Importance of interaction with adrenergic neurons for antifibrillatory action of bretylium in the dog.
The present study was designed to investigate whether or not interaction with the adrenergic neurons is important for the antifibrillatory effect of bretylium. The direct action of bretylium on cardiac electrophysiological properties, as indicated by effective refractory period prolongation, was also assessed. In pentobarbital-anesthetized, open-chest dogs, bretylium, 5 mg/kg i.v., increased ventricular fibrillation threshold rapidly and markedly. The effect peaked in 1 h and was sustained for at least 3 h. Complete adrenergic neuronal blockade also occurred within 30 min. Effective refractory period lengthening was minimal and variable. When bretylium's access to the adrenergic neurons was prevented either by antagonism of the presynaptic amine transport pump with desipramine or by chemical sympathectomy with 6-hydroxydopamine, the antifibrillatory effect was absent. Furthermore, when blockade of adrenergic neurotransmission by bretylium was reversed by the administration of d-amphetamine, ventricular fibrillation threshold also decreased. Data from all groups of experiments revealed that changes in effective refractory period did not correlate, in either magnitude or direction, with changes in ventricular fibrillation threshold. Thus, it can be concluded that interaction with adrenergic neurons is important for bretylium's antifibrillatory action and that absence of sympathetic neurotransmission contributes to the elevation of ventricular fibrillation threshold.
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D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001949:Bretylium Compounds / Q000627:therapeutic use*; D003891:Desipramine / Q000494:pharmacology; D003913:Dextroamphetamine / Q000494:pharmacology; D004285:Dogs; D004558:Electric Stimulation; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006892:Hydroxydopamines / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects*; D009638:Norepinephrine / Q000378:metabolism; D016627:Oxidopamine; D010646:Phentolamine / Q000494:pharmacology; D011941:Receptors, Adrenergic / Q000502:physiology*; D013563:Sympathectomy, Chemical; D013997:Time Factors; D014693:Ventricular Fibrillation / Q000188:drug therapy*
D001949:Bretylium Compounds; D006892:Hydroxydopamines; D011941:Receptors, Adrenergic; D016627:Oxidopamine; C045166:bretylium; D003891:Desipramine; D003913:Dextroamphetamine; D009638:Norepinephrine; D010646:Phentolamine