Responsiveness of cardiac Na+ channels to antiarrhythmic drugs: the role of inactivation.

Elementary Na+ currents were recorded at 9 degrees C in inside-out patches from cultured neonatal rat heart myocytes. In characterizing the sensitivity of cooled, slowly inactivating cardiac Na+ channels to several antiarrhythmic drugs including propafenone, lidocaine and quinidine, the study aimed to define the role of Na+ inactivation for open channel blockade. In concentrations (1-10 mumol/liter) effective to depress NPo significantly, propafenone completely failed to influence the open state of slowly inactivating Na+ channels. With 1 mumol/liter, tau open (at -45 mV) in cooled, (-)-DPI-modified, noninactivating Na+ channels proved to be drug resistant and could not be flicker-blocked by 10 mumol/liter propafenone. The same drug concentration induced in (-)-DPI-modified Na+ channels a discrete block with association and dissociation rate constants of 16.1 +/- 5.3 x 10(6) mol-1 sec-1 and 675 +/- 25 sec-1, respectively. Quinidine, known to have a considerable affinity for activated Na+ channels, in lower concentrations (5 mumol/liter) left tau open unchanged or reduced, in higher concentrations (10 mumol/liter) tau open only slightly to 81% of the predrug value whereas NPo declined to 30%, but repetitive blocking events during the conducting state could never be observed. Basically the same drug resistance of the open state was seen in cardiac Na+ channels whose open-state kinetics had been modulated by the cytoplasmic presence of F- ions. But in this case, propafenone reduced reopening and selectively abolished a long-lasting open state. This drug action is unlikely related to the inhibitory effect on NPo since hyperpolarization and the accompanying block attenuation did not restore the channel kinetics. It is concluded that cardiac Na+ channels cannot be flicker-blocked by antiarrhythmic drugs unless Na+ inactivation is removed.