Peripheral muscarinic control of norepinephrine release in the cardiovascular system

Abstract

Activation of muscarinic cholinergic receptors located at the terminal adrenergic nerve fiber inhibits the process of exocytotic norepinephrine (NE) release. This neuromodulatory effect of acetylcholine and related compounds has been discovered as a pharmacological phenomenon. Subsequently, evidence for a physiological role of the presynaptic muscarinic inhibition was obtained on organs known to be innervated by the autonomic ground plexus (Hillarp, Acta. Physiol. Scand. 46, Suppl. 157: 1-68, 1959) in which terminal adrenergic and cholinergic axons run side by side. Thus, in the heart electrical vagal stimulation inhibits the release of NE evoked by stimulation of sympathetic nerves, and this is reflected by a corresponding decrease in the postsynaptic adrenergic response. On the other hand, muscarinic antagonists such as atropine enhance the NE release evoked by field stimulation of tissues innervated by the autonomic ground plexus. The presynaptic muscarine receptor of adrenergic nerve terminals probably restricts the influx of calcium ions that triggers the release of NE. However, the sequence of events between recognition of the muscarinic compound by the receptor and the process of exocytosis still remains to be clarified.

Inhibition of the Pial Artery Constriction Induced by Sympathetic Stimulation by Local Microapplication of a Cholinomimetic Agent

“…However, considering that only high con centrations of carbachol and atropine were effec tive, it remains an open question whether the results are in favor of a physiologically or a pharmacologi cally relevant mechanism. This kind of inhibition differs from that reported on by Muscholl (1980), in which, for many organs, the receptor involved ap pears to be muscarinic.…”

“…First, we have demonstrated that the mus carinic action of carbachol at 10-5 M or 10-4 M was effectively blocked by the concentration of atropine present (10-7 M or 10-6 M). It seems reasonable to assume that prejunctional muscarinic receptors, if present, are similar to post junctional muscarinic re ceptors, as has been described by Muscholl (1980) for the rabbit heart. Second, the study by Edvinsson et al (1977) on isolated cat pial arteries showed that, after preincubation with tritiated norepinephrine, the amount of radioactivity released during field stimu lation of the perivascular sympathetic nerves was reduced in the presence of nicotine or acetyl choline-this reduction being antagonized by addition of hexamethonium but not by addition of atropine.…”

Muscarinic receptor modulation of basal and beta-adrenergic stimulated function of the failing human left ventricle.

“…This may be relevant in the setting of heart failure, where G i activity is increased (5,(15)(16)(17)(18). The effects of acetylcholine may have been secondary to stimulation of inhibitory muscarinic receptors on adrenergic nerve terminals (6,26). This mechanism may be particularly relevant in heart failure, since prejunctional modulation of norepinephrine release is most pronounced in the setting of increased sympathetic nerve firing rate (26), as occurs in heart failure (27).…”

“…The effects of acetylcholine may have been secondary to stimulation of inhibitory muscarinic receptors on adrenergic nerve terminals (6,26). This mechanism may be particularly relevant in heart failure, since prejunctional modulation of norepinephrine release is most pronounced in the setting of increased sympathetic nerve firing rate (26), as occurs in heart failure (27). Another potential mechanism relates to cardiac production of cGMP in response to muscarinic stimulation, possibly related to increased nitric oxide activity (8).…”

Neuro-cardiac interaction in malignant ventricular arrhythmia and sudden cardiac death

“…At the cellular level, interaction between sympathetic and vagal nerves can occur via pre-and / or post-junctional mechanisms. As an example, for effects of vagal activity on sympathetic stimulation, acetylcholine binds to muscarinic acetylcholine receptors (mAChRs), primarily the m3 subtype present on the pre-synpatic sympathetic nerve terminals to inhibit noradrenaline release and principally the m2 subtype on cardiac myocytes to modulate intracellular cAMP at a number of stages (Muscholl 1980). …”