Pharmacology of Peripheral NT Flashcards

Question

Ephedrine

Answer 1

Indirectly acting sympathomimetic amine, promotes catecholamine release Used as a nasal decongestant because of NA-mediated vasoconstriction it produces in the vasculature of the nose. May have some direct action on beta2adrenoceptors int he bronchi Poor agonist at adrenoceptors but excellent substrates for NET/uptake 1. Then transported by VMAT into vesicles, displacing NA, which is subsequently expelled into synaptic space by reverse transport via NET Imipramine and other NET inhibitors interfere with effect

Answer 2

COMT inhibitor | Used in Parkinson's disease with L-DOPA and carbidopa: also reduces metabolism of L-DOPA in the periphery

Answer 3

Beta2-adrenoceptor selective agonist (long-acting)

Answer 4

Directly blocks NA release by a nerve impulse Agents can transiently stimulate release of NA because of capacity to displace amine from stores Selectively accumulate into neurons by Uptake 1/NET (compete with NA so can potentiate exogenously applied NA) Stored into vesicles, replace NA, can transiently serve as indirectly-acting sympathomimetic agents, but after block the release of NA evoked by APs Guanethidine not an agonist at postsynaptic adrenoceptors so doesn't elicit a response In past was used to treat uncontrolled hypertension

Answer 5

Inhibits choline transporter (ChT) which normally cotransports choline with Na+ from the extracellular fluid into the cytoplasm of the cholinergic neuron Supply of choline is the rate limiting step of ACh synthesis

Answer 6

Use-dependent blocker of ganglionic nicotinic receptor | decamethonium more specific

Answer 7

Tricyclic antidepressant, inhibits the norepinephrine transporter (NET). Interferes with indirectly sympathomimetic amine action

Answer 8

Beta2 adrenoceptor agonist (ultra long acting) | Used in treating COPD

Answer 9

Muscarinic antagonist - semi-synthetic derivative Produces bronchodilation Used to treat COPD and asthma

Answer 10

``` DOPA decarboxylase (DDC) substrate. Can cross BBB so used to boost DA synthesis in the Parkinsonian brain Used in conjunction with carbidopa and entacaptone to reduce peripheral decarboxylation and so reduce side effects ```

Answer 11

Mixed alpha1/beta adrenoceptor antagonist Alpha1 blockade --> vasodilation Beta1 blockade --> reflex sympathetic increase in HR Together --> decrease BP Can be used in treating hypertension associated with pregnancy

Answer 12

Irreversible long acting anticholinesterase | Used as an insecticide to kill lice

Answer 13

Indirectly increases the extracellular concentration of adenosine (unclear mechanisms) An antifolate type anti cancer and immunosuppressive drug

Answer 14

Irreversibly antagonises adult Nm nAChR (alpha1)2beta1deltaepsilon + brain (alpha7)5. Ganglionic nAChR insensitive

Answer 15

Irreversible non selective muscarinic antagonist

Answer 16

Stimulates then depolarising blocking agent of nAChR ganglionic Tertiary amine

Answer 17

Selective beta2 antagonist

Answer 18

Results in alpha-methylnoradrenaline production. False transmitter. PNS= antihypertensive. CNS= alpha2 agonist Action similar to clonidine. Hypotensive drug during pregnancy

Answer 19

Beta3 adrenoceptor selective agonist Relaxes detrusor smooth muscle and increases bladder capacity: used for patients with an overactive bladder. Potential for treatment of obesity as promotes lipolysis?

Answer 20

Selective MAO-A inhibitor (preferentially degrades serotonin, NA, DA)

Answer 21

Beta1 adrenoceptor antagonist Secondary action makes it chosen antihypertensive: one of its metabolites is a beta3 adrenoceptor agonist, which mediates increased NO production and thus vasodilation

Answer 22

Medium acting anticholinesterase, also activates nAChR directly at NMJ Basic group interacts with CAS and transfers carbamyl (i.e. instead of acetyl) group to Ser203. Carbamylated AChE is more stable than acetylated AChE and takes minutes to hydrolyze so medium acting Charged so only acts peripherally Used IV to reduce neuromuscular blockade after surgery (and give orally to limit parasympomimetic effects) and orally to treat myasthenia gravis

Answer 23

Non depolarising blocker at NMJ. Inhibits cardiac muscarinic receptor so induces mild tachycardia Metabolised by liver or excreted unchanged in the urine

Answer 24

Irreversible alpha adrenoceptor antagonist and NET/ENT inhibitor. Blocks ENT at 10 times lower conc than needed to block uptake 1 NET. Antihypertensive drug (obsolete) as they reduce BP so much that it triggers reflex tachycardia. Covalently binds to the receptor and causes long lasting inhibition. So retains clinical use in preparing patients with phaeochromocytoma for surgery (since surgical manipulation tens to cause a massive release of catecholamine into the circulation)

Answer 25

