Mulitple agents potentiate alpha(1)-adrenoceptor-induced conduction depression in canine cardiac Purkinje fibers

Background: Halothane more so than isoflurane potentiates an alpha(1)-adren oceptor (alpha(1)-AR)-mediated action of epinephrine that abnormally slows conduction in Purkinje fibers and may facilitate reentrant arrhythmias. Thi s adverse drug interaction was further evaluated by examining conduction re sponses 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 epineph rine with verapamil, lidocaine, and L-palmitoyl carnitine, a potential isch emic metabolite, Methods: Action potentials and conduction times were measured in vitro usin g two microelectrodes in groups of canine Purkinje fibers stimulated at 150 pulses/min. Conduction was evaluated each minute after exposure to 5 mu M epinephrine (or phenylephrine) alone or with the test drugs. Changes in the rate of phase 0 depolarization (V-max) and the electrotonic spread of intr acellular current were measured during exposure to epinephrine with octanol to evaluate the role of inhibition of active and passive (intercellular co upling) membrane properties in the transient depression of conduction veloc ity. Results: Lidocaine (20 mu M) and octanol (0.2 mM) potentiated alpha(1)-AR-i nduced conduction depression like halothane (0.4 mM), with maximum depressi on at 3-5 min of agonist exposure, no decrease of V-max and little accentua tion at a rapid (250 vs. 150 pulses/min) stimulation rate. Thiopental (95 m u M), propofol (50 mu M) and verapamil (2 mu M) similarly potentiated epine phrine responses, whereas etomidate (10 mu M) did not. Between groups, the decrease of velocity induced by epinephrine in the presence of (10 mu M) L- palmitoyl carnitine (-18%) was significantly greater than that resulting fr om epinephrine alone (-6%; 0.05 less than or equal to P less than or equal to 0.10). Current injection experiments were consistent with marked transie nt inhibition of cell-to-cell coupling correlating with alpha(1).AR conduct ion depression in fibers exposed to octanol, Conclusions Anesthetic "sensitization" to the arrhythmogenic effects of cat echolamines may be a special case of a more general phenomenon by which not only some anesthetics and antiarrhythmic drugs bur also possible ischemic fatty acid ms tabolites potentiate conduction depression due to acute alpha (1)-AR-mediated cell-to-cell uncoupling.