Role of the adrenergic nerve terminal in digitalis-induced cardiac toxicity: a study of the effects of pharmacological and surgical denervation.
This study determined whether the protective action of bretylium against ouabain-induced ventricular arrhythmia in the cat is related to an action of bretylium on the adrenergic nerve terminal. Bretylium pretreatment (20 mg/kg, i.v.) administered 2 h prior to ouabain (2 micrograms/kg/min, i.v. until death) increased the dose of ouabain to produce premature ventricular contraction, ventricular tachycardia, and death from 77.2 +/- 5.2 to 107.7 +/- 6.7 micrograms/kg; from 84.9 +/- 5.2 to 113.9 +/- 7.1 micrograms/kg; and from 108.8 +/- 4.0 to 146.7 +/- 5.7 micrograms/kg, respectively (p less than 0.05). Surgical denervation 2 weeks prior to the experiment or 6-hydroxydopamine (6OH dopamine), 20 mg/kg, i.v., administered 3 or 14 days prior to the ouabain infusion did not protect against the arrhythmogenic effects of ouabain. When bretylium was administered to cats pretreated with 6OH dopamine 3 days prior to the ouabain infusion or to surgically denervated cats, the protective action against ouabain-induced arrhythmia did not develop. Since 6OH dopamine and surgical denervation prevented the action of bretylium on ouabain-induced ventricular arrhythmia, it appears that bretylium is acting on the adrenergic nerve terminal. Thus, agents like bretylium that act on the adrenergic nerve terminal, leaving it structurally intact but not functional, are effective against ouabain-induced ventricular arrhythmia while procedures which cause the degeneration of the adrenergic nerve terminal, such as 6OH dopamine and surgical denervation, are not. These observations indicate that for the protective effect of sympathectomy against ouabain-induced arrhythmia to develop, the adrenergic nerve terminal must be present, although not functional as far as adrenergic neurotransmission is concerned. Changes in the heart rate or blood pressure did not appear to be a factor in the protective effect of bretylium.
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D001794:Blood Pressure / Q000187:drug effects; D001949:Bretylium Compounds / Q000494:pharmacology*; D001950:Bretylium Tosylate / Q000494:pharmacology*; D002415:Cats; D003714:Denervation; D004071:Digitalis Glycosides / Q000633:toxicity*; D005260:Female; D006321:Heart / Q000294:innervation*; D006339:Heart Rate / Q000187:drug effects; D006892:Hydroxydopamines / Q000494:pharmacology; D008297:Male; D010042:Ouabain / Q000633:toxicity; D012110:Reserpine / Q000494:pharmacology; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology*
D001949:Bretylium Compounds; D004071:Digitalis Glycosides; D006892:Hydroxydopamines; D010042:Ouabain; D001950:Bretylium Tosylate; D012110:Reserpine