``` Non selective alpha adrenoceptor antagonist Antihypertensive drug (obsolete) as they reduce BP so much that it triggers reflex tachycardia ```

Answer 26

Alpha1 adrenoceptor selective agonist Nasal decongestant Phenylephrine also used to treat acute hypotension e.g. from septic shock

Answer 27

Non selective muscarinic agonist Naturally occurring cholinomimetic alkaloid: tertiary amine Stable to hydrolysis by AChE Used to treat glaucoma + emergency lowering of intraocular pressure of both open-angle and angle-closure glaucoma. It contracts the ciliary muscle --> traction on trabecular network around Schlemm canal --> immediate drop in intraocular pressure due to increased drainage of aqueous humour. Action within a few minutes, lasts 4-8h, can be repeated Also rapid miosis, accommodation, sweat, tears, saliva (low selectivity)

Answer 28

M1 selective antagonist Decreases gastric acid secretion so can treat ulcer (but now H2 receptor agonists and PPIs better) Synthetic

Answer 29

AChE reactivator, Used as an antidote for organophosphate poisoning Cationic group interacts with the anionic site of AChE, which brings the oxime group into close proximity with the phosphorylated serine. Oxime = v strong nucleophile, and takes the phosphate, which frees the serine hydroxyl group. Only works before aging. Can't reach CNS

Answer 30

Alpha1 adrenoceptor selective antagonist Decrease peripheral vascular resistance and lower BP by causing relaxation of both arterial and venous smooth muscle. Thus useful to treat hypertension without same reflex tachycardia as non selective alpha adrenoceptor antagonists Terazosin and doxazosin have longer half lives than prazosin

Answer 31

Non selective beta adrenoceptor antagonist Treatment of hypertension: 1. decreases CO 2. Inhibits renin release 3. Decrease in TPR with long term use 4. Inhibits SNS so causes mild decrease in HR

Answer 32

Inhibits vesicular monoamine transporter (VMAT) by binding very tightly to the amine binding site. Leads not only to a block of uptake but also to a long-lasting depletion of stored NA/5-HT since the vesicles allow leakage of the stored amine into cytoplasm where it is metabolised by MAO. Acts in periphery and brain. Used as an antihypertensive, but discontinued as causes profound psychological depression (perhaps due to 5-HT depletion).

Answer 33

Medium acting reversible anticholinesterase, can reach the CNS as uncharged and lipophilic Useful in mild to moderate dementia assocated with Alzheimer's disease and Parkinson's

Answer 34

Beta2 adrenoceptor selextive agonist (short acting) | Used mainly for bronchodilator action in ashthma. Taken by inhalation as needed.

Answer 35

Beta2 adrenoceptor selective agonist (long lasting) | Used prophylactically in chronic asthma.

Answer 36

M3 antagonist

Answer 37

Agonist for all P2X and some P2Y receptors (ATP antagonist)

Answer 38

Depolarising blocker at the NMJ. Short duration of action and thus much faster recovery compared to other NM blockers. Short duration as hydrolysed by plasma cholinesterase (BuChE)

Answer 39

Alpha1A-adrenoceptor selective antagonist Allow better bladder emptying (alpha1 adrenoceptors mediate contraction of smooth muscle of the bladder, this inhibits) and thus reduce urinary retention associated iwth benign prostatic hypertrophy. Alpha1B mediates vasoconstriction: these thus produce much less postural hypotension

Answer 40

Cleaves synaptobrevin in specific inhibitory interneurons in the CNS Enters body through puncture wounds in skin. Spreads through tissue spaces into the lymphatic and vascular systems Enters nervous system at NMJ: C-terminal heavy chain binds to some ganglioside that are enriched on the peripheral terminals of motor neurons. This enables endocytosis. Moves towards cell body in endoscope by retrograde axonal transport. Discharged into intersynaptic space. Binds to presynaptic membrane of inhibitory interneurons, is endocytosed. Acidic nature of synaptic vesicles causes insertion of the N-terminal light chain into the cytoplasm where it cleaves synaptobrevin. Inhibitory interneurons thus unable to release GABA/glycine thus disinhibition of motor neurone which is then more excitable which leads to tetanic contractions of skeletal muscle.

