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

Abstract

. 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. . 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. . 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. . 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. . 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.

A third class of anti‐arrhythmic action. Effects on atrial and ventricular intracellular potentials, and other pharmacological actions on cardiac muscle, of MJ 1999 and AH 3474

“…Although not all authors have been able to show the effect, there is much evidence that reduction of sympathetic activation decreases the probability not only of catecholamine-induced cardiac arrhythmias, but also of ouabain-induced ventricular fibrillation. Surgical removal of sources of sympathetic transmitters (Mendez, Aceves & Mendez, 1961) and sympathetic neurone blocking drugs devoid of class I actions (Papp & Vaughan Williams, 1969a) protect against ouabain-induced ventricular fibrillation, and laevopropranolol is more effective in this respect than the dextro-form, which has only 1/100 the /3-adrenoceptor blocking activity of the laevo-isomer (Barrett & Cullum, 1968), although both isomers are equipotent in their class I actions. The recent evidence of Raper & Wale (1968) and of Blackburn, Byrne, Cullum, Farmer & Levy (1970) support the view that p-adrenoceptor blockade contributes to protection against ouabain-induced arrhythmias.…”

Adrenergic Neuron Blocking Drugs

“…This is apparently the case since KUNTZMAN et al (1970) reported plasma levels in man of approximately 4 x IO-6M following intramuscular administration of a therapeutic dose (300 mg). PAPP and VAUGHAN WILLIAMS (1969), as did BIGGER and JAFFE (1971), speculated that it was possible that the antiarrhythmic action of bretylium was due to dampening of activity in sympathetic nerves. ARAVINDAKSHAN and GETTES (1975) reported that in the isolated rabbit heart, bretylium (~ 1 X 10-4 M) was ineffective in preventing ventricular fibrillation induced by either perfusion with low potassium solutions or by the introduction of premature stimuli.…”

The effect of altered thyroid state on atrial intracellular potentials

“…Intracellular potential records were obtained with 3M-KCI-filled micropipettes from atria driven at awide range of frequencies. The maximum rate of rise of the intracellular action potential was recorded with a differentiator (Papp & Vaughan Williams, 1969b). The nutrient solution contained (mM) NaCl, 125; KCI, 5-6; CaCl2, 2-16; NaHCO3, 25; glucose, 11, and was gassed with 95 % 02, 5 % C02, with resultant pH 7-4.…”