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).
METHODS AND 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.