Gen. Pharmac. Vol. 31, No. 3, pp. 415–418, 1998 ISSN 0306-3623/98 $19.00 + .00 Copyright  1998 Elsevier Science Inc. PII S0306-3623(98)00026-3 Printed in the USA. All rights reserved Action-Potential Duration and Contractility in Canine Cardiac Tissues: Action of Inotropic Drugs Pe ´ter P. Na ´na ´si, 1 * Andra ´s Varro ´ 2 and David A. Lathrop 3 1 Department of Physiology, University Medical School of Debrecen, P. O. Box 22, H-4012 Debrecen, Hungary [Fax: +36-52-432289; E-mail: nanasi@phys.dote.hu]; 2 Department of Pharmacology, Albert Szent-Gyo ¨ rgyi Medical University, H-6701 Szeged, Hungary; and 3 Department of Pediatrics and Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH 45202, USA ABSTRACT. 1. Inotropic and electrophysiologic effects of veratrine, vesnarinone, d-sotalol and tetra- ethylammonium (TEA) were compared. Action-potential duration (APD) and contractility were mea- sured in isolated canine Purkinje fiber and ventricular trabecular muscle preparations by using standard microelectrode techniques. Each drug significantly increased APD and force development in either tissue. 2. Drug-induced increases in force development were normalized to increases in APD. The order of efficacy was found to be vesnarinoneveratrineTEA in ventricular myocardium, whereas it was veratrinevesnarinone=d-sotalol=TEA in Purkinje fibers. 3. The force–APD relation was linear for all drugs in the concentrations used. 4. Simultaneous measurements of APD, force development and intracellular sodium ion activity (a i Na ) in the presence of either veratrine or lidocaine indicated a linear relation between force develop- ment and changes in a i Na . 5. The relation between APD and force development was different in ventricular and Purkinje fiber preparations. Differences in the veratrine sensitivity of the force–APD relation observed between Pur- kinje and ventricular preparations suggest that a i Na -dependent changes in Na  /Ca 2 exchange may play a more important role in regulation of force generation in Purkinje fibers than in ventricular myocar- dium. gen pharmac 31;3:415–418, 1998.  1998 Elsevier Science Inc. KEY WORDS. Cardiac muscle, Purkinje fibers, electrophysiology, action-potential duration, contrac- tility, intracellular sodium ion activity INTRODUCTION and force development in Purkinje fibers and ventricular muscle in the presence of inotropic agents that also increase APD. Positive inotropy has long been associated with compounds that in- crease action-potential duration (APD); however, the mechanisms responsible for the increase in contractility have not been eluci- METHODS dated well. APD may be increased by inhibition of outward K + cur- Adult mongrel dogs of either sex weighing from 12 to 15 kg were rents during the action-potential plateau—for example, by tetraeth- anesthetized with Na-pentobarbitone (30 mg/kg, IV). After the ylammonium (TEA) (Kenyon and Gibbons, 1979) or d-sotalol chest was opened, the heart was rapidly removed. Small free-run- (Berger et al., 1989; Varro ´ et al., 1991). APD may also be increased ning Purkinje fibers and ventricular trabeculae (diameter less than by increasing inward currents. The veratrum alkaloids that affect 1 mm) were dissected and individually mounted in a Plexiglas Na + -channel inactivation increase APD (Catterall, 1980; Honer- chamber allowing for continuous superfusion with bathing solution ja ¨ger, 1982). Other drugs (e.g., vesnarinone) both inhibit outward containing (in mM): NaCl, 153; KCl, 5.4; CaCl 2 , 2.7; MgCl 2 , 1.05; K + current and increase inward Ca 2+ current (Lathrop et al., 1993). HEPES, 5.4; and glucose, 11.0. The pH of this superfusate was The increased contractility produced by each of these drugs is ulti- 7.40.05 at 37°C when gassed with 100% O 2 . One end of each mately attributed to increases in intracellular Ca 2+ concentration preparation was attached to a stationary stainless steel hook; its op- that may result either from prolonged Ca 2+ entry through voltage- posite end was connected to the lever arm of an RCA-5734 mecha- sensitive Ca 2+ channels or from a decreased Ca 2+ efflux through the noelectronic transducer tube (Harrison, USA) mounted on a micro- Na + /Ca 2+ exchanger resulting from increases in intracellular sodium manipulator to allow measurement of the contractile force. ion activity (a i Na ) and a greater time spent at depolarized membrane Preparations were continuously paced at 0.33 Hz by using 1-msec potentials (Horackova, 1984; Horackova and Vassort, 1973). The wide isolated constant current pulses of twice diastolic threshold relative contributions of these two mechanisms in regulation of through a pair of platinum electrodes. Conventional 3 M KCl-filled force development likely account for differences in pharmacologic glass microelectrodes having resistances ranging from 10 to 20 response of different cardiac preparations to increases in APD. This MOhm were used to record transmembrane potential. Recordings study was therefore initiated to examine the relation between APD were referenced to ground by using an Ag-AgCl-KCl-agar electrode in the superfusion chamber. Action potentials and contractile re- *To whom correspondence ahould be addressed. Received 2 September 1997; accepted 12 January 1998. sponses were photographed on Polaroid film.