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Co-transmitters

Physiology and Pharmacology

QuestionAnswer
Identifying other neurotransmitters Experimentally, when isolated nerves are electrically stimulated to trigger AP the neurotransmitter released can be identified Repeat in presence of selective blocker and see if the same effect occurs Allows identification based on what was blocked
Co-transmitters with ACh ATP VIP - vasoactive intestinal polypeptide
Role of ATP in parasympathetic nerves Important in urinary bladder Helps control bladder function ACh stimulates contraction of muscle which can be blocked by atropine ATP activates P2x channels causing Ca influx and inducing contraction
Evidence for effects of ATP on depolarisation in PSNS Nerve stimulation of urinary bladder in presence of atropine shows small excitatory junction potentials due to ATP When alpha-beta methylATP is added to block Px2 this excitation is lost
Evidence for effects of ATP on Ca release in PSNS When atropine is added, the frequency of calcium transients in muscle decreases by a small amount When Px2 is blocked there is almost complete removal of Ca transients Shows ACh plays small role and ATP plays large role in Ca influx
Evidence for effects of ATP on contraction on PSNS On addition of atropine, there is a large decrease in contraction strength On addition of P2x blockers there is a small decrease in contraction strength Shows ACh plays large role and ATP plays small role in contraction
Clinical relevance of ATP in PSNS Urge incontinence linked to lack of P2X3 and P2X5 receptors Costs around £2000000000 per year for NHS for mainly anti muscarine drugs Possible manipulation of purine pathway could be cheaper
Co-transmitters with NA Dopamine - CNS ATP - binds NA to storage granules to reduce osmolarity NPY - neuropeptide Y
Role of ATP in SNS Made and stored in nerve endings - can be broken down into adenosine which also binds to receptors Important in vascular system as it acts on P2X receptors to depolarise smooth muscle Stimulates both rapid and slow contraction
Evidence for effects of ATP on depolarisation in SNS Nerve stimulation shows both rapid and slow excitation Addition of a b methylene ATP removes rapid excitation Addition of phentolamine removes slow depolarisation Shows NA does slow depolarisation and ATP does rapid depolarisation
Evidence for effects of ATP on contraction in SNS Originally, contraction occurs slowly as calcium transients occur When prazosin is added, ATP effects are isolated and contraction becomes much faster and less strong ATP seems to speed up overall response
ATP in SNS and vas deferens Contraction of vas deferens to sympathetic nerve stimulation mediated by P2X1 receptors P2X1 knockout mice the adrenergic component in augmented Male fertility is decreased by 90% in P2X1 knockout mice
Neuropeptides De novo synthesis at the cell body level Inactivation of the released peptide neurotransmitter is by peptide hydrolysis Carried to synapse by axoplasmic transport
Examples of neuropeptides Substance P Enkephalin NPY VIP
Discovery of morphine like peptides Morphine found to inhibit release of ACH from nerves in myenteric plexus Morphine's inhibition of ACh release prevented by naloxone, a specific antagonist of opioid receptors Acts at u-opioid receptors as a neuromodulator
Enkephalin Morphine like substance Mouse vas deferens with added brain extracts Inhibits ACh release in a dose dependant fashion Naloxone blocks this action Isolated two pentapeptides called enkephalins
Clinical relevance of enkephalins Naloxone for opioid overdose - reversal of opioid induced respiratory depression Opioids cause constipation and can reduce fertility
VIP from PSNS Important in submandibular salivary gland - relaxes vascular SM Atropine blocks saliva production but does not decrease blood flow to the gland VIP is present in cholinergic fibres innervating the gland, so appears involved in increasing blood flow
Clinical relevance of VIP VIP knockout mice are hypertensive VIP inhales to treat pulmonary hypertension
Nitric oxide - endothelial cells Released by endothelial cells (nitric oxide synthase 3) Relaxes smooth muscle Inhibitors therefore increase blood pressure NO donor glyceryl trinitrate us used to treat angina - metabolised to produce NO
Nitric oxide - neurons Soe autonomic nerves express nitric oxide synthase 1 Present in blood vessels and heart Made following rises in Ca levels in nerve endings Released to act on adjacent smooth muscle - dilating effect
Location of NOS Varicosities for ACh, VIP and NO closely aligned Staining for NOS1 shows that it is localised with ACh vesicles
Clinical relevance of NO Sildenafil inhibits phosphodiesterase type 5 that usually breaks down NO Increases the action of neuronally released NO Non-lifestyle uses in angina, pulmonary hypertension, microvasculature disorder and Alzheimer's
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