jun 29;423(1):1-7. doi: 10.1016/s0014-2999(01)01047-0.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Barium / pharmacology
  • Calcium / pharmacology
  • Chromans / pharmacology
  • Dose-Response Relationship, Drug
  • Electric Stimulation
  • Female
  • Guinea Pigs
  • Humans
  • Insulin Resistance
  • Ion Channels / drug effects*
  • Ion Channels / physiology
  • Isoxazoles / pharmacology*
  • Membrane Potentials / drug effects
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / drug effects*
  • Muscle, Smooth, Vascular / physiology
  • Pioglitazone
  • Potassium Channels / drug effects
  • Potassium Channels / physiology
  • Prostaglandin D2 / analogs & derivatives
  • Prostaglandin D2 / pharmacology
  • Rosiglitazone
  • Thiazoles / pharmacology*
  • Thiazolidinediones*
  • Troglitazone

Substances

  • Chromans
  • Ion Channels
  • Isoxazoles
  • Potassium Channels
  • Thiazoles
  • Thiazolidinediones
  • Rosiglitazone
  • Barium
  • 9-deoxy-delta-9-prostaglandin D2
  • 2,4-thiazolidinedione
  • Troglitazone
  • JTT 501
  • Prostaglandin D2
  • Calcium
  • Pioglitazone