rate and force are increased; blood pressure rises (more blood for increased activity of skeletal muscles – running!).
4 Vasoconstriction in skin and viscera and vasodilatation in skeletal muscles (appropriate redistribution of blood to muscles).
5 To provide extra energy, glycogenolysis is stimulated and the blood glucose level increases. The gastrointestinal tract and urinary bladder relax.
Adrenoceptors
These are divided into two main types: α‐receptors mediate the excitatory effects of sympathomimetic amines, whereas their inhibitory effects are generally mediated by β‐receptors (exceptions are the smooth muscle of the gut, for which α‐stimulation is inhibitory, and the heart, for which β‐stimulation is excitatory). Responses mediated by α‐ and β‐receptors can be distinguished by: (i) phentolamine and propranolol, which selectively block α‐ and β‐receptors, respectively; and (ii) the relative potencies, on different tissues, of norepinephrine (NE), epinephrine (E) and isoprenaline (I). The order of potency is NE > E > I where excitatory (α) responses are examined, but for inhibitory (β) responses this order is reversed (I >> E > NE).
β‐Adrenoceptors are not homogeneous. For example, norepinephrine is an effective stimulant of cardiac β‐receptors, but has little or no action on the β‐receptors mediating vasodilatation. On the basis of the type of differential sensitivity they exhibit to drugs, β‐receptors are divided into two types: β1 (heart, intestinal smooth muscle) and β2 (bronchial, vascular and uterine smooth muscle).
α‐Adrenoceptors are divided into two classes, originally depending on whether their location is postsynaptic (α1) or presynaptic (α2). Stimulation of the presynaptic α2‐receptors by synaptically released norepinephrine reduces further transmitter release (negative feedback). Postsynaptic α2‐receptors occur in a few tissues, e.g. brain, vascular smooth muscle (but mainly α1).
Acetylcholine
Acetylcholine is the transmitter substance released by the following:
1 All preganglionic autonomic nerves (i.e. both sympathetic and parasympathetic).
2 Postganglionic parasympathetic nerves.
3 Some postganglionic sympathetic nerves (i.e. thermoregulatory sweat glands and skeletal muscle vasodilator fibres).
4 Nerve to the adrenal medulla.
5 Somatic motor nerves to skeletal muscle endplates (Chapter 6).
6 Some neurones in the central nervous system (Chapter 22).
Acetylcholine receptors (cholinoceptors)
These are divided into nicotinic and muscarinic subtypes (originally determined by measuring the sensitivity of various tissues to the drugs nicotine and muscarine, respectively).
Muscarinic receptors
Acetylcholine released at the nerve terminals of postganglionic para‐sympathetic fibres acts on muscarinic receptors and can be blocked selectively by atropine. Five subtypes of muscarinic receptor exist, three of which have been well characterized: M1, M2 and M3. M1‐receptors occur in the brain and gastric parietal cells, M2‐receptors in the heart and M3‐receptors in smooth muscle and glands. Except for pirenzepine, which selectively blocks M1‐receptors (Chapter 12), clinically useful muscarinic agonists and antagonists show little or no selectivity for the different subtypes of muscarinic receptor.
Nicotinic receptors
These occur in autonomic ganglia and in the adrenal medulla, where the effects of acetylcholine (or nicotine) can be blocked selectively with hexamethonium. The nicotinic receptors at the skeletal muscle neuromuscular junction are not blocked by hexamethonium, but are blocked by tubocurarine. Thus, receptors at ganglia and neuromuscular junctions are different, although both types are stimulated by nicotine and therefore called nicotinic.
Actions of acetylcholine
Muscarinic effects are mainly parasympathomimetic (except sweating and vasodilatation), and in general are the opposite of those caused by sympathetic stimulation. Muscarinic effects include: constriction of the pupil, accommodation for near vision (Chapter 10), profuse watery salivation, bronchiolar constriction, bronchosecretion, hypotension (as a result of bradycardia and vasodilatation), an increase in gastro‐intestinal motility and secretion, contraction of the urinary bladder and sweating.
Nicotinic effects include stimulation of all autonomic ganglia. However, the action of acetylcholine on ganglia is relatively weak compared with its effect on muscarinic receptors, and so parasympathetic effects predominate. The nicotinic actions of acetylcholine on the sympathetic system can be demonstrated, for example, on cat blood pressure, by blocking its muscarinic actions with atropine. High intravenous doses of acetylcholine then cause a rise in blood pressure, because stimulation of the sympathetic ganglia and adrenal medulla now results in vasoconstriction and tachycardia.
8 Autonomic drugs acting at cholinergic synapses
Acetylcholine released from the terminals of postganglionic parasympathetic nerves (left,
drugs that act directly on receptors (nicotinic and muscarinic agonists); and
anticholinesterases, which inhibit acetylcholinesterase and so act indirectly by allowing acetylcholine to accumulate in the synapse and produce its effects.
Muscarinic agonists (top left) have few uses, but pilocarpine (as eyedrops) is sometimes used to reduce intraocular pressure in patients with glaucoma (Chapter 10). Bethanechol was used to stimulate the bladder in urinary retention, but it has been superseded by catheterization.
Anticholinesterases (bottom left) have relatively little effect at ganglia and are used mainly for their nicotinic effects on the neuromuscular junction. They are used in the treatment of myasthenia gravis and to reverse the effects of competitive muscle relaxants used during surgery (Chapter 6).
Muscarinic