Calcium channel blockers depress atrioventricular (AV) nodal properties in vivo in a frequencydependent manner, suggesting that selective drug action during supraventricular arrhythmias may result from use-dependent properties. The present study was designed to examine whether or not the rate-dependent actions of diltiazem account for its therapeutic effects during atrial fibrillation. The determinants of the ventricular response to atrial fibrillation (concealed AV nodal conduction and AV node functional refractory period, AVFRP) were evaluated at multiple cycle lengths (with extrastimulus techniques) and during electrically induced atrial fibrillation (with indirect indexes from RR interval histograms) in anesthetized dogs. In the presence of diltiazem, AVFRP increased progressively relative to control as rate accelerated. At cycle lengths comparable to sinus rhythm in humans, AVFRP increased 10%, 17%, and 32% after doses 1, 2, and 3 of diltiazem, respectively. Drug-induced increases in AVFRP were greater at basic cycle lengths just above the Wenckebach point (17%, 48%, and 81%) and were maximal during atrial fibrillation (39%, 86%, and 154% increases for doses 1, 2, and 3, respectively). Diltiazem also increased the AV conduction system effective refractory period in a frequency-dependent manner without affecting the atrial effective refractory period, thereby increasing the potential zone of concealment into the AV node. Frequency-dependent increases in the zone of concealment were produced by diltiazem and were associated with marked increases in the standard deviation of RR interval histograms during atrial fibrillation (257%, 526%, and 923% increases after doses 1, 2, and 3, respectively). The combination of rate-dependent increases in AVFRP and zone of concealment resulted in a marked amplification of diltiazem's effects during atrial fibrillation, with mean RR interval increases (88%, 200%, and 300% after doses 1, 2, and 3, respectively) that were 8-10 fold greater than increases in AVFRP at cycle lengths comparable to sinus rhythm in humans. We conclude that diltiazem's frequency-dependent effects lead to highly selective depression of AV nodal function during atrial fibrillation. (Circulation 1989;80:380-
Antiarrhythmic drug effects on maximal upstroke velocity (V^,) are frequency dependent, which implies that the effects of these drugs on conduction should also be rate dependent. Previous in vivo studies have been limited by assumptions about unchanging propagation pathway, and by the empirical use of a first-order recovery model. To explore time-dependent antiarrhythmic drug-induced conduction slowing in vivo, we used 56-electrode epicardial mapping in chloralose-anesthetized dogs with formalin-induced atrioventricular block. Intervaldependent changes in conduction time were assessed under control conditions and then after three loading and maintenance infusions of procainamide. Under control conditions, epicardial activation time (86±26 msec at a basic cycle length of 300 msec) was unchanged (87±24 msec) by pauses up to 6.6 ±2.2 seconds. Procainamide caused conduction slowing that dissipated as a function of recovery interval, with 94±6% recovery over a maximum pause of 6.7±1.5 seconds, but did not alter activation pattern. Drug-induced changes in conduction were evaluated by use of a mathematical model assuming phase 0 inward current proportional to conduction velocity squared. Conduction changes were better fitted by this "quadratic model" (least sum of squared deviations 3.9 xlO~3 by mapping in five dogs, 2.7 xlO~2 by use of QRS duration in nine dogs) than by a monoexponential model (sum of squared deviations 5.7xlO" 3 by mapping, 3.4xlO~2 with QRS;/7<0.01 vs. quadratic model for each). As predicted by theoretical analysis, recovery time constants from the quadratic model were similar to time constants for procainamideinduced changes in V^ In vitro, and significantly longer than values obtained with a monoexponential model. Drug-induced changes in QRS duration were highly correlated with simultaneous changes measured by epicardial mapping (r=0.95,p<0.001), indicating that QRS duration is a valid index of drug effects on ventricular conduction. We concluded that procainamide causes interval-dependent changes in ventricular conduction in vivo that are consistent with a proportional relation between phase 0 inward current and the square of conduction velocity. These observations have important potential implications for the dosedependent and heart rate-dependent effects of antiarrhythmic drugs. Antiarrhythmic drug effects on conduction have been shown to be qualitatively frequency dependent in man for procainamide, 4 calcium channel blockers, 5 and a variety of sodium channel blockers.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2025 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.