The effects of bretylium on C fibre excitation and noradrenaline release by acetylcholine and electrical stimulation.

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1. The effects of bretylium on the excitation of postganglionic adrenergic C fibres by acetylcholine and the release of noradrenaline by acetylcholine and electrical stimulation of the splenic nerves have been studied using the in situ and cross perfused cat spleen.2. Close arterial injections of acetylcholine (10-200 mug) evoked a brisk asynchronous discharge in fine filaments of the splenic nerve which reduced the height of the orthodromic C fibre compound action potential.3. Hexamethonium abolished both the excitation of C fibres and release of noradrenaline by acetylcholine, whereas the liberation of noradrenaline by electrical stimulation of the splenic nerves remained unchanged.4. Bretylium (0.5 and 1.0 mg) given close arterially blocked the output of noradrenaline and contractions of the spleen that occurred in response to nerve stimulation (30 c/s) but had much less effect on the responses to acetylcholine.5. Bretylium (2-4 mg) given close arterially blocked the output of noradrenaline and contractions of the spleen caused by both nerve stimulation (30 c/s) and acetylcholine.6. The close arterial injection of (+)-amphetamine sulphate (100 mug) after bretylium (2-4 mg) partially restored the output of noradrenaline and contractions of the spleen to both nerve stimulation and acetylcholine.7. The difference in the sensitivity to blockade by bretylium of the effects of nerve stimulation and the sympathomimetic effects of acetylcholine did not exist if the more "physiological" frequency of stimulation of 10 c/s was employed.8. The close arterial injection of acetylcholine (100 mug) caused a mean average fibre discharge frequency of 5.4 spikes/sec.9. Bretylium in amounts sufficient to completely block the sympathomimetic effects of acetylcholine did not alter the excitation of C fibres by acetylcholine.10. The significance of these results is discussed both in relation to the mode of action of bretylium and to the use of these differential effects of bretylium as evidence for the "cholinergic link" hypothesis.