Elementary properties and the interaction of single myocardial Na+ channels with antiarrhythmic drugs
Kohlhardt, M.
Arzneimittel-Forschung 39(1a): 126-129
1989
ISSN/ISBN: 0004-4172 PMID: 2541732 Document Number: 327059
Excitability of atrial and ventricular cardiocytes depends basically on the availability of Na+ channels which are, in analogy to Na+ channels in other excitable membranes, voltage-dependent and tetrodotoxin-sensitive. Cardiac Na+ channels may be characterized by an unitary conductance of about 15 pS and an almost voltage-insensitive open state of 1.5-2.0 ms (at 19 degrees C). They may open more than once during membrane depolarization (reopening), an effective inactivation becomes rapidly dominating and terminates channel activity. Several experimental arguments including spontaneous failure of inactivation, subconductance states, multiple non-activatable states, and a differential tendency to reopen are indicative of a heterogeneous population. Several organic compounds and naturally occurring toxins interfere with Na+ channels by interacting with channel-associated binding sites. Class 1 antiarrhythmic drugs were proven in patch-clamp experiments to block cardiac Na+ channels in an all-or-none fashion thereby reducing the channel open probability. Unblocked Na+ channels exhibit essentially normal properties. Channel modification is the other response to the interaction with organic (or inorganic) molecules and causes repetitive activity by removal of inactivation. Pharmacologically induced removal of inactivation is kinetically indistinguishable from spontaneous failure of inactivation. This is followed by a prolongation of action potential duration which is, in heart muscle, potentially an antiarrhythmic principle.