title: Opioid receptor agonists D-Ala-2-Me-Phe-4-Met-(O)-ol enkephalin and ethylketocyclazocine in the brain accentuate digoxin-induced arrhythmias.
abstract: OBJECTIVE
  To examine the potential effects of two opioid receptor agonists in the brain on digoxin-induced cardiac arrhythmias and to explore cholinergic mechanisms in any potential effect on arrhythmias.
  
  
  RESULTS
  Digoxin-induced arrhythmias were produced in guinea pigs (weighing between 280 and 350 g) that received digoxin 50 micrograms/kg intravenous bolus plus digoxin 500 micrograms/kg/h intravenously. Animals received D-Ala-2-Me-Phe-4-Met-(O)-ol enkephalin (FK 33,824) (50 or 100 micrograms/kg), ethylketocyclazocine (EKC) (50, 10 or 1 micrograms/kg) or saline (control) into the lateral cerebroventricle prior to digoxin. FK 33,824 produced significant (P less than 0.05) dose-dependent reductions in the threshold for digoxin-induced arrhythmias. The mean digoxin dosage at the development of fatal arrhythmias after the 100 micrograms/kg of FK 33,824 was 30% lower than the control group. EKC also produced significant (P less than 0.05) dose-dependent reductions in the threshold for digoxin-induced arrhythmias and the mean dose at development of fatal arrhythmias was 67% lower than the control group after 50 micrograms/kg of EKC. In the absence of digoxin, the highest dosages of each of these opioids did not produce arrhythmias. Changes in blood pressure and heart rate were unlikely explanations for the observed actions of these opioids because D-Ala-2-Me-Phe-4-Met-(O)-ol enkephalin accentuated the increase in blood pressure that accompanied digoxin while EKC reduced the blood pressure response to digoxin and neither altered the heart rate response to digoxin. In the control group, fatal digoxin-induced arrhythmias were ventricular tachyarrhythmias in two-thirds of cases and complete heart block in the remainder. These opioids accentuated the development of complete heart block. The role of the cholinergic system was explored for only EKC because both opioids produce similar effects on arrhythmias, using atropine sulphate which crosses the blood brain-barrier and atropine methylnitrate which does not enter the central nervous system. Atropine sulphate, but not atropine methylnitrate, slightly blunted but did not reverse the action of EKC.
  
  
  CONCLUSIONS
  These data indicate that: two opioids in the brain--D-Ala-2-Me-Phe-4-Met-(O)-ol enkephalin and EKC--alter the threshold for development of digoxin-induced arrhythmias, specifically accentuating development of complete heart block produced by digoxin; and cholinergic mechanisms play only a small role in modulating the action of EKC on digoxin-induced bradyarrhythmias.
authors.affiliation: Department of Medicine (Cardiology), University Hospital (Shaughnessy), University of British Columbia, Vancouver.
authors.forename: S W
authors.initials: SW
authors.lastname: Rabkin
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000175:diagnosis; D001285:Atropine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D001286:Atropine Derivatives / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D001812:Blood-Brain Barrier; D001923:Brain Chemistry; D004077:Digoxin / Q000008:administration & dosage / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004562:Electrocardiography; D004745:Enkephalins / Q000008:administration & dosage / Q000494:pharmacology*; D016314:Ethylketocyclazocine / Q000008:administration & dosage / Q000494:pharmacology*; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D010276:Parasympatholytics / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D001286:Atropine Derivatives; D004745:Enkephalins; D010276:Parasympatholytics; D016314:Ethylketocyclazocine; D004077:Digoxin; D001285:Atropine; C006649:methylatropine