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.

The action of reserpine, 6-hydroxydopamine, and bretylium on digitalis-induced cardiotoxicity.

This study determined whether the protective effect of reserpine against ouabain-induced ventricular arrhythmias in the cat is due to an action of the drug on the adrenergic nerve terminal. Reserpine (5 mg/kg i.p.) administered 24 h prior to ouabain (2 micrograms/kg per min i.v., until death) increased the dose of ouabain to produce premature ventricular contractions, ventricular tachycardia, and death from 77.3 +/- 5.2 to 105.0 +/- 6.0; 84.9 +/- 5.2 to 132.7 +/- 9.1; and 108.8 +/- 4.0 to 165.7 +/- 10.4 micrograms/kg, respectively (P less than 0.05). When 6-hydroxydopamine (6OHDA; 20 mg/kg i.v.) was given 3 days prior to the experiment, the protective effect of reserpine was not evident. When bretylium (20 mg/kg i.v., 2 h prior to ouabain) was administered to animals previously treated with reserpine, the dose of ouabain which produced premature ventricular contractions, ventricular tachycardia, and death was increased to 109.0 +/- 7.2; 146.1 +/- 12.6; and 165.8 +/- 7.6 micrograms/kg, respectively (P less than 0.05). However, the magnitude of this protective action was similar to that produced by reserpine alone. Lathers et al. (Fed. Proc. 40, 672, 1981) reported that bretylium alone provides protection of a similar order of magnitude as reserpine. Thus, the effects of reserpine and bretylium were not additive; this indicates that the two agents may be acting on the same locus or they may be acting at different sites with the action of one drug masking or blocking the action of the other. Since 6OHDA prevented the action of reserpine on ouabain-induced ventricular arrhythmia and since 6OHDA only produces degeneration of adrenergic nerve terminals, it is probable that the protective effect of both reserpine and bretylium is due to an action at the adrenergic nerve terminal. The heart rate and blood pressure were not involved in the antiarrhythmic effects of reserpine.