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

Abstract

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.

Kinetics of interaction of disopyramide with the cardiac sodium channel: Fast dissociation from open channels at normal rest potentials

“…Even in the unmodified channel, the drug can associate and dissociate repeatedly with the open channel to produce "flickering." This result differs from that of Benz and Kohlhardt [4] who reported that the observation of repetitive blocking and unblocking events requires the removal of inactivation. In the simple sequential blocking model used in the analysis of the results, the total charge transferred during channel opening should, on average, be unchanged during the presence of drug [43,44].…”

Blockade of cardiac sodium channels. Competition between the permeant ion and antiarrhythmic drugs.

“…There is some controversy whether it blocks open channels. Our own studies, those of Zilberter et al (42) Benz and Kohlhardt (43), and Grant et al (27) show no change in mean open time, whereas others, e.g., Baumgarten et al (37), report a decrease in open time. There are fewer studies with disopyramide.…”

Future of antiarrhythmic drugs

“…Additive and synergistic interactions between drugs that prolong APD and those that have high affinity for the inactive state of the Na þ channel have been predicted, e.g. lidocaine and quinidine [17,18]. Combination therapy using lower doses of each drug has indicated greater efficacy and fewer side effects than high doses of the individual drugs.…”