title: Mechanisms of the putative cardioprotective effect of hexamethonium in anesthetized dogs given a large dose of bupivacaine.
abstract: BACKGROUND
  Some reports suggest that activation of the autonomic nervous system by bupivacaine could participate in its cardiotoxicity. This is based in part on the fact that hexamethonium suppresses cardiac disturbances in anesthetized rabbits given small intracerebroventricular doses of bupivacaine. The aims of the current study were to determine, in anesthetized dogs, (1) whether the activation of the autonomic nervous system is deleterious after a large intravenous dose of bupivacaine and (2) whether the parasympathetic or sympathetic system is implicated in the bupivacaine-induced deleterious activation of the autonomic nervous system.
  
  
  METHODS
  We used an electrophysiologic model in closed-chest dogs anesthetized with sodium pentobarbital. In group 1 (n = 6), dogs were given 4 mg/kg intravenous bupivacaine over 10 s. In group 2 (n = 6), dogs were given the same dose of bupivacaine 5 min after having received 0.2 mg/kg intravenous atropine sulfate. In group 3 (n = 9), dogs were pretreated with 10 mg/kg intravenous hexamethonium and then given bupivacaine 4 mg/kg. In addition, in group 3, the right atrium was paced at a basic cycle length of 400 ms to obtain a heart rate similar to that of group 1.
  
  
  RESULTS
  Bupivacaine in group 1 induced significant bradycardia; lengthening of PR, atria-His, His-ventricle, and QTc intervals; and QRS widening. The first derivative of left ventricular pressure was significantly decreased, whereas left ventricular end-diastolic pressure was increased. Atropine pretreatment did not modify cardiac disturbances induced by bupivacaine. Hexamethonium pretreatment induced significantly less QRS widening and QTc lengthening than was seen in group 1 but worsened the bupivacaine effects on bradycardia, atria-His and PR intervals, mean aortic pressure, and first derivative of left ventricular pressure. Moreover, atrial pacing in group 3 induced alterations of QRS similar to those in group 1.
  
  
  CONCLUSIONS
  Considering that marked slowing of ventricular conduction velocity (i.e., QRS widening) is known to facilitate reentrant ventricular arrhythmias, we conclude that (1) the activation of the autonomic nervous system by bupivacaine is not as deleterious as previously suggested; (2) the parasympathetic system is not markedly implicated in the worsening of direct bupivacaine cardiotoxicity; and (3) the sympathetic nervous system acts only by inducing a less marked bradycardia, which slows ventricular conduction velocity in a use-dependent manner, facilitating reentrant arrhythmias.
authors.affiliation: Department of Anesthesiology, University-Hospital of Nîmes, France.
authors.forename: J E
authors.initials: JE
authors.lastname: de La Coussaye
authors.forename: J J
authors.initials: JJ
authors.lastname: Eledjam
authors.forename: P
authors.initials: P
authors.lastname: Bruelle
authors.forename: J Y
authors.initials: JY
authors.lastname: Lefrant
authors.forename: B
authors.initials: B
authors.lastname: Bassoul
authors.forename: P A
authors.initials: PA
authors.lastname: Peray
authors.forename: G
authors.initials: G
authors.lastname: Desch
authors.forename: A
authors.initials: A
authors.lastname: Sassine
mesh_terms: D000758:Anesthesia; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D016275:Atrial Function; D001285:Atropine / Q000494:pharmacology; D002045:Bupivacaine / Q000097:blood / Q000633:toxicity*; D002304:Cardiac Pacing, Artificial; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects; D004594:Electrophysiology; D005260:Female; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006325:Heart Atria / Q000187:drug effects; D006329:Heart Conduction System / Q000187:drug effects / Q000502:physiology; D006331:Heart Diseases / Q000139:chemically induced* / Q000517:prevention & control*; D006339:Heart Rate / Q000187:drug effects; D018738:Hexamethonium; D006584:Hexamethonium Compounds / Q000627:therapeutic use*; D008297:Male; D008954:Models, Biological; D010275:Parasympathetic Nervous System / Q000187:drug effects / Q000502:physiology; D010424:Pentobarbital; D015222:Sodium Channels / Q000187:drug effects
chemical_list: D000959:Antihypertensive Agents; D006584:Hexamethonium Compounds; D015222:Sodium Channels; D018738:Hexamethonium; D001285:Atropine; D010424:Pentobarbital; D002045:Bupivacaine