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

Abstract

Block of cardiac sodium channels is enhanced by repetitive depolarization. It is not clear whether the changes in drug binding result from a change in affinity that is dependent on voltage or on the actual state of the channel. This question was examined in rabbit ventricular myocytes by analyzing the kinetics of block of single sodium channel currents with normal gating kinetics or channels with inactivation and deactivation slowed by pyrethrin toxins. At -20 and -40 mV, disopyramide 100 microM blocked the unmodified channel. Mean open time decreased 45 and 34% at -20 and -40 mV during exposure to disopyramide. Exposure of cells to the pyrethrin toxins deltamethrin or fenvalrate caused at least a tenfold increase in mean open time, and prominent tail currents could be recorded at the normal resting potential. The association rate constant of disopyramide for the normal and modified channel at -20 mV was similar, approximately 10 x 10(6)/M/sec. During exposure to disopyramide, changes in open and closed times and in open channel noise at -80 and -100 mV are consistent with fast block and unblocking events at these potentials. This contrasts with the slow unbinding of drug from resting channels at similar potentials. We conclude that the sodium channel state is a critical determinant of drug binding and unbinding kinetics.

Mechanisms Underlying the Effects of the Pyrethroid Tefluthrin on Action Potential Duration in Isolated Rat Ventricular Myocytes

“…The early inward current was greatly increased (Fig. 6c), with a relatively large amplitude and fast kinetics consistent with pyrethroid-modified I Na (Grant et al, 1993;Spencer et al, 2001). Importantly, in all myocytes examined, the pyrethroid-sensitive current included de novo, a persistent inward current (Fig.…”

“…This action underlies the neurotoxic basis for sensorimotor changes typical of pyrethroid effects in both vertebrates and invertebrates (de Weille et al, 1990;Tabarean and Narahashi, 1998;Vais et al, 2000). In addition, these agents may produce cardiotoxic effects mediated by I Na prolongation in cardiac myocytes (Grant et al, 1993;Spencer et al, 2001). Since global use of pyrethroids has increased, especially in regions burdened by arthropod-borne diseases, a consequent rise in acute pyrethroid exposures in humans demands a more complete understanding of their mode of action (Gupta et al, 2003;Habtewold et al, 2004).…”

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

“…This is an example of use-dependent unblocking (35). A Prior studies from this laboratory have shown that disopyramide blocks normal open sodium channels and those in which the inactivation process has been slowed or removed (19). The influence of 50 ,gM disopyramide on single sodium channels with inactivation removed by deltamethrin was examined at external sodium concentrations of 120 and 180 mM.…”

“…We conclude that the influence of the permeant ion concentration on the blocking action of antiarrhythmic drugs may depend importantly on their blocking mechanism. Some of these results have been communicated in abstract form ( 19,25).…”

“…In this study, we have explored the potential mechanisms by which external sodium concentration may influence the blocking action of lidocaine, a drug which primarily blocks inactivated sodium channels, and disopyramide, a drug which blocks open sodium channels (1,19). Macroscopic sodium current was measured in cultured atrial myocytes under voltage clamp.…”