DUAL ACTIONS OF THE NOVEL CLASS-III ANTIARRHYTHMIC DRUG NE-10064 ON DELAYED POTASSIUM CHANNEL CURRENTS IN GUINEA-PIG VENTRICULAR AND SINOATRIAL NODE CELLS

We have investigated the concentration-dependent modulation, by the no vel class III antiarrhythmic compound NE-10064, of the delayed potassi um channel current I-Ks in isolated guinea pig sinoatrial nodal (SAN) and ventricular cells. At concentrations greater than 1 mu M, the drug potently inhibited I-Ks in each of the cell types investigated. The c oncentration-dependent inhibition of I-Ks (IC50 = 700 nM) was the same in ventricular and SAN cells. At near-threshold drug concentrations, we also observed increases of I-Ks activity in both SAN and ventricula r cells. The NE-10064-induced enhancement of I-Ks was more pronounced at voltages near the I-Ks activation threshold (0 mV), than at more po sitive voltages in both cell types. Furthermore, the agonistic effects of the drug were more prominent before steady-state effects of the co mpound were attained, which suggests parallel agonistic and antagonist ic pathways. Our results demonstrate that I-Ks channels in cells of th e sinoatrial node region of the guinea pig heart respond to NE-10064 i n the same manner as cells of the ventricle and that this compound, al though a potent inhibitor of I-Ks activity, possesses an interesting b ut as yet mechanistically unidentified agonistic action at low concent rations in both cell types.