The effect of bretylium on intracellular cardiac action potentials in relation to its anti-arrhythmic and local anaesthetic activity.

1. The initial effect of bretylium tosylate on isolated rabbit atria was to increase conduction velocity, contraction heights, spontaneous frequency and maximum driven frequency, and to reduce electrical threshold. At concentrations of 200 mg/l. or less, these were the only effects, and were consistent with the known sympathomimetic actions of bretylium.2. At extremely high concentrations, 1,200 and 2,400 mg/l., the initial actions were succeeded by weak quinidine-like effects; reduced conduction velocity, spontaneous and maximum driven frequencies, and rate of rise of action potential. The electrical threshold was raised, but contraction heights were not reduced.3. The local anaesthetic activity of bretylium, measured by reductions in the frog nerve action potential, was 1/90 that of procaine and 1/300 that of propranolol, on a molar basis.4. Acute pretreatment with bretylium, 20 mg/kg intravenously, significantly increased the amount of infused ouabain required before the appearance of the first signs of atrial arrhythmia in anaesthetized guinea-pigs, but did not prevent ventricular arrhythmias.5. Pretreatment with bretylium 30 mg/kg subcutaneously 24 hr, and again 4 hr before ouabain infusion, increased the dose of ouabain inducing atrial irregularity and slightly but significantly reduced the incidence of ventricular fibrillation.