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Acetylcholine - Effects

Acetylcholine has muscarinic and nicotinic effects by stimulation of the corresponding receptors.

Muscarinic effects

Muscarinic effects thus called because they resemble those of muscarine, compound extracted from a mushroom, and result from stimulation of muscarinic receptors.

There are several types of muscarinic receptors M1, M2, M3, M4 and M5, coupled to G proteins. Schematically, M1 and M3 receptors are coupled to phospholipase C which induces a rise of inositol-triphosphate, IP3, diacylglycerol, DAG, and of Ca2+; M2 receptors are coupled to K+ channels and to adenylcyclase whose activity they reduce.

Endogenous acetylcholine has peripheral muscarinic effects, the best known, and central ones. Muscarinic effects are inhibited by atropine.

Cardiac effects

The cholinergic innervation of auricles is much more important than that of the myocardium. An injection of acetylcholine or the stimulation of the parasympathetic induces:

• Bradycardia, even transitory discontinuation of heart beats (vagal escape) by sinus effect.
• decrease of atrioventricular conduction.
• decrease of the strength of atrium contractions.
• Cardiac slowing is explained at least partly by cellular hyperpolarisation resulting from opening of potassium channels linked to the G proteins and potassium exit out of the cell, inducing an increase in polarization. The decrease of the force of contraction comes from a decrease of Ca2+ entry in the cell, probably by inhibition of adenylcyclase.

Intravenous injection of very low doses of acetylcholine in animals or in human beings causes immediate and fugacious fall of the arterial pressure resulting from cardiac slowing and vasodilation.

Vascular effects

Vessels have muscarinic receptors but do not receive cholinergic innervation

Acetylcholine injection induces an arteriolar vasodilation by release by the endothelium of a vasodilator compound, called initially EDRF (endothelium derived relaxing Factor) then identified as nitric oxyde, NO.

The paradoxical vasoconstriction induced by acetylcholine on coronary vessels presenting atherosclerotic lesions is explained by absence of EDRF release by damaged or absent endothelial cells and direct stimulation of the smooth muscles.

Effects on smooth muscles (except vascular)

By stimulation of phospholipase C, acetylcholine elicits:

• intestine: an increase in tone with sometimes an increase in the peristaltic contractions. Nausea and vomiting testify to this stimulative action.
• ureters: increase in tone.
• bronchi: bronchoconstriction. An aerosol of acetylcholine can cause an attack of asthma.

Effects on secretions (receptors m3)

Acetylcholine increases, by activation of C phospholipase, digestive (abundant saliva), bronchial, cutaneous (sweat) and lacrimal secretions.

Effects on the eye (receptors m3)

Acetylcholine induces a decrease of iris diameter or miosis, which facilitates the flow of aqueous humor and tends to lower the intra-ocular pressure.

Central effects

Muscarinic effects in the central nervous system are complex and not well characterized. According to conditions, the stimulation of the post-synaptic muscarinic receptors elicits a depolarization or an hyperpolarisation. In animals, their stimulation induces facilitation of training but also hypothermia, tremors, seizures.

Nicotinic effects

The nicotinic effects of acetylcholine resemble those of nicotine and result from activation of acetylcholine nicotinic receptors, receptor-channels, which, in an activated state, let sodium and calcium enter into cells, thus creating a depolarization.

Nicotinic receptor- channels are members of the ligand-gated ion-channel family, also called ionotropic receptors. Nicotinic receptors have a pentameric structure forming a central channel which can be open or closed and are activated by acetylcholine. Two molecules of acetylcholine are needed for activation of one receptor and opening the channel. They have a fast response.

However, nicotinic receptors are not strictly identical in ganglia of the autonomic nervous system, in the neuromuscular junction and in brain. One distinguishes those which are inhibited by bungarotoxin A, polypeptide extracted from a snake venom and those which are not . But their way of operating is similar, leading to a depolarization mainly by sodium entry in the cell.

Acetylcholine, by its nicotinic effects, is responsible for synaptic transmission. The principal steps of synaptic transmission are represented as follows.

Autonomic ganglia effects

Acetylcholine is responsible of transmission in the autonomic nervous system. The presynaptic nerve releases acetylcholine which, by activating nicotinic receptors, induces a depolarization at the origin of a new impulse in the postsynaptic nerve. This ganglionic stimulation elicits in its turn a release of acetylcholine by the parasympathetic terminations and noradrenaline by the adrenergic terminations.

Neuromuscular junction effects

The stimulation of nicotinic receptors by acetylcholine is responsible of neuromuscular transmission.

In the vicinity of the muscle, the motor nerve covered with its myelin sheath is divided into a bouquet of final branches deprived of myelin. These final branches are very rich in mitochondria and small synaptic vesicles (300 to 500 Å) containing acetylcholine.

The stimulation of the motor nerve induces acetylcholine release in the synaptic cleft of the neuromuscular junction. On the other hand direct stimulation of the muscle, even if it causes contractions, does not induce acetylcholine release.

Acetylcholine acts selectively on the neuromuscular junction:

• applied to the junction, in low quantity acetylcholine elicits a muscular contraction, in large quantity acetylcholine can inhibit the muscular contractions resulting from the stimulation of the nerve.
• applied to the nerve or the muscle apart from the junction, it does not cause any effect.

The nerve action potential elicits a localized postjunctional depolarization called end-plate potential. When this depolarization reaches a sufficient threshold, it appears, by opening of the voltage-dependant cation channels, a postsynaptic potential appears which propagates in muscular fibers.

Notice

Myasthenia (Myasthenia gravis) results in a muscular weakness. It is generally an acquired disease, of immunological origin, due to damage of neuromuscular nicotinic receptors by antibodies. There are also forms of genetic origin, resulting from a defect of acetylcholine synthesis or release or from a damage to neuromuscular receptors.

Central nervous system effects

Stimulation of nicotinic receptors of the central nervous system induces, by opening of cation channels, a depolarization whose consequences are difficult to systematize.

The respective roles of muscarinic and nicotinic receptors in the central effects of acetylcholine are difficult to distinguish.

There is a brain cholinergic deficiency in Alzheimer disease and directly and indirectly acting cholinomimetic agents are used for its treatment.

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