Effects of ambasilide, quinidine, flecainide and verapamil on ultra-rapid delayed rectifier potassium currents in canine atrial myocytes

Objective: A dog atrial ultra-rapid delayed rectifier current (I-Kur.d) is involved in canine atrial repolarization and shares similarities with the h uman atrial ultra-rapid delayed rectifier (I-Kur), Almost no information is available about the actions of antiarrhythmic drugs on I-Kur.d. This study evaluated effects of ambasilide, quinidine, flecainide and verapamil on I( Kur.)d in isolated canine atrial myocytes. Methods: Standard whole-cell pat ch clamp techniques were used to study the effects of multiple concentratio ns of each drug. Results: All drugs produced reversible concentration-, vol tage- and time-dependent I-Kur.d inhibition. Significant effects of quinidi ne, flecainide and ambasilide were noted at atrial-effective antiarrhythmic concentrations in the dog. Upon the onset of a depolarizing pulse, block d eveloped exponentially in relation to time, with the blocking rate-constant increasing with drug concentration, consistent with open-channel blockade and permitting the calculation of forward and reverse rate-constants. For a ll drugs, the 50% blocking concentration (EC50) showed significant voltage- dependence, decreasing at more positive potentials. The magnitude of voltag e-dependent block was directly related to the degree of drug-induced shift in the voltage dependence of activation (r=0.97), pointing to open-channel block as a mechanism for voltage-dependent action. An additional component of voltage-dependence suggested that blocking sites were subjected to 17-21 % of the transmembrane voltage field. Conclusions: Ambasilide, quinidine, f lecainide and verapamil inhibit I-Kur.d, with preferential action on the op en state. I-Kur.d inhibition may play a role in antiarrhythmic effects in c anine atrial arrhythmia models. Comparisons between the effects of these dr ugs on I-Kur and previously studied effects on I-Kur suggest potential oppo rtunities for investigating the molecular structural determinants of drug-b locking action on atrial-specific ultrarapid delayed rectifiers. (C) 2000 E lsevier Science B.V. All rights reserved.