The Blocking Action of Choline 2:6‐xylyl Ether Bromide on Adrenergic Nerves

Abstract

Choline 2:6‐xylyl ether bromide (TM 10), given systemically to cats in doses of 5 to 15 mg./kg., abolishes the effects of adrenergic nerve stimulation whilst leaving the reactions of the effector organs to adrenaline unimpaired. The effects of a single dose may take up to one hour to become fully established and last for more than twenty‐four hours. Apart from transitory ganglionic blockade, cholinergic autonomic nerves are unaffected even by large doses of TM 10. Doses of TM 10 which produce effective blockade do not impair conduction along adrenergic nerve trunks; the drug must, therefore, act at, or close to, the nerve terminals. TM 10 prevents the output of noradrenaline from the spleen on stimulating the splenic nerves; but, in acute experiments, it does not influence the liberation of pressor amines from the stimulated suprarenals. Examination of some ethers related to TM 10 revealed no correlation between TM 10‐like adrenergic blocking activity and local anaesthetic activity. The action of TM 10 on adrenergic nerves does not, therefore, seem to be accounted for by axonal block.

The Identification of the Impurity Responsible for the Reported Pressor Activity of Xylocholine

“…A higher association rate constant for the o-tolyl compound is necessary on the basis of both Paton's rate theory (Paton, 1961) and the " occupation" theory of drug action, since by the former theory the faster rate is inherent in the stimulant action and by the occupation theory a sufficient proportion of the receptors must be occupied by the agonist to produce stimulation before blockade can develop by interaction with the more slowly associating and dissociating antagonist. Recovery of the sympathetic ganglia from the blockade produced by xylocholine appears to be virtually complete after 20 min (Exley, 1957), and this is confirmed by the observed response to the administration of o-tolyl choline ether bromide alone. It is clear, however, that the ganglia have not returned to normal, since if the number of receptors available for association with the two choline aryl ethers was the same as it was before the first administration of the drug mixture, a second dose would elicit the same response as the first, no alteration in the ratio of the concentrations of the two drugs in the biophase being a necessary consequence of similar distributions of the two drugs.…”

An Investigation of the Action of Tyramine and Its Interrelationship With the Effects of Other Sympathomimetic Amines

“…It is unlikely that choline 2,6-xylyl ether potentiates the action of tyramine by releasing noradrenaline, and so adding to the effect of tyramine in this respect, because it does not affect noradrenaline responses. Furthermore, neither Exley (1957) Strong circumstantial evidence for the view that the response to tyramine is mediated by the release of noradrenaline was provided by the observations of Rand (1958a and that an infusion of noradrenaline or its precursors would restore the diminished pressor activity of tyramine in the spinal cat whose tissue catechol amines had been depleted by chronic reserpine treatment. This led them to suggest that the catechol amines replenished the tissue stores of noradrenaline, thus increasing the potential for release.…”

STUDIES ON THE ANTAGONISM BETWEEN THE OPTICAL ISOMERS OF N‐(1‐PHENYLETHYL)GUANIDINE

“…The precise mode of action of adrenergic-neurone blocking drugs is not yet fully known, but in some way, or ways, they inhibit the release of noradrenaline from the nerve endings during nerve stimulation by an action at, or close to, the nerve terminal (Exley, 1957;Boura & Green, 1959;Hertting, Axelrod & Patrick, 1962;. The ability of ( +)-N-(l-phenylethyl)guanidine to reverse a well-established adrenergic-nerve block suggests that it cannot be acting by stopping the uptake of the blocking drug, but probably displaces it from the site at the nerve terminal at which it acts.…”