T Gen. Pharmac. Vol. 21, No.5, pp. 747-751, 1990 Printed in Great Britain. All rights reserved 0306-3623j90 $3.00 + 0.00 Copyright © 1990 Pergamon Press pic USE-DEPENDENT ACTION OF ANTIARRHYTHMIC DRUGS IN FROG SKELETAL MUSCLE AND CANINE CARDIAC PURKINJE FIBER PETER P. NANASI,* ANDRAS VARR6, 1 DAVID A. LATHROP 1 and MIKLOS DANK6 Department of Physiology, University Medical School of Debrecen, P.O. Box 22, H-4012 Debrecen, Hungary and 1 Department of Pediatrics, University of Cincinnati College of Medicine, Eiland and Bethesda Ave., Cincinnati, OH 45229, U.S.A. (Received 2 January 1990) Abstract---!. Conventional microelectrode techniques were used to study the effect of quinidine (10 lidocaine (20 and verapamil (3-10 ,uM) on action potential upstroke (V::;,.) in frog skeletal muscle and dog Purkinje fiber. 2. The frequency-dependent nature of v:., depression induced by these drugs was similar in both preparations, however, quinidine was more potent in skeletal muscle while lidocaine was in Purkinje fibers. 3. In skeletal muscle tetrodotoxin (3 and 15 nM) and low concentrations of antiarrhythmic drugs proportionally reduced the maximum velocity of depolarization and repolarization (V: .. and V,;;.,, respectively), whereas v.;; .. was more depressed than .. by high concentrations (50-200 of antiarrhythmics. Decreases in the overshoot potential were proportional to the .. block in the case of each drug. 4. These results indicate that therapeutically relevant concentrations of quinidine and lidocaine inhibit skeletal muscle Na+ channels in a use-dependent manner similar to heart, while at higher concentrations the K + channels may also be blocked. Therapeutic implications of the results are: discussed. INTRODliCTION It is well known that class I antiarrhythmic agents (Vaughan Williams, 1975) depress excitability, maxi- mum upstroke velocity (V!..) and conduction in cardiac tissues in a use-dependent manner (Hondeghem and Katzung, 1984; Campbell, 1983; Grant et al., 1984) which is believed to play an important role in their therapeutic action. Although the effects of these drugs on the fast Na + current or the •• were studied extensively in different cardiac preparations (Courtney, 1980; Grant et a!., 1984; Campbell, 1983; Varr6 et al., 1985) there are only few data available in skeletal muscle with therapeutically relevant concentrations (Andersson, 1973; Harvey and Rang, 1974). In addition, considerable differ- ences between cardiac and skeletal muscle have been reported in respect of sensitivity and mode of action of tetrodotoxin (TTX) (Jaimovich et a/., 1976; Clarkson eta/., 1988) indicating that the Na + chan- nels in these preparations are not fully identical. However, Courtney (1981) did not observe substan- tial differences between guinea-pig cardiac and frog skeletal muscle on fast Na + current with lidocaine, mexiletine and tocainide. In our previous work (Nanasi et a!., 1987) we studied the effect of bency- clane on v;;; •• in dog cardiac Purkinjc fibers and frog skeletal muscle. Both the magnitude and the use- dependent nature of the bencyclane-induced v;;; •• block were comparable. In the present report we *To whom correspondence should be addressed: Dr Peter P. Namisi, Children's Hospital Research Foundation, Division of Cardiology, Eiland and Bethesda Avenues, Cincinnati, OH 45229, U.S.A. 747 compared the effects of therapeutic concentrations of quinidine and lidocaine, and high concentrations of verapamil on V •• in frog skeletal muscle and canine Purkinje strands. It was found, that the use-depen- dent depression of v;;;., induced by the studied antiarrhythmic drugs was similar in the two different preparations, therefore, changes in the function of skeletal muscles may be anticipated during the thera- peutic application of these agents. METHODS Electrophysiological measurements in frog skeletal muscle The experiments were performed in superficial fibers of frog sartorius muscle (Rana esculenta) at room temperature in Ringer's solution (Na +, 120.2; K + 2.5; Ca2+ 1.8; CI- 121.1; HPOl- 2.15; H 2 P04 0.85 mM) buffered at pH 7.0 ± 0.05. Two glass microelectrodcs, filled with 2.5 M KCI, were inserted into the same fiber for the purpose of stimulation and recording. Transmembrane potential changes and their first time derivatives, obtained using an analogue dilferentiator, were monitored on a dual beam digital storage oscilloscope (Gould OS-4000) and displayed on a chart recorder (Servogor 460) for later analysis. Trains of electrical stimuli (I in amplitude and 0.5 msec in duration for each pulse) were delivered through the current passing microclectrode. The train durations were 45 msec and 10 sec for trains of 100 and 4Hz frequency, respectively. In both cases, the use-dependent reduction of V ;:;., was calculated using the following formula: v+ ·v· y = la0_!!'ta.X 1st (Drug) , I OO V last/ V 1st (Control) (I) and the term of (I 00- Y) gave the measure of block as percentage. Changes in the maximum velocity of repolariz- ation (V,;;.,) were calculated in the same way, while changes in the overshoot potential (OSP) were given as differences