The effects of bretylium on the subcellular distribution of noradrenaline and on adrenergic nerve function in rat heart.

1. The effects of bretylium were investigated on the content and subcellular distribution of noradrenaline in the rat heart and on the response to stimulation of the sympathetic nerves supplying the heart.2. In most experiments bretylium produced no change in the total noradrenaline content of the heart but significant changes were produced in the subcellular distribution of noradrenaline.3. Treatment with amphetamine both prevented and antagonized the bretylium-induced adrenergic neurone blockade and most of the accompanying changes in the subcellular distribution of noradrenaline.4. There was a temporal correlation between the bretylium-induced depletion of noradrenaline from the microsomal (P(2)) fraction and adrenergic neurone blockade.5. The onset of adrenergic neurone blockade was also accompanied by an elevation of the noradrenaline content in the low-speed coarse (P(1A)) fraction and in the mitochondrial (P(1B)) fraction; this elevation was prevented by pretreatment with alpha-methyl-p-tyrosine.6. It is concluded that although the elevation of the noradrenaline content of the P(1A) and P(1B) fractions and a depletion of amine from the P(2) fraction are associated with the onset of adrenergic neurone blockade only the depletion from the P(2) fraction is required for its maintenance. This conclusion supports the hypothesis that only a small portion of the noradrenaline content of an adrenergically-innervated organ is associated with the release of transmitter, for when this small ;store' is depleted, by agents like bretylium, the nerves fail to function.

The antagonism of adrenergic neurone blockade by amphetamine and dexamphetamine in the rat and guinea-pig.

1. In isolated rat mesentery preparations, intra-arterial injection of the following drugs rapidly suppressed vasoconstrictor responses to sympathetic nerve stimulation: bretylium (75-100 mug), guanethidine (10-20 mug) and bethanidine (20-30 mug); with phenoxypropylguanidine (15-30 mug) the onset of blockade was slower. The blockade caused by these or higher concentrations was rapidly abolished by intra-arterial injection of amphetamine (100 mug) as also was the blockade caused by infusing bretylium or guanethidine for 10-20 min. Partial blockade was produced by 20 mug of reserpine and this was only slightly and briefly antagonized by amphetamine.2. In mesentery preparations taken from rats 24 h after subcutaneous injection of bretylium 50 mg/kg, guanethidine 10 mg/kg, phenoxypropylguanidine 10 mg/kg or reserpine 0.1 mg/kg, responses to sympathetic nerve stimulation were greatly impaired. Only in the preparations from the bretylium-treated rats did amphetamine antagonize the blockade. The adrenergic neurone blocking effect of bethanidine 10 mg/kg was evident at 12 h but not at 24 h after injection.3. In rat mesentery amphetamine did not cause vasoconstriction but briefly potentiated the vasoconstrictor effect of sympathetic nerve stimulation. Responses to noradrenaline were not importantly affected.4. The contractile responses of the rat inferior eyelid caused by stimulation of the cervical sympathetic nerve was greatly reduced 17-27 h after subcutaneous injection of bretylium 300 mg/kg, bethanidine 30 mg/kg, guanethidine 10 mg/kg or reserpine 0.3 mg/kg. Intravenous dexamphetamine (0.5 mg/kg) powerfully antagonized the effect of bretylium, weakly antagonized the blockade by bethanidine and guanethidine and caused no change in the response of reserpine-treated animals.5. The vas deferens taken from guinea-pigs 24 h after subcutaneous injection of either bretylium or guanethidine showed greatly impaired responses to hypogastric nerve stimulation. Amphetamine largely restored the contractile response in bretylium-treated rats but caused only weak antagonism in the guanethidine-treated animals.

Antifibrillatory action of bretylium: role of the sympathetic nervous system.

This study was performed to assess the role of cardiac sympathetic nerves in the in vivo antifibrillatory action of bretylium using the technique of electrically induced ventricular fibrillation. An initial study determined that 3 mg/kg of nortriptyline, an adrenergic amine uptake inhibitor, was sufficient to prevent the adrenergic neuron blockade produced by 5 mg/kg of bretylium in pentobarbital anesthetized dogs. Electrical ventricular fibrillation threshold (VFT) was then determined in two groups of pentobarbital anesthetized dogs using gated trains of increasing current applied to the epicardial surface of the right ventricle during atrial pacing. After determination of an initial VFT in both groups, one group of dogs (n = 8) received 3 mg/kg nortriptyline, the other group received saline (n = 9). The VFT was redetermined in both groups, after which all dogs received 5 mg/kg of bretylium, intravenously, and VFT was then measured at 15 and 90 min after bretylium. In saline-treated dogs, bretylium produced a significant increase in VFT from a control value of 6.9 +/- 1.6 mA (mean +/- SEM) to 31.0 +/- 0.5 mA at 15 min (p less than 0.05) and 45.1 +/- 4.8 mA at 90 min (p less than 0.05). In nortriptyline-treated dogs, however, nortriptyline itself produced an increase in VFT which was reversed by bretylium, and VFT after bretylium was not significantly elevated until 90 min to a value of 25.2 +/- 9.6 mA (control: 5.2 +/- 0.9 mA). These data demonstrate that pretreatment with nortriptyline attenuates and delays the onset of the acute antifibrillatory effect of bretylium and suggests a role for the cardiac adrenergic neuron as a potential target for part of the beneficial effects to be derived from antifibrillatory drugs.