The Sympathetic Nervous System is one of two branches of the Autonomic Nervous System, and is involved in the subconscious regulation of organs and maintenance of homeostasis.
Each sympathetic nerve is made up of two neurones linked in serial. The preganglionic neurone has its cell body in the spinal cord, and has a short axon leading to the autonomic ganglia, which are located in the Sympathetic Chain. The Sympathetic chain is a group of cell bodies located either side of the spinal cord.
The postganglionic neurone has its cell body at the autonomic ganglia, and has a long axon which synapses with the target organ.
All sympathetic neurones are attached to the spinal cord in the Thoraco-Lumbar region.
The neurotransmitter at the autonomic ganglia is Acetyl Choline, and activates nicotinic ACh receptors. For more information about ACh receptors see Parasympathetic Nervous System
Most postganglionic sympathetic neurones use Noradrenaline as their neurotransmitter.
Noradrenaline is the product of an enzyme controlled reaction pathway.
- L-Tyrosine is converted by the enzyme tyrosine hydroxylase (found in the cytoplasm) to DOPA (dihydroxyphenylalanine). This is the rate limiting step, and is activated by stimulation of the sympathetic nerves or the adrenal medulla.
- Dopa is converted by DOPA decarboxylase (found in the cytosol) to Dopamine.
- Dopamine is converted by dopamine-β-hydroxylase to noradrenaline.
- (noradrenaline can then be converted by phenylethanolamine n-methyltransferase to adrenaline - this only happens in the adrenal medulla)
Noradrenaline is stored in vesicles. When stimulated these merge with the cell membrane and open to release Noradrenaline into the synaptic cleft by exocytosis.
NA is released when the varicosities are depolarised, causing the opening of calcium channels.
Noradrenaline release is regulated by homotrophic feedback. Some of the released NA activates presynaptic receptors (receptors on the same cell). This inhibits the enzyme adenylyl cyclase, and prevents the calcium channels opening.
NA is taken up by both the pre-synaptic and post-synaptic cell.
- 70% of NA is taken back up by the presynaptic cell, via active transport, and is recycled.
- Some of the NA is taken up by the postsynaptic cell, where it is metabolised.
- A small amount of NA overflows from the synaptic cleft into the tissue fluid. This eventually finds its way into the liver where it is metabolised.
The NA that is metabolised is converted to DOMA by Monoamine Oxidase or catechol-o-methyl transferase.
Noradrenaline acts on adrenoreceptors (adrenoceptors) which are split into 2 subtypes.
- α (which are split into α1 and α2)
- β (which are split into β1, β2 and β3)
Different receptor subtypes cause different responses, because they are coupled to different second-messenger systems.
- α1 - cause smooth muscle contraction in most cells (apart from relaxation in GI tract).
- α2 - found on presynaptic cell and inhibit release of both noradrenaline and acetylcholine.
- β1 - increases cardiac output by increasing heart rate and force of contraction.
- β2 - relaxes smooth muscle and increases NA release in sympathetic neurones
- β3 - causes thermogenesis (shivering) in skeletal muscle.
All types of adrenoreceptors are responsive to both Noradrenaline and Adrenaline and will display similar responses to both.
Second Messenger Systems
There are two main second messenger systems for Adrenoreceptors:
1. Adenylyl cyclase is activated, creating Cyclic AMP. This activates a kinase, which in turn phosphorylates a protein, leading to the cell response. This method is used in most receptors.
2. α1 receptors follow a different pathway. Phospholipase C is activated, which causes production of ITP, and the release of calcium and leads to the cell response. In addition diacylglygerol is produced, activating a kinase, which then phosphorilates a protein and again eliciting the cell response.
There are two types of agonist - direct acting or indirectly acting:
Directly Acting Agonists
These act by eliciting a response from the adrenoreceptors. Some of these are naturally occurring, including:
Some are synthetic, and act on either α or β receptors:
- Phenylephrine - decongestant + raises blood pressure (α1)
- clonidine - lowers blood pressure (α2)
- Isoprenaline - cardiac stimulation (β 1 and 2)
- Salbutamol and terbutaline - bronchial dilation and uterine inhibition - (β2)
Indirectly Acting Agonists
Also known as sympathomimetics, these have structures similar to adrenaline or noradrenaline but do not directly stimulate receptors. They act by stimulating the release or noradrenaline.
Antagonists bind to the receptor without causing a response, preventing the agonist from binding. They can be selective for alpha and beta receptors.
Indirect antagonists act by interfering with synthesis.
These are very rarely used:
- Phentolamine (α1&2)
- Prazosin (α1)
These are widely used, most commonly in hypertension, but also for ischaemic heart disease, glaucoma and hyperthyroidism.
- propranolol (β1&2)
- metoprolol and atenolol (β1)
- butoxamine (β2)
Combined Alpha and Beta Blockers
These are very rarely used, mainly for hypertension, and include the drug Labetalol.
Indirectly Acting Antagonists
These act by inhibiting the production of NA, and include MAO Inhibitors.