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Use-Dependent Effects of the Class III Antiarrhythmic Agent NE-10064 (Azimilide) on Cardiac Repolarization: Block of Delayed Rectifier Potassium and L-Type Calcium Currents.

Fermini, Bernard; Jurkiewicz, Nancy K.; Jow, Brian; Guinosso, Peter J. Jr.; Baskin, Elizabeth P.; Lynch, Joseph J. Jr.; Salata, Joseph J.
Journal of Cardiovascular Pharmacology: August 1995
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Summary: We studied the effects of NE-10064 (azimilide), a new antiarrhythmic agent reported to be a selective blocker of the slowly activating component of the delayed rectifier, IKs. In ferret papillary muscles, NE-10064 increased effective refractory period (ERP) and decreased isometric twitch tension in a concentration-dependent manner (0.3-30 [mu]M). Increases in ERP showed reverse use-dependence, and were greater at 1 than at 3 Hz. In contrast, changes in tension were use dependent, with larger decreases observed at 3 than at 1 Hz. In guinea pig ventricular myocytes, NE-10064 (0.3-3 ([mu]M) significantly prolonged action potential duration (APD) at 1 Hz. At 3 Hz, NE-10064 (0.3-1 [mu]M) increased APD only slightly, and at 10 [mu]M decreased APD and the plateau potential. NE-10064 potently blocked the rapidly activating component of the delayed rectifier, IKr (IC50 0.4 [mu]M), and inhibited IKs (IC50 3 [mu]M) with nearly 10-fold less potency. NE-10064 (10 [mu]M) did not block the inward rectifier potassium current (IKl). NE-10064 (10 [mu]M) blocked the L-type calcium current (ICa) in a use-dependent manner; block was greater at 3 than at 1 Hz. We conclude that (a) NE-10064's block of potassium currents is relatively selective for IKr over IKs, (b) NE-10064 inhibits ICa in a use-dependent fashion, and (c) NE-10064's effects on ERP and tension in papillary muscle as well as APD and action potential plateau level in myocytes may be explained by its potassium and calcium channel blocking properties.

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