Adrenergic Neurone-blocking Agents related to Choline 2,6-Xylyl Ether Bromide (TM 10), Bretylium and Guanethidine

Abstract

SEVERAL compounds have been shown to block transmission at peripheral adrenergic nerve terminals without antagonizing the effects of adrenaline and noradrenaline. They include the quaternary ammonium salts choline 2,6-xylyl-ether bromide (TM 10) (I)^1–2, bretylium (III)^3,4, and related substances^3,5–7. The two compounds named have been shown to act by preventing the release of the adrenergic transmitters at the nerve endings^4,5. Guanethidine (IV) also blocks peripheral adrenergic mechanisms. Its action, like that of reserpine but in contrast to that of bretylium⁸, is associated with marked depletion of peripheral stores of catechol amines^9,10. This depletion is accompanied by depression of the sympathomimetic responses to tyramine and amphetamine¹¹, which apparently act by releasing peripheral catechol amines¹². Responses to tyramine and amphetamine are also affected by bretylium; but only when the drug has been administered for several weeks does the degree of depression equal that seen 24 hr. after guanethidine^13,14. Whether the depletion of catechol amines is responsible for the adrenergic nerve blockade caused by either drug is uncertain. Depression of the responses of the nictitating membranes of cats to sympathetic nerve stimulation follows rapidly after intravenous injection of guanethidine, but depression of equivalent responses to tyramine is slight at this time and becomes prominent only after several hours¹⁴. Similarly, the depletion of catechol amines by guanethidine¹⁰ is relatively slow in onset.