Multiple agents potentiate α1-adrenoceptor-induced conduction depression in canine cardiac Purkinje fibers

Abstract

Background: Halothane more so than isoflurane potentiates an α1- adrenoceptor (α1-AR)-mediated action of epinephrine that abnormally slows conduction in Purkinje fibers and may facilitate reentrant arrhythmias. This adverse drug interaction was further evaluated by examining conduction responses to epinephrine in combination with thiopental and propofol, which 'sensitize' or reduce the dose of epinephrine required to induce arrhythmias in the heart, and with etomidate, which does not, and responses to epinephrine with verapamil, lidocaine, and L-palmitoyl carnitine, a potential ischemic metabolite. Methods: Action potentials and conduction times were measured in vitro using two microelectrodes in groups of canine Purkinje fibers stimulated at 150 pulses/min. Conduction was evaluated each minute after exposure to 5 μM epinephrine (or phenylephrine) alone or with the test drugs. Changes in the rate of phase 0 depolarization (V(max)) and the electrotonic spread of intracellular current were measured during exposure to epinephrine with octanol to evaluate the role of inhibition of active and passive (intercellular eoupling) membrane properties in the transient depression of conduction velocity. Results: Lidocaine (20 μM) and octanol (0.2 mM) potentiated α1-AR-induced conduction depression like halothane (0.4 mM), with maximum depression at 3-5 min of agonist exposure, no decrease of V(max), and little accentuation at a rapid (250 vs. 150 pulses/min) stimulation rate. Thiopental (95 μM), propofol (50 μM), and verapamil (2 μM) similarly potentiated epinephrine responses, whereas etomidate (10 μM) did not. Between groups, the decrease of velocity induced by epinephrine in the presence of (10 μM) L-palmitoyl carnitine (-18%) was significantly greater than that resulting from epinephrine alone (-6%; 0.05 ≤ P ≤ 0.10). Current injection experiments were consistent with marked transient inhibition of cell-to-cell coupling correlating with α1-AR conduction depression in fibers exposed to octanol. Conclusions: Anesthetic 'sensitization' to the arrhythmogenic effects of catecholamines may be a special case of a more general phenomenon by which not only some anesthetics and antiarrhythmic drugs but also possible ischemic fatty acid metabolites potentiate conduction depression due to acute α1-AR-mediated cell-to-cell uncoupling.