Answer 41

Non specific MAO inhibitor

Answer 42

Competitive substrate for choline acetyltransferase (CAT) Converted to acetyltriethylcholine which is then released in place of ACh. It is far less potent at both n+mAChR, so is a 'false transmitter'.

Answer 43

Reversible muscarinic antagonist (short acting) | Synthetic

Answer 44

Agonist for nicotinic receptors in CNS - full agonist for (alpha7)5, partial agonist for (alpha4)2(beta2)3 (this partial effect, unlike complete nicotine withdrawal, allows it to stimulate some dopamine release in the mesolimbic dopaminergic pathway that helps in relieving some withdrawal symptoms, but some serious mental/mood problems)

Answer 45

Inhibits vesicular ACh transporter (VAChT). Non-competitive and reversible blocker.

Answer 46

Selective alpha2-adrenoceptor agonist Vet use Used as sedative, often in combination with ketamine No imidazoline receptor effect

Answer 47

Alpha adrenoceptor-selective agonist | Topically given to relieve nasal congestion by causing vasoconstriction in nasal mucosa

Answer 48

Alpha2 adrenoceptor selective antagonist

Answer 49

Release stored NT (ie displaces NA from storage vesicles)

Answer 50

Competitive antagonist of ganglionic nAChR

Answer 51

Highly potent nicotinic agonist selective for ganglionic and CNS receptors Many autonomic side effects so not used clinically

Answer 52

NAChR agonist on autonomic ganglion, no block but three times more potent than nicotine and slightly more ganglion-sensitive

Answer 53

Selective MAO-B inhibitor

Answer 54

Reversible non-specific muscarinic cholinergic antagonist

Answer 55

Muscarinic antagonist, and block exceptional sympathetic neurons that are cholinergic to salivary and sweat glands Naturally occurring alkaloid

Answer 56

Muscarinic antagonist, short-acting | Synthetic

Answer 57

M2 selective muscarinic antagonist

Answer 58

Reversible covalent anticholinesterase inhibitor. Intermediate acting. Charged so only acts peripherally Basic group interacts with CAS and transfers carbamyl (i.e. instead of acetyl) group to Ser203. Carbamylated AChE is more stable than acetylated AChE and takes minutes to hydrolyze so medium acting Physostigmine can be used to treat glaucoma by topical application to the eye (same mechanism as pilocarpine?)

Answer 59

Irreversible anticholinesterase inhibitor

Answer 60

Anti-AChE Uncharged, so can cross BBB so useful in treating Alzheimer's disease (NB loss of cholinergic neurons in basal forebrain and resultant decrease in cholinergic NT thought to underlie, at least in part, the memory loss/intellectual degeneration/personality changes of AD) Recently withdrawn due to severe hepatotoxicity

Answer 61

Uptake 2 inhibitor (ENT)

Answer 62

Selective MAO-B inhibitor

Answer 63

Selective MAO-A inhibitor

Answer 64

Non-depolarising blocking agent at NMJ. Hydrolysed by BuChE

Answer 65

Gallamine is 1st synthetic successor to curare nAChR antagonist at NMJ - at higher concentrations is a M2 selective antagonist so causes changes in HR. Now replaced by compounds with fewer side effects

Answer 66

Directly-acting muscarinic agonist/cholinomimetic agent Synthetic esters of choline For methacholine - presence of beta methyl group improves selectivity for mAChR and reduces hydrolysis by cholinesterases

Answer 67

Directly-acting muscarinic agonist/cholinomimetic agent Chemically a hybrid of methacholine and carbachol Lacks nicotinic actions but non-selectively activates mAChR subtypes Stimulates detrusor of bladder via M3 receptor, whereas trigone and sphincter muscles are relaxed. --> urination --> bethanechol increases bladder function

