title: Troglitazone inhibits voltage-dependent calcium currents in guinea pig cardiac myocytes.
abstract: BACKGROUND
  It has been suggested that intracellular Ca2+ overload in cardiac myocytes leads to the development of diabetic cardiomyopathy. Troglitazone, an insulin-sensitizing agent, is a promising therapeutic agent for diabetes and has been shown to prevent diabetes-induced myocardial changes. To elucidate the underlying mechanism of troglitazone action on cardiac myocytes, the effects of troglitazone on voltage-dependent Ca2+ currents were examined and compared with classic Ca2+ antagonists (verapamil and nifedipine).
  
  
  RESULTS
  Whole-cell voltage-clamp techniques were applied in single guinea pig atrial myocytes. Under control conditions with CsCl internal solution, the voltage-dependent Ca2+ currents consisted of both T-type (ICa,T) and L-type (ICa,L) Ca2+ currents. Troglitazone effectively reduced the amplitude of ICa,L in a concentration-dependent manner. Troglitazone also suppressed ICa,T, but the effect of troglitazone on ICa,T was less potent than that on ICa,L. The current-voltage relationships for ICa,L and the reversal potential for ICa,L were not altered by troglitazone. The half-maximal inhibitory concentration of troglitazone on ICa,L measured at a holding potential of -40 mV was 6.3 micromol/L, and 30 micromol/L troglitazone almost completely inhibited ICa,L. Troglitazone 10 micromol/L did not affect the time courses for inactivation of ICa,L and inhibited ICa,L mainly in a use-independent fashion, without shifting the voltage-dependency of inactivation. This effect was different from those of verapamil and nifedipine. Troglitazone also reduced isoproterenol- or cAMP-enhanced ICa,L.
  
  
  CONCLUSIONS
  These results demonstrate that troglitazone inhibits voltage-dependent Ca2+ currents (T-type and L-type) and then antagonizes the effects of isoproterenol in cardiac myocytes, thus possibly playing a role in preventing diabetes-induced intracellular Ca2+ overload and subsequent myocardial changes.
authors.affiliation: Second Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Nakajima
authors.forename: K
authors.initials: K
authors.lastname: Iwasawa
authors.forename: H
authors.initials: H
authors.lastname: Oonuma
authors.forename: H
authors.initials: H
authors.lastname: Imuta
authors.forename: H
authors.initials: H
authors.lastname: Hazama
authors.forename: M
authors.initials: M
authors.lastname: Asano
authors.forename: T
authors.initials: T
authors.lastname: Morita
authors.forename: F
authors.initials: F
authors.lastname: Nakamura
authors.forename: J
authors.initials: J
authors.lastname: Suzuki
authors.forename: S
authors.initials: S
authors.lastname: Suzuki
authors.forename: Y
authors.initials: Y
authors.lastname: Kawakami
authors.forename: M
authors.initials: M
authors.lastname: Omata
authors.forename: Y
authors.initials: Y
authors.lastname: Okuda
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects* / Q000502:physiology*; D020746:Calcium Channels, L-Type; D020747:Calcium Channels, T-Type; D002316:Cardiotonic Agents / Q000494:pharmacology; D002839:Chromans / Q000494:pharmacology*; D000242:Cyclic AMP / Q000494:pharmacology; D004553:Electric Conductivity; D006168:Guinea Pigs; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D009543:Nifedipine / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D000077288:Troglitazone; D014700:Verapamil / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D020747:Calcium Channels, T-Type; D002316:Cardiotonic Agents; D002839:Chromans; D007004:Hypoglycemic Agents; D013844:Thiazoles; D045162:Thiazolidinediones; D014700:Verapamil; D000242:Cyclic AMP; D000077288:Troglitazone; D009543:Nifedipine; D007545:Isoproterenol