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(Circulation. 1999;99:2942-2950.)
© 1999 American Heart Association, Inc.

Basic Science Reports

Troglitazone Inhibits Voltage-Dependent Calcium Currents in Guinea Pig Cardiac Myocytes

Toshiaki Nakajima, MD; Kuniaki Iwasawa, MD; Hitoshi Oonuma, MD; Hiroyuki Imuta, PhD; Hisanori Hazama, MD; Michiko Asano, MD; Toshihiro Morita, MD; Fumitaka Nakamura, MD; Jun-ichi Suzuki, MD; Seiji Suzuki, MD; Yasushi Kawakami, MD; Masao Omata, MD; Yukichi Okuda, MD

From the Second Department of Internal Medicine, Faculty of Medicine, University of Tokyo (T.N., K.I., H.O., H.I., H.H., M.A., T.M., F.N., J.S., M.O.), and the Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba (S.S., Y.K., Y.O.), Ibaraki, Japan.

Correspondence to T. Nakajima, MD, Second Department of Internal Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.

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 (I_Ca,T) and L-type (I_Ca,L) Ca²⁺ currents. Troglitazone effectively reduced the amplitude of I_Ca,L in a concentration-dependent manner. Troglitazone also suppressed I_Ca,T, but the effect of troglitazone on I_Ca,T was less potent than that on I_Ca,L. The current-voltage relationships for I_Ca,L and the reversal potential for I_Ca,L were not altered by troglitazone. The half-maximal inhibitory concentration of troglitazone on I_Ca,L measured at a holding potential of -40 mV was 6.3 µmol/L, and 30 µmol/L troglitazone almost completely inhibited I_Ca,L. Troglitazone 10 µmol/L did not affect the time courses for inactivation of I_Ca,L and inhibited I_Ca,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 I_Ca,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.

Key Words: troglitazone • myocytes • calcium • isoproterenol • diabetes • cardiomyopathy

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