title: Effect of intracerebroventricular picrotoxin and muscimol on intravenous bupivacaine toxicity. Evidence supporting central nervous system involvement in bupivacaine cardiovascular toxicity.
abstract: BACKGROUND
  The authors have previously shown that administration of bupivacaine into the cerebral ventricles of rabbits results in CNS-mediated cardiac dysrhythmias and that these CNS-mediated dysrhythmias could be terminated by CNS administration of a drug (midazolam) that enhances GABAergic activity. The goal of the current investigation was to determine whether the CNS-mediated cardiotoxicity that occurs after direct CNS administration of bupivacaine contributes to bupivacaine's cardiovascular toxicity following intravenous administration.
  
  
  METHODS
  Three groups of rabbits were pretreated by intracerebroventricular administration of mock CSF (control), muscimol (a GABA agonist), or picrotoxin (a GABA chloride channel blocker). A fourth group received intravenous hexamethonium as a pretreatment. After pretreatment, all groups received intravenous bupivacaine at 1.5 mg.kg-1.min-1 and the bupivacaine dose and plasma concentration at the onset of dysrhythmias and cardiovascular collapse were determined. It was hypothesized that pretreatment with muscimol and hexamethonium would increase the threshold for cardiac dysrhythmias, while pretreatment with picrotoxin would decrease the threshold for dysrhythmias.
  
  
  RESULTS
  The bupivacaine plasma concentration required to produce cardiac dysrhythmias was significantly greater in the muscimol and hexamethonium groups compared to control. The bupivacaine plasma concentration at the onset of dysrhythmias was not different from control in the picrotoxin group. The bupivacaine plasma concentration that produced cardiovascular collapse did not differ from control in any of the groups.
  
  
  CONCLUSIONS
  It was concluded that the data generally support the hypothesis that bupivacaine-mediated cardiac dysrhythmias are, at least in part, mediated by CNS actions of the drug.
authors.affiliation: Department of Anesthesiology, University of Washington, Seattle 98195.
authors.forename: C M
authors.initials: CM
authors.lastname: Bernards
authors.forename: A A
authors.initials: AA
authors.lastname: Artru
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000517:prevention & control; D001794:Blood Pressure / Q000187:drug effects; D002045:Bupivacaine / Q000037:antagonists & inhibitors* / Q000097:blood / Q000633:toxicity; D002490:Central Nervous System / Q000187:drug effects; D004569:Electroencephalography; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D018738:Hexamethonium; D006584:Hexamethonium Compounds / Q000494:pharmacology; D007276:Injections, Intraventricular; D008297:Male; D009118:Muscimol / Q000008:administration & dosage / Q000494:pharmacology*; D010852:Picrotoxin / Q000008:administration & dosage*; D011817:Rabbits
chemical_list: D000959:Antihypertensive Agents; D002045:Bupivacaine; D018738:Hexamethonium; D006584:Hexamethonium Compounds; D009118:Muscimol; D010852:Picrotoxin