title: Multiple agents potentiate alpha1-adrenoceptor-induced conduction depression in canine cardiac purkinje fibers.
abstract: BACKGROUND
  Halothane more so than isoflurane potentiates an alpha1-adrenoceptor (alpha1-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 microm epinephrine (or phenylephrine) alone or with the test drugs. Changes in the rate of phase 0 depolarization (Vmax) 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 coupling) membrane properties in the transient depression of conduction velocity.
  
  
  RESULTS
  Lidocaine (20 microm) and octanol (0.2 mm) potentiated alpha1-AR-induced conduction depression like halothane (0.4 mm), with maximum depression at 3-5 min of agonist exposure, no decrease of Vmax, and little accentuation at a rapid (250 vs. 150 pulses/min) stimulation rate. Thiopental (95 microm), propofol (50 microm), and verapamil (2 microm) similarly potentiated epinephrine responses, whereas etomidate (10 microm) did not. Between groups, the decrease of velocity induced by epinephrine in the presence of (10 microm) 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 alpha1-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 alpha1-AR-mediated cell-to-cell uncoupling.
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
authors.forename: A H
authors.initials: AH
authors.lastname: Kulier
authors.forename: L A
authors.initials: LA
authors.lastname: Turner
authors.forename: S
authors.initials: S
authors.lastname: Vodanovic
authors.forename: S
authors.initials: S
authors.lastname: Contney
authors.forename: D A
authors.initials: DA
authors.lastname: Lathrop
authors.forename: Z J
authors.initials: ZJ
authors.lastname: Bosnjak
mesh_terms: D000200:Action Potentials; D000316:Adrenergic alpha-Agonists / Q000009:adverse effects / Q000494:pharmacology; D000777:Anesthetics / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000503:physiopathology; D004285:Dogs; D004357:Drug Synergism; D004837:Epinephrine / Q000009:adverse effects / Q000494:pharmacology; D005045:Etomidate / Q000009:adverse effects / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism; D006221:Halothane / Q000009:adverse effects / Q000494:pharmacology; D006321:Heart / Q000294:innervation*; D066298:In Vitro Techniques; D008012:Lidocaine / Q000009:adverse effects / Q000494:pharmacology; D009431:Neural Conduction / Q000187:drug effects* / Q000502:physiology; D000442:Octanols / Q000009:adverse effects / Q000494:pharmacology; D010172:Palmitoylcarnitine / Q000494:pharmacology; D015742:Propofol / Q000009:adverse effects / Q000494:pharmacology; D011690:Purkinje Fibers / Q000187:drug effects* / Q000502:physiology; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects* / Q000502:physiology; D013874:Thiopental / Q000009:adverse effects / Q000494:pharmacology; D014700:Verapamil / Q000009:adverse effects / Q000494:pharmacology
chemical_list: D000316:Adrenergic alpha-Agonists; D000777:Anesthetics; D005227:Fatty Acids; D000442:Octanols; D018340:Receptors, Adrenergic, alpha-1; D010172:Palmitoylcarnitine; D008012:Lidocaine; D014700:Verapamil; D013874:Thiopental; D006221:Halothane; D015742:Propofol; D004837:Epinephrine; D005045:Etomidate