The Actions of Bretylium: Adrenergic Neurone Blocking and Other Effects

Abstract

Bretylium caused a specific and lasting depression of many excitatory and inhibitory responses evoked by electrical stimulation of the peripheral sympathetic nervous system, probably by impairing conduction of impulses in adrenergic neurones with consequent failure of noradrenaline and adrenaline release. This effect, which will be referred to as the adrenergic neurone blocking action, was preceded by weak sympathomimetic effects. In the presence of bretylium the effects of adrenaline and noradrenaline were increased, as after sympathectomy. Concentrations producing blocking of adrenergic neurones did not prevent the release of adrenaline and noradrenaline from the adrenal medulla by splanchnic nerve stimulation or by the injection of dimethylphenylpiperazinium iodide, nor did they cause antiparasympathetic or parasympathomimetic effects. No action on the central nervous system has been detected. Curare-like neuromuscular block occurred with 10 to 30 times the amount required to block the response to adrenergic nerve stimulation alone and was accompanied by signs of temporary synaptic block in autonomic ganglia. A drenergic nerve trunks and sensory nerves in the skin were readily blocked for long periods by topical application of bretylium, whereas the phrenic nerve of the rat was not. Bretylium had little effect on gastrointestinal propulsion or on the sensitivity of smooth muscle to acetylcholine, 5-hydroxytryptamine, adrenaline, or noradrenaline, but moderate amounts depressed the peristaltic reflex and the sensitivity of the guinea-pig ileum to histamine. Bretylium caused postural hypotension in the cat in doses which had little effect on the supine blood pressure. Experiments on the nictitating membrane indicated that compensation for the effects of bretylium on low rates of stimulation of postganglionic sympathetic nerves could be attained by a small increase in the rate of stimulation, whereas compensation for its effects on high rates required an increase in the rate of stimulation beyond physiological limits.

Effects of the Adrenergic Drugs on the Chrono- And Inotropic Responses to the Cholinergic Stimulation of the Isolated Guinea-Pig’s Atria

“…It has been reported that betylium inhibits the atrial responses to the sympathetic as well as vagal stimulation (25). On the other hand, no effect of bretylium on the parasympa thetic nervous system and on the responses of the rabbit's intestine to acetylcholine has been reported elsewhere (27). The depressant effect of bretylium on the negative responses of the atria to cholinergic stimulation may partly be due to the blocking effect of bretylium on the endogenous noradrenaline, supposedly regulating the choli nergic transmission mechanism in the isolated heart, and partly to the decrease in sensitivity of the atria to endogenously released acetylcholine.…”

Action of Tyramine on the Salivary Amylase Secretion From Rabbit Parotid Gland in Reference to That of Nicotine

“…It may be considered that as well as nicotine, the effect of tyramine on amylase secretion is mediated through catecholamine in adrenergic receptor level. The stimulating effect of bretylium on amylase secretion, similar to its sympa thomimetic effects in various organs, may be sympathomimetic one, which is mainly at tributable to a peripheral release of catecholamines from adrenergic tissues (12). After pretreatment with bretylium, the increases in amylase secretion and flow rate produced by sympathetic nerve stimulation were remarkably inhibited, but the increases in amylase secretion produced by noradrenaline, tyramine and nicotine were not.…”

PHARMACOLOGICAL STUDIES OF XYLOPININE, 2,3,10,11-TETRAMETHOXY-5,6-13,13a-TETRAHYDRO-8-DIBENZO (a-g) QUINOLIZINE, SEMISYNTHESIZED FROM PHELLODENDRINE ISOLATED FROM PHELLODENDRON AMURENSE RUPR.

“…But the question remains to be settled whether xylopinine releases serotonin in various tissues including the central nervous system or depresses the release of nor adrenaline from the adrenergic nerve terminal as bretylium (36).…”