Vagal M3 bronchoconstriction and autonomic control of the airways
The vagus nerve narrows human airways through M3 receptors, a subtype of acetylcholine receptor, while circulating adrenaline widens them through beta2 receptors.
Remember
In human airways the vagus constricts through acetylcholine at M3 receptors, and circulating adrenaline dilates through beta2 receptors. In COPD, muscarinic antagonists are often more effective than beta2 agonists because they block the dominant vagal constrictor tone.
Memory aid
the vagus squeezes the airways, adrenaline opens them
Use it to keep the direction of each signal straight: the vagus narrows the airways and circulating adrenaline widens them.
Two opposing inputs set the width of the airways in humans. The first is the vagus nerve, the main parasympathetic nerve to the chest. The parasympathetic nervous system is the branch of the autonomic (involuntary) nervous system that slows and conserves. The vagus releases acetylcholine, which acts on M3 muscarinic receptors on bronchial smooth muscle (the airway muscle). That causes bronchoconstriction (narrowing of the airway).
This vagal signal is the dominant tonic input, meaning a steady background tone, present even in healthy lungs.
The opposing signal opens the airways. Circulating adrenaline, carried in the blood, acts on beta2 receptors on the same muscle and relaxes it. Human airway smooth muscle has little, if any, direct sympathetic nerve supply, so the dilating signal comes mainly from adrenaline travelling in the blood.
That explains the drugs. A muscarinic antagonist (a drug that blocks muscarinic receptors), such as ipratropium (short-acting) or tiotropium (long-acting), blocks M3 receptors so that acetylcholine cannot bind and the muscle relaxes. A beta2 agonist such as salbutamol copies adrenaline to relax the muscle instead. The two classes add together because they work through different pathways: one removes the constricting signal and the other adds a dilating one.
In COPD (chronic obstructive pulmonary disease, long-term airway and lung damage most often caused by smoking) much of the narrowing is fixed by structural damage, but a substantial reversible part comes from vagal tone. The bronchoconstriction has a substantial parasympathetic component, so muscarinic antagonists are often more effective than beta2 agonists.
Key facts
- Vagal signal
- the vagus nerve releases acetylcholine, which acts on M3 muscarinic receptors on bronchial smooth muscle to cause bronchoconstriction
- Dilating signal
- circulating adrenaline acts on beta2 receptors to relax bronchial smooth muscle
- Nerve supply
- human airway smooth muscle has little, if any, direct sympathetic nerve supply, so the dilating signal comes mainly from adrenaline travelling in the blood
- Beta1 receptors
- they act mainly in the heart, not the airways
- COPD
- the bronchoconstriction has a substantial parasympathetic component, so muscarinic antagonists are often more effective than beta2 agonists
- Short and long acting
- ipratropium is an example of a short-acting muscarinic antagonist and tiotropium an example of a long-acting one
- M2 receptors
- on the vagal nerve endings they act as a brake that limits further acetylcholine release, so the M3 receptors on the smooth muscle are the ones to block
Exam traps
- Vagal stimulation does not cause bronchodilation. M3 receptors are the constrictor receptors on airway muscle, so vagal stimulation causes bronchoconstriction, and claiming that it causes bronchodilation reverses the direction of the effect.
- Sympathetic nerves supply the airways of some other species, but in human airways they play little if any role in directly controlling smooth muscle tone, and the dilating signal comes mainly from circulating adrenaline.
- Blocking M2 receptors on nerve endings does not counteract the constrictor signal, because M2 receptors act as a brake that reduces acetylcholine release, and removing the brake can increase release.
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