title: The calcium antagonist diltiazem has antiarrhythmic effects which are mediated in the brain through endogenous opioids.
abstract: The purpose of this study was to examine the hypothesis that the calcium channel blocker, diltiazem, modulates catecholamine-induced arrhythmias through CNS mechanisms. Rats, that had catheters previously inserted into the lateral cerebral ventricle and femoral artery, received diltiazem, 10 or 50 micrograms/kg or the diluent, into the lateral cerebral ventricle (i.c.v.). Epinephrine was infused to produce arrhythmias. The onset of ventricular arrhythmias, premature ventricular complexes, occurred at a significantly (P less than 0.05) greater dose of epinephrine, after diltiazem, compared to the control group and in a dose-dependent manner, with the mean (+/- 1 SEM) dose of epinephrine being 198 +/- 5, 175 +/- 13 and 115 +/- 15 micrograms/kg in the groups treated with 50 and 10 micrograms/kg of diltiazem and the control groups, respectively. The development of fatal arrhythmias, mainly ventricular tachyarrhythmias, occurred at significantly (P less than 0.05) greater concentrations of epinephrine with diltiazem, 50 and 10 micrograms/kg, 225 +/- 5 and 183 +/- 13 micrograms/kg, respectively, compared to controls, 131 +/- 15 micrograms/kg. Endogenous opioids of the mu-type were implicated in this action of diltiazem, because the mu opioid antagonist naloxone, 1 mg/kg (i.v.), significantly (P less than 0.05) antagonized the antiarrhythmic effects of centrally administered diltiazem and the mu opioid agonist DAGO (i.c.v.), did not further enhance the suppression of epinephrine-induced arrhythmias, produced by diltiazem, 50 micrograms/kg. Atropine sulfate, which crosses the blood-brain barrier and atropine methylnitrate, which does not enter the brain, each at 1 mg/kg (i.v.), produced an equal and significant antagonism of the effect of diltiazem, 50 micrograms/kg, that was less than that of naloxone. The combination of naloxone plus atropine sulfate completely prevented the effect of diltiazem, 50 micrograms/kg, on arrhythmias. The antiarrythmic action of diltiazem could not be explained by alteration of the blood pressure or heart rate response to epinephrine. The results suggest that: (a) calcium channels on neurons in the CNS play an important role in the modulation of epinephrine-induced cardiac arrhythmias, (b) diltiazem can suppress arrhythmias through CNS mechanisms, (c) activation of the parasympathetic nervous system mediates some of the effect of diltiazem, but (d) the mechanism of action of diltiazem is modulated through endogenous opioids.
authors.affiliation: Department of Medicine (Cardiology), University Hospital (Shaughnessy), University of British Columbia, Vancouver, Canada.
authors.forename: S W
authors.initials: SW
authors.lastname: Rabkin
mesh_terms: D000109:Acetylcholine / Q000502:physiology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D001285:Atropine / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D004110:Diltiazem / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004723:Endorphins / Q000502:physiology*; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000494:pharmacology; D004837:Epinephrine / Q000037:antagonists & inhibitors*; D006339:Heart Rate / Q000187:drug effects; D007276:Injections, Intraventricular; D009270:Naloxone / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D000889:Anti-Arrhythmia Agents; D004723:Endorphins; D004745:Enkephalins; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009270:Naloxone; D001285:Atropine; D004110:Diltiazem; D000109:Acetylcholine; D004837:Epinephrine