ATROPINE‐RESISTANT EFFECTS OF THE MUSCARINIC AGONISTS McN‐A‐343 AND AHR 602 ON CARDIAC PERFORMANCE AND THE RELEASE OF NORADRENALINE FROM SYMPATHETIC NERVES OF THE PERFUSED RABBIT HEART

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Abstract
The effects of 4‐(m‐chlorophenylcarbamoyloxy)‐2‐butynyltrimethylammonium chloride (McN‐A‐343) and N‐benzyl‐3‐pyrrolidyl acetate methobromide (AHR 602) on cardiac performance and noradrenaline release from terminal sympathetic fibres were measured in isolated perfused hearts of rabbits. In the presence of sufficient atropine to block muscarinic receptors, high concentrations of McN‐A‐343 and AHR 602 caused no cardiac stimulation and there was no increase in the resting output of noradrenaline into the perfusates. McN‐A‐343 and AHR 602 increased both the mechanical responses and the transmitter overflow evoked by electrical stimulation of the sympathetic nerves (SNS) but inhibited both parameters during perfusion with 1,1‐dimethyl‐4‐phenylpiperazinium (DMPP). The effects were atropine‐resistant and qualitatively similar to those seen with cocaine. Hexamethonium inhibited DMPP, but affected neither SNS per se nor the facilitatory effects of McN‐A‐343 and AHR 602 on SNS. McN‐A‐343, cocaine and desipramine (but not AHR 602 or hexamethonium) blocked the net cardiac noradrenaline uptake and increased the positive chronotropic effect of noradrenaline. Prior perfusion with concentrations of cocaine and desipramine sufficient to block uptake reduced or abolished the facilitatory effects of both McN‐A‐343 and AHR 602 on SNS. Cocaine, McN‐A‐343 and AHR 602 displayed local anaesthetic properties on the guinea‐pig wheal and frog nerve plexus tests, and their relative potencies in this respect were similar to those for inhibition of DMPP‐evoked transmitter overflow. Hexamethonium did not produce local anaesthesia. The results indicate that the facilitated release of noradrenaline after SNS and the inhibition of release after DMPP produced by McN‐A‐343 and AHR 602 are the result of their combined local anaesthetic action and inhibition of amine uptake.

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