Autonomic Transmission Notes

AUTONOMIC TRANSMISSION

-the synapses between cardiac/ smooth muscle are en passant junctions where post ganglionic autonomic nerves release transmitter from varicosities

Synapses on cardiac and smooth muscle (en passant junctions, varicosities): structure and function in comparison with NMJ

Cholinergic transmission

-cholinergic nerves: nerves use ACH as the neurotransmitter

-The first separation between ACH receptors was shown using selective agonists. Nicotine high affinity nicotinic receptors, whilst muscarine has a high affinity for muscarinic rececptors.

-Dale’s experiment also showed ACH produces 2 kinds of effect on cat’s blood pressure which shows the existence of two different types of cholinergic receptors: nicotinic and muscarinic.

-when a small amount of Acetylcholine is injected (2micro grams) it leads to a decrease in blood pressure due to vasodilation. The vasodilation is caused by the Ach acting on muscarinic receptors on the endothelial cells which release NO and this relaxes the smooth muscles of blood vessels

-after atropine is injected, muscarinic antagonist, the same starting dose has no effect whereas a much larger dose is given 5mg – it leads to a rise in blood pressure due to stimulation of the sympathetic ganglia

Nicotinic receptors

Distribution

preganglionic nerves of the autonomic nervous system: both sympathetic and parasympathetic release acetyl choline which act on nicotinic receptors on the post ganglionic neurones

function

-activated by nicotine

-ligand gated ion channels- when two ACH bind, leads to the opening of ion channels- non selective cat ion channels- potassium, sodium

-fast transmission

sub-types

-nicotinic receptors are isolated from electric organs of electric eels whose surface membranes are isolated and the protein sloubilised with a weak detergent.

-two subtypes of nicotinic receptors

-N1 subtypes- located on the postganglionic cell bodies

-N2 subtypes found on the muscle cell in the NMJ

-nicotinic receptors are found in the NMJ and in the autonomic ganglia but both are of different subtypes. This was shown using bis-methonium derivatives. Changing the number of carbons between charged nitrogen groups and compare the potencies. NMJ had a peak blocking effect when decamethonium was applied. Whereas autonomic ganglia the peak blocking effect was observed with hexamethonium

-local and systemic actions of agonists (nicotine)

-nicotine, dimethylphenyl piperazinium

-both sympathetic and parasympathetic ganglia are stimulated- tachycardia, increase in blood pressure, increased bronchial, salivary, sweat secretions

local and systemic actions of antagonists

-hexamethonium, tubocurarine

-all autonomic ganglia are inactivated, hypotension, loss of cardiovascular reflexes, inhibition of secretions

-trimptephan- is a short acting drug and used as an intravenous infusion to produce controlled hypotension and minimize bleeding during surgery.

muscarinic receptors

distribution

post ganglionic nerves of the parasympathetic nervous system release ACH which act on muscarinic receptors on the target organs

-found on smooth muscle and the pacemaker region of the heart

-Exception: Post ganlionic nerves of the sympathetic nervous system release ACH which act on muscarinic receptors on the sweat glands

function

-activated by muscarine

-Ach receptors are coupled via G proteins to their response mechanisms

sub-types

-G protein coupled 7 transmembrane receptor- single polypeptide that folds to form 7 membrane spanning alpha helical segments. Protein has a extracellular N terminus which can be glycosylated, cytoplasmic loops, hydrophilic domain at the C terminus

-M1 subtype- (Gq coupled) autonomic ganglia-mediates slow EPSP postganglionic, cerebral cortex, gastric parietal cells – excitatory effects- slow muscarinic excitation mediated by ACH in sympathetic ganglia and central neurons- excitation produced by decrease in K conductance- deficiency of this kind lead to dementia , increased gastric acid secretion following vagal stimulation antagonist: pirenzipine- decreases gut motility and decreases secretions

-M2 subtype : Gi coupled: found in the heart and presynaptic terminals of peripheral and central neurons -found in the heart- binding of ACH leads to the activation of Gi proteins which inhibit adenylate cyclase- less cAMP- less activation of protein kinase A (ai) , less phosphorylation of voltage gated calcium ion channels, less calcium ions enter during an action potential- less calcium ions,whilst there is activation of K channels via the binding of the By complex in the sinoatrial node- slowing heart rate and decreased cardiac output antagonist: gallamine

M3 subtype: activates Gq: exocrine glands (gastric, salivary) and smooth muscle (GI tract, eye, airways, bladder) – stimulation of glandular secretions (salivary, bronchial, sweat) and contraction of visceral smooth muscle. They also mediate relaxation of smooth muscle (mainly vascular) due to the release of N0 from neighbouring endothelial cells antagonist: darifenacin- smooth muscle (including bladder)- urinary incontinence

Existence of receptor subtypes M1, M2, M3: ganglionic vs. neuromuscular nicotinic receptors

Autonomic innervations of bronchial muscle

PARASYMPATHETIC INNERVATION: Dominant innervations of bronchial smooth muscle- embedded in the walls of the bronchi and bronchioles

-poastganglionic fibres innervate airway smooth muscle- m3 receptors found on bronchial smooth muscle and glands – bronchoconstriction and mucus secretion

-M1 receptors are found in glanglia and on postsynaptic cells- facilitate nicotinic neurotransmission

-M2 receptors- inhibitory autoreceptors mediating negative feedback on acetylcholine release by postganglionic cholinergic nerves

Sympathetic innervations: innervate tracheobronchial blood vessels and glands but not airway smooth muscle

-B adrenoreceptors are abundantly expressed on human airway smooth muscle- agonists relax airways

Drugs that act on muscarinic receptors...

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