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

We studied the effects of NE-10064 (azimilide), a new antiarrhythmic a gent reported to be a selective blocker of the slowly activating compo nent of the delayed rectifier, IKs. In ferret papillary muscles, NE-10 064 increased effective refractory period (ERP) and decreased isometri c twitch tension in a concentration-dependent manner (0.3-30 mu M) Inc reases in ERP showed reverse use-dependence, and were greater at 1 tha n at 3 Hz. In contrast, changes in tension were use dependent, with la rger decreases observed at 3 than at 1 Hz. In guinea pig ventricular m yocytes, NE-10064 (0.3-3 mu M) significantly prolonged action potentia l 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 de layed rectifier, I-Kr (IC50 0.4 mu M), and inhibited I-Ks (IC50 3 mu M ) with nearly 10-fold less potency. NE-10064 (10 mu M) did not block t he inward rectifier potassium current (I-Kl). NE-10064 (10 mu M) block ed the L-type calcium current (I-Ca) in a use-dependent manner; block was greater at 3 than at 1 Hz. We conclude that (a) NE-10064's block o f potassium currents is relatively selective for I-Kr over I-Ks, (b) N E-10054 inhibits I-Ca in a use-dependent fashion, and (c) NE-10064's e ffects on ERP and tension in papillary muscle as well as APD and actio n potential plateau level in myocytes may be explained by its potassiu m and calcium channel blocking properties.