Enhancement of procainamide - induced rate - dependent conduction slowing by elevated myocardial extracellular potassium concentration in vivo WAYNE

Procainamide, a type 1A antiarrhythmic drug, blocks sodium channels and reduces the maximum rate of rise of the cardiac action potential (Vmax) in a rate-dependent fashion. In vitro, the magnitude of this rate-dependent reduction in Vmax is greater in tissue that is partially depolarized at rest than in tissue with a normal resting potential. Reductions in Vmax produced by drugs that block sodium channels are also directly related to the reductions in longitudinal conduction velocity of action potential propagation in papillary muscle preparations. We therefore sought to determine whether the rate-dependent conduction slowing induced by procainamide in the intact canine heart is enhanced in myocardial tissue abnormally depolarized by an elevated myocardial extracellular potassium concentration, [K+ ]0. QRS duration and epicardial activation times were measured as indexes of myocardial conduction. QRS duration and epicardial activation times were measured at control (4.0 mM) and at intermediate (6.5 mM) and high (9.2 mM) myocardial [K+ ]O in the presence or absence of a clinically relevant procainamide concentration (12.2 ± 2.6 g/ml) at the longest obtainable interstimulus interval of 440 msec and at 330, 280, and 250 msec. Intermediate and high myocardial [K+4 o alone induced rate-dependent conduction slowing as the frequency of stimulation increased (cycle length 440 msec to 330, 280, and 250 msec). In the presence of procainamide, rate-dependent conduction slowing was observed at all levels of myocardial [K ], and the amount of rate-dependent change in conduction time increased as the myocardial [K+]1 was increased. In addition, the magnitude of the difference between the rate-dependent changes in conduction time produced by high myocardial [K+]1 in the presence of procainamide compared with high [K + ] alone was significantly greater than the difference at control myocardial [K' 10. This observation shows enhancement of procainamide-induced ratedependent conduction slowing by high [K+4]1. Therefore, as predicted by studies of longitudinal conduction velocity and Vmax in papillary muscle preparations, rate-dependent conduction slowing in the presence of a clinically relevant concentration of procainamide is enhanced by high myocardial [K + ]o depolarization. This effect of elevated myocardial [K + SO may be important to the antiarrhythmic actions of procainamide in abnormal myocardium, especially in situations such as acute ischemia in which the distribution of high [K+]4 and resting depolarization are inhomogeneous. Circulation 76, No. 6, 1380-1387, 1987. MOSTUNDERSTANDING OF the electrophysiologic action of antiarrhythmic drugs is based on their effects in normal myocardial tissue with normal resting membrane potential.1 However, the abnormal myocardium, including acutely ischemic myocardium in which lifeFrom the Department of Medicine, Division of Cardiology, University of North Carolina at Chapel Hill, Chapel Hill, NC. Supported by grants PO1 HL27430 and T32 HL07470 from NHLBI. Address for correspondence: Leonard S. Gettes, M.D., Division of Cardiology, CB# 7075, Burnett-Womack Bldg., University of North Carolina, Chapel Hill, NC 27599. Received Oct. 17, 1986; revision accepted Aug. 20, 1987. 1380 threatening arrhythmias originate, often contains hyperkalemic and acidotic2 tissue with resting membrane depolarization.3 4 For this reason, the effects of antiarrhythmic drugs on depolarized tissue may be important to the antiarrhythmic actions of these drugs. It is known that antiarrhythmic drugs produce more sodium-channel blockade5' 6 and more reduction of maximum rate of rise in cardiac action potential (Vmax) in depolarized tissue than in normal tissue.7 8 It is also known that the effects of antiarrhythmic drugs are rate dependent, with more sodium-channel CIRCULATION by gest on A ril 6, 2017 http://ciajournals.org/ D ow nladed from LABORATORY INVESTIGATION-ELECTROPHYSIOLOGY blockade5, 6and more reduction ofVmax at rapid rates than at slow rates,9' 10 and that this rate dependence is greater in potassium-depolarized tissue. 11t-5 However, the greater rate-dependent effects of antiarrhythmic drugs in potassium-depolarized tissue in vitro have not been shown to occur in the hyperkalemic intact heart. We therefore hypothesized that procainamide would cause more rate-dependent conduction slowing, as a consequence of its effect on sodium conductance and Vmax, in hearts with high extracellular myocardial potassium concentration, [K+ SO, than in hearts with a normal [K]10. We studied rate-dependent conduction slowing during ventricular pacing in intact dog hearts using intramyocardial ion-selective potassium electrodes to monitor myocardial [K ± 10 online during hyperkalemia produced by potassium infusion and measuring QRS duration and epicardial conduction times as indexes of myocardial conduction.