A Muscarinic Mechanism Inhibiting the Release of Noradrenaline From Peripheral Adrenergic Nerve Fibres by Nicotinic Agents

The effects of cholinomimetic drugs on responses to sympathetic nerve stimulation and noradrenaline in the rabbit ear artery

“…Since methacholine is virtually devoid of nicotinic activity, and muscarine reduced the responses to sympathetic nerve stimulation, it is suggested that impairment of noradrenaline release may result from an action of cholinomimetic drugs on muscarinic receptors of terminal adrenergic neurones. Other evidence for such receptors has been advanced by Lindmar et al (1968), who found that acetylcholine reduced the amount of noradrenaline released by dimethylphenylpiperazinium from the isolated perfused rabbit heart, and by Haeusler et al (1968), who observed that atropine increased about 80-fold the amount of noradrenaline liberated from the isolated perfused cat heart by acetylcholine.…”

“…Since nicotine acted like acetylcholine in the experiments cited, and since the actions of acetylcholine were exhibited in the presence of atropine, these excitatory and inhibitory effects of acetylcholine were taken to be nicotinic. However, a muscarinic action of acetylcholine on noradrenergic axons has been demonstrated by Lindmar, Loffelholz & Muscholl (1968) and by Haeusler, Thoenen, Haefely & Huerlimann (1968). They showed, first, that acetylcholine, methacholine and pilocarpine caused a reduction in the amount of noradrenaline released from the perfused rabbit or cat heart by nicotine and dimethylphenylpiperazinium, and, second, that the inhibitory effects of these drugs on noradrenaline release were abolished by atropine.…”

Sixth Gaddum Memorial Lecture National Institute for Medical Research, Mill Hill, January 1977

“…As shown schematically in Figure 7, the following presynaptic receptors have been postulated: (a) muscarinic inhibitory cholinoceptors (Loffelholz and Muscholl, 1969;Steinsland, Furchgott & Kirpekar, 1973;Langer, Enero, Adler-Graschinsky, Dubocovich & Giorgi, 1976); (b) dopamine inhibitory receptors (Langer, 1973;Enero & Langer, 1975;Long, Heintz, Cannon & Kim, 1975); (c) opiate inhibitory receptors, which are activated by morphine and also by the naturally occurring pentapeptides met and leu-enkephalin (Hughes, Kosterlitz & Leslie, 1975 (Hedqvist, 1970;Stjmrne, 1973;Dubocovich & Langer, 1975;Hedqvist, 1976); (e) adenosine inhibitory receptors (Hedqvist & Fredholm, 1976); (f) angiotensin II facilitatory receptors (Starke, 1970(Starke, , 1971Hughes & Roth, 1971) and (g) nicotinic facilitatory receptors (Lindmar, Loffelholz & Muscholl, 1968;Loffelholz, 1970).…”

“…In addition, I had the privilege of working for two years with one of Gaddum's collaborators, Dr Marthe Vogt. The time spent with Dr Marthe Vogt in Babraham (1967 and1968) was a stimulating and rewarding experience. It was during these two years that my interest in noradrenaline release during nerve stimulation started and this has developed further during the last eight years.…”

Comparison of effects of six cholinomimetic drugs on inhibition of uptake of 3H‐(±)‐noradrenaline by guinea‐pig atria

“…The facilitation is produced by very low concentrations of acetylcholine (Malik & Ling, 1969a), and after termination of infusions of acetylcholine, methacholine, muscarine, carbachol and arecoline (Rand & Varma, 1970). During infusions of acetylcholine and methacholine in concentrations of about 01 to 5 ug/ml (ca 5X10-7 to 25X10-5M), responses of the artery are depressed, the effect probably being due to the muscarinic inhibition of noradrenaline release (Lindmar et al, 1968). However, with larger concentrations of acetylcholine and methacholine they tend to increase towards control levels (Rand & Varma, 1971); this effect may well be due to inhibition of re-uptake of noradrenaline, especially since responses to injected noradrenaline were considerably enhanced by such concentrations.…”