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(Circulation. 1998;98:2446-2452.)
© 1998 American Heart Association, Inc.

Basic Science Reports

Mechanisms of Vasorelaxation Induced by Troglitazone, a Novel Antidiabetic Drug, in the Porcine Coronary Artery

Junya Kawasaki, MD; Katsuya Hirano, MD, PhD; Junji Nishimura, MD, PhD; Masatoshi Fujishima, MD, PhD; ; Hideo Kanaide, MD, PhD

From the Division of Molecular Cardiology, Research Institute of Angiocardiology and Second Department of Internal Medicine (M.F.), Faculty of Medicine, Kyushu University, Fukuoka, Japan.

Correspondence to Professor Hideo Kanaide, MD, PhD, Division of Molecular Cardiology, Research Institute of Angiocardiology, Faculty of Medicine, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. E-mail kanaide{at}molcar.med.kyushu-u.ac.jp

Background—Troglitazone (TRO), a novel antidiabetic drug, has been reported to decrease blood pressure and relax vascular strips. The mechanism of relaxation induced by TRO was determined in terms of Ca²⁺ signaling in smooth muscle cells.

Methods and Results—Front-surface fluorometry and fura 2–loaded medial strips of porcine coronary artery were used to examine the effects of TRO on cytosolic Ca²⁺ concentrations ([Ca²⁺]_i) and contractions. The sustained contraction induced by 100 nmol/L U46619 was similar to that induced by 60 mmol/L K⁺ depolarization (60K⁺). TRO concentration dependently decreased [Ca²⁺]_i and the force of these contractions. The concentration of TRO required to induce 50% inhibition of U46619-induced force (2.9 µmol/L) was significantly lower than that required in the case of 60K⁺-induced force (7.3 µmol/L). Replacing extracellular Ca²⁺ with Mn²⁺ gradually quenched fluorescence at 360 nm excitation. This decline was accelerated by 100 nmol/L U46619 and 30K⁺ to a similar extent, indicating a similar activation of Ca²⁺ influx. TRO completely inhibited U46619-activated influx but partly inhibited depolarization-activated influx. Cumulative applications of extracellular Ca²⁺ during stimulations with U46619 or 118K⁺ induced stepwise increases in [Ca²⁺]_i and force. TRO shifted the [Ca²⁺]_i-force relation to the right during both stimulations.

Conclusions—TRO relaxes coronary artery by decreasing [Ca²⁺]_i and Ca²⁺ sensitivity of contractile apparatus. Inhibition of Ca²⁺ influx was important in decreasing [Ca²⁺]_i. TRO more effectively inhibits receptor-operated Ca²⁺ influx than voltage-operated Ca²⁺ channels.

Key Words: vasodilation • calcium channels • diabetes mellitus • fura 2

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