Selective depletion of noradrenaline: a proposed mechanism of the adrenergic neurone‐blocking action of bretylium

The effects of bretylium have been investigated on the content and sub-cellular distribution of noradrenaline in cat spleen and on the overflow of noradrenaline in response to stimulation of the splenic nerve.2. Bretylium, 15 min after its administration, produces a significant depletion of noradrenaline in only the supernatant fraction of an homogenate; at this time adrenergic neurone blockade is evident. This depletion of noradrenaline is apparent up to 18 h later but has disappeared 7 days after the administration of bretylium when nerve function is also restored.3. Both the development of the neurone blockade and the depletion of noradrenaline are prevented by previous administration of (+)-amphetamine.4. In bretylium-pretreated cats the noradrenaline content of the supernatant fraction is replenished and the neurone blockade is abolished after treatment with (+)-amphetamine.5. The depletion of noradrenaline, which is evident 30 min, 60 min and 18 h after treatment with bretylium, from other subcellular fractions-especially the high-speed particulate fraction-appears to be unassociated with adrenergic neurone blockade.6. It is concluded that bretylium produces its adrenergic neurone-blocking activity by depleting noradrenaline from a "store" whose amine appears in the supernatant fraction after homogenization. Whilst bretylium is present this "store" cannot refill with noradrenaline.