Autonomic nervous system: anatomy, receptors and physiological effects

At a glance

• Two efferent divisions. Sympathetic outflow is thoracolumbar (T1 to L2) with short preganglionic fibres to the paravertebral chain. Parasympathetic outflow is craniosacral (cranial nerves III, VII, IX, X and S2 to S4) with long preganglionic fibres to ganglia near the organ.
• All preganglionic neurons release ACh onto nicotinic (N_N) receptors. Parasympathetic postganglionic neurons release ACh onto muscarinic receptors. Sympathetic postganglionic neurons release noradrenaline, with two exceptions: sweat glands (ACh, muscarinic) and the adrenal medulla (no postganglionic neuron).
• Most organs have dual, opposing control. Blood vessels are the main exception: almost all are controlled by sympathetic tone alone.
• Paper 1 tests receptor-level explanations of drug effects, toxidromes and bedside autonomic signs. Clinical disorders are in autonomic dysfunction.

Receptors

Receptor	G protein	Main effects
Alpha-1	Gq	Arteriolar and venous constriction; pupil dilation (radial muscle); bladder neck and prostate contraction; pilomotor
Alpha-2	Gi	Presynaptic inhibition of noradrenaline release; central fall in sympathetic outflow; less insulin release
Beta-1	Gs	Higher heart rate, contractility and AV conduction; renin release from juxtaglomerular cells
Beta-2	Gs	Bronchodilation; vasodilation in skeletal muscle; uterine relaxation; glycogenolysis; K⁺ shift into cells; tremor
Beta-3	Gs	Detrusor relaxation; lipolysis
M2	Gi	Slower SA node firing and AV conduction
M3	Gq	Gland secretion; bronchoconstriction; detrusor contraction; pupil constriction (sphincter) and accommodation (ciliary muscle); endothelial nitric oxide release (vasodilation)
N_N	Ion channel	Transmission at all autonomic ganglia and the adrenal medulla

Organ effects

Organ	Sympathetic	Parasympathetic
Heart	Beta-1: rate, force, conduction up	M2 (vagus): rate and AV conduction down
Pupil	Alpha-1: mydriasis	M3 (III nerve): miosis, near accommodation
Airways	Beta-2 (circulating adrenaline): bronchodilation	M3 (vagus): bronchoconstriction, mucus
Gut	Alpha and beta: less motility, sphincters contract	M3: motility and secretion up, sphincters relax
Bladder	Beta-3: detrusor relaxes; alpha-1: outlet contracts (storage)	M3: detrusor contracts (voiding)
Male sexual function	Ejaculation	Erection (nitric oxide)
Sweat glands	M3 (sympathetic cholinergic)	None
Liver and fat	Glycogenolysis, gluconeogenesis, lipolysis	None

Reflex control of blood pressure

Stretch receptors in the carotid sinus (afferents in IX) and aortic arch (afferents in X) fire faster as pressure rises. The nucleus tractus solitarius increases vagal output to the heart and inhibits the rostral ventrolateral medulla, so sympathetic tone to heart and vessels falls. On standing, about 500 to 800 mL of blood pools below the heart. Baroreceptors unload, sympathetic outflow rises, heart rate climbs 10 to 20/min and vessels constrict.

• Neurogenic orthostatic hypotension (failure of the efferent sympathetic limb): fall of at least 20 mmHg systolic or 10 mmHg diastolic within 3 minutes of standing, with an inadequate heart rate rise. A ratio of heart rate rise to systolic fall below 0.5 beats/min per mmHg suggests a neurogenic cause (orthostatic hypotension).
• Valsalva manoeuvre: phase II pressure recovery and phase IV overshoot need intact sympathetic vasoconstriction; the heart rate changes test vagal function.
• Deep breathing heart rate variation (sinus arrhythmia) tests cardiovagal function and is lost early in diabetic autonomic neuropathy.

Worked examples

The transplanted heart. The denervated SA node fires at its intrinsic rate, about 90 to 110/min (lower with age). In a healthy person at rest, vagal tone holds the rate near 70/min, which is why full-dose atropine raises it. After transplantation the heart is denervated:

Test	Innervated heart	Transplanted heart
Resting rate	60 to 80/min	90 to 110/min
Atropine	Rate rises	No change
Carotid sinus massage	Rate falls	No change
Exercise	Prompt rise	Delayed rise, driven by circulating catecholamines
Adenosine	Normal response	Exaggerated; reduce the dose

Adrenaline at different doses. Adrenaline has higher beta-2 affinity than alpha-1. At low infusion rates, beta-2 vasodilation in muscle lowers diastolic pressure while beta-1 raises heart rate and systolic pressure. At higher doses alpha-1 vasoconstriction dominates. Intramuscular adrenaline in anaphylaxis (0.01 mg/kg, maximum 0.5 mg in adults) works through alpha-1 (vasoconstriction, less mucosal oedema), beta-1 and beta-2 (bronchodilation, less mast cell mediator release) (adrenaline pharmacology).

Beta-blocker in a patient on insulin. Non-selective blockade blunts beta-2 glycogenolysis and the adrenergic warning symptoms of hypoglycaemia (tremor, palpitations). Sweating persists because it is cholinergic (hypoglycaemia).

How it's tested

• Toxidromes: muscarinic blockade gives hot, dry, flushed skin, mydriasis, tachycardia and urinary retention (anticholinergic toxidrome); cholinesterase inhibition gives the opposite plus nicotinic weakness.
• Horner syndrome: a three-neuron sympathetic path (hypothalamus to C8 to T2, to the superior cervical ganglion, along the internal carotid artery). Ptosis comes from loss of sympathetic tone to Müller muscle (Horner syndrome).
• Receptor-selective drugs: beta-blockers, bronchodilators, tamsulosin, mirabegron, clonidine.
• Hyperkalaemia treatment: salbutamol drives potassium into cells (hyperkalaemia).
• Autonomic dysreflexia: after spinal cord injury above T6, a stimulus below the lesion (full bladder) triggers unchecked sympathetic vasoconstriction, while the baroreflex can only respond with bradycardia and flushing above the lesion.

Pitfalls

• Vasodilation from muscarinic agonists comes from endothelial M3 receptors and nitric oxide, not from parasympathetic nerves to vessels.
• Atropine first causes a paradoxical slowing at very low doses (central vagal stimulation or presynaptic M1 block). Give at least 0.5 mg in adults.
• Cardioselectivity of beta-1 blockers is relative and is lost at higher doses.
• Beta-3 agonists can raise blood pressure; check it after starting mirabegron.
• Postural tachycardia syndrome is a heart rate rise of at least 30/min within 10 minutes of standing without orthostatic hypotension, which is the opposite pattern to neurogenic orthostatic hypotension.