Journal Article

Preferential inhibition of I<sub>Kr</sub> by MCI-154, a putative cardiotonic Ca<sup>2+</sup> sensitizer, in guinea pig atrial cells

Koji Eto, Keitaro Hashimoto and Haruaki Nakaya

in Cardiovascular Research

Published on behalf of European Society of Cardiology

Volume 38, issue 3, pages 685-694
Published in print June 1998 | ISSN: 0008-6363
Published online June 1998 | e-ISSN: 1755-3245 | DOI:
Preferential inhibition of IKr by MCI-154, a putative cardiotonic Ca2+ sensitizer, in guinea pig atrial cells

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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

Journal Article.  6370 words.  Illustrated.

Subjects: Cardiovascular Medicine

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