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Cardiovascular Research 1998 38(3):685-694; doi:10.1016/S0008-6363(98)00048-0
© 1998 by European Society of Cardiology
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Copyright © 1998, European Society of Cardiology

Preferential inhibition of IKr by MCI-154, a putative cardiotonic Ca2+ sensitizer, in guinea pig atrial cells

Koji Etoa,1,1, Keitaro Hashimotoa and Haruaki Nakayab,*

aDepartment of Pharmacology, Yamanashi Medical University, 1,100 Shimokato, Tamaho-cho, Yamanashi 409-38, Japan
bDepartment of Pharmacology, Chiba University School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan

* Corresponding author. Tel.: +81 (43) 226 2050; Fax: +81 (43) 226 2052; E-mail: nakaya@-med.m.chiba-u.ac.jp

Objective: To define the electrophysiologic mechanism(s) by which MCI-154, a putative Ca2+ sensitizer, produces a positive inotropic response without a positive chronotropic response, we examined effects of MCI-154 on the action potential of atrial preparations and the membrane currents of atrial myocytes. Methods: The action potentias were recorded from left atrial and sinoatrial node preparations of guinea pigs by the use of standard microelectrode techniques. The whole-cell membrane currents were recorded from enzymatically-dissociated guinea pig atrial myocytes using conventional patch clamp techniques. Results: In isolated left atria, MCI-154 increased the developed tension in a concentration-dependent manner. MCI-154 at concentrations of 10 and 100 µM increased the action potential duration (APD) in left atria stimulated at 0.5 Hz. In sinoatrial node preparations MCI-154 at a concentration of 100 µM produced a negative chronotropic response and prolonged APD. In single right atrial myocytes, MCI-154 at concentrations of 10 and 100 µM failed to increase the inward L-type Ca2+ current, but decreased the delayed rectifier K+ current (IK) in a concentration-dependent manner. MCI-154 decreased IK elicited by short depolarizing pulses more markedly than that induced by long depolarizing pulses. In addition, MCI-154 produced only a little inhibition of IK in the presence of E-4031, a specific blocker of rapidly activating component of IK (IKr). Conclusions: MCI-154 preferentially blocks IKr and the inhibitory action on IKr may be partly involved in the negative chronotropic and positive inotropic responses in atrial preparations.

KEYWORDS MCI-154; Ca2+-sensitizer; Negative chronotropism; The delayed rectifier K+ current; Action potential duration

1 Present address: Department of Medicine (Division of Cardiology), Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku 173, Tokyo, Japan.


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