Acta Physiologica 73. (1989)
1. szám - PHYSIOLOGY-PATHOPHYSIOLOGY - A. Varró-Y. Nakaya-V. Elharraf-B. Surawicz: Frequency-dependent and independent effects of tetrodotoxin on Vmax in cardiac fibers
Acta Physiologica Hungarica, Volume 73 (1), pp. 47—52 (1989) FREQUENCY-DEPENDENT AND INDEPENDENT EFFECTS OF TETRODOTOXIN ON Vmax IN CARDIAC FIBERS A. Varró,* Y. Nakaya,* V. Elharrar,* B. Surawicz* INSTITUTE FOR DRUG RESEARCH BUDAPEST, HUNGARY »KRANNERT INSTITUTE OF CARDIOLOGY 1001 W. TENTH STREET, INDIANOPOLIS, USA Received Mai 6, 1987 Accepted September 20, 1987 Superfusion with 3 /íM tetrodotoxin (TTX) induced both a use-dependent and a frequency-independent depression of the rate rise of the action potential (Vmax) in dog Purkinje and guinea pig ventricular muscle fibers. The recovery from block was fast and exponential with a time constant of 225.4 -f 7.1 ms in dog Purkinje fibers (n = 6). The onset kinetics of the frequency-dependent Vmax block was rapid, i.e. reached steady state after 3.0 i 0.3 beats in guinea pig ventricular muscle (n=6). The rapid use-dependent interactions with sodium channel make TTX similar to antiarrhythmic drugs with fast kinetics i.e. lidocaine, mexiletine, and tocainide, but unlike antiarrhythmic drugs, TTX-induces a large frequency-independent Vmax block at the same concentrations. Keywords: tetrodotoxin, use-dependent Vmax, dog Purkinje fiber, guinea pig papillary muscle Nerve and skeletal muscle fibers are very sensitive to tetrodotoxin (TTX) which blocks sodium channels in the nanomolar range [4]. However, much higher TTX concentrations i.e. within micromolar range [1, 6] are required to produce similar degree of sodium channel blockade in cardiac muscle fibers. These TTX concentrations are not fundamentally different from those reported to block sodium channel using local anaesthetic type antiarrhythmic drugs in cardiac muscle [5, 13]. Several studies [1, 6, 7, 10] have shown that TTX depresses sodium channels in a frequency-dependent i.e. use-dependentmanner in cardiac muscle, but there is no agreement among investigators concerning the kinetics of this use-dependent effect. Although the relation between the maximum rate of rise of action potential (Vmax) measurements have been used in a large number of studies to obtain meaningful data about the use-dependent effect of most antiarrhythmic drugs. In this study, we measured Vmax in cardiac Purkinje and ventricular muscle fibers to characterize the kinetics of the onset and dissipation of Vmax block by 3 /iM TTX. Correspondence should be addressed to András Varró Institute for Drug Research 1325 Budapest, P.O.B. 82, Hungary Acta Physiologica Hungarica 73, 1989 Akadémiai Kiadó, Budapest