Answer 68

Local anaesthetic | Hydrolysed by BuChE > AChE

Answer 69

Selective alpha2 adrenoceptor agonist Antihypertensive - partly via inhibition of NA release, partly via CNS alpha2 stimulation reducing SNS outflow (presynaptic modulation): Clonidine binds to imidazoline receptors Adjunct in treating drug addiction: helps ameliorate some adverse sympathetic actions during drug withdrawal in addicts

Answer 70

Indirectly acting sympathomimetic amine. Poor agonist at adrenoceptors but excellent substrates for NET/uptake 1. Has an alpha-methyl group that makes it a poor substrate for MAO, so acts as a weak inhibitor of MAO. Is a weak base so once taken up by VMAT reduces transvesicular pH gradient and thus vesicular packaging of amines. Some displaced NA leaves nerve ending to stimulate the receptors. Used in narcolepsy and ADHD and abused recreationally. Ritalin (methylphenidate) and MDMA have similar effects though MDMA also stimulates 5HT2 receptors (so is hallucinogenic).

Answer 71

Uptake 2 inhibitor (ENT)

Answer 72

Given in acute cardiac failure, acute severe asthma, or anaphylactic shock (where it coutneracts the systemic vasodilation and reduction in tissue perfusion that is caused by massive histamine release) Acts on bronchial smooth muscle to relieve bronchospasm Given with local anaesthetics to produce vasoconstriciton at the site of injection, prolongs their action

Answer 73

Beta-selective adrenoceptor agonist. Beta2 = bronchodilator so used to be used in asthma treatment but stopped due to beta1= cardiac effects (problem)

Answer 74

Similar but more potent than propranolol: i.e. Non selective beta adrenoceptor antagonist Treatment of hypertension: 1. decreases CO 2. Inhibits renin release 3. Decrease in TPR with long term use 4. Inhibits SNS so causes mild decrease in HR Timolol reduces production of aqueous humor in the eye. Used topically in treatment of chronic open-angle glaucoma.

Answer 75

Given as a bolus injection to terminate supraventricular tachycaria (slows rate and force of contraction of the heart via A1 receptors)

Answer 76

Donate NO in vivo rapidly --> vasodilation --> antianginal therapy

Answer 77

• Inhibits liver triglyceride production and VLDL secretion when used in very large doses. Increases levels of tissue plasminogen activator.

Answer 78

Small protein tubular structure that allow free movements of ions from the interior of one cell to the interior of the next. Electrical synapses

Answer 79

Synchronous firing | Thalamus, also circadian rhythm in SCN nucleus

Answer 80

Adrenal hormone release HR up BP up Bronchioles dilate Intestinal motility and secretion inhibited Glucose metabolism increases Pupils dilate Hairs become erect due to piloerector muscles Cutaneous and splanchnic blood vessels constrict Blood vessels in skeletal muscle dilate

Answer 81

1: spinal cord to autonomic ganglion. Myelinated B fibres. ACh 2. autonomic ganglion to effector organ. Unmyelinated C fibres. ACh/NA

Answer 82

Adrenal medulla - directly innervated by a nerve from the spinal cord.

Answer 83

Craniosacral Cranial: III (ciliary ganglion), VII, IX, X. Head and neck, vagus does thoracic cavity and first 2/3 colon Sacral S2-4: Pelvic splanchnic nerves. Supplies lower GI tract, bladder, genitalia

Answer 84

Close to target organ or within wall of target organ

Answer 85

Thoracolumbar Cell bodies in lateral horns T1-L2/L3

Answer 86

ACh | NANC: VIP, substance P, CCK, NO

Answer 87

Paravertebral on each side of the vertebral column. Also to some unpaired prevertebral ganglia (coeliac, superior and inferior mesenteric) on ventral surface of aorta, aorticorenal and pelvic ganglia

Answer 88

NA and ATP ATP faster effect, NA more long-lasting effect Ones supplying sweat glands ACh

Answer 89

Bulbous varicosities distributed along axons within their target organ At each varicosity, autonomic axons form an en passant synapse with their end organ target Increases number of targets that a single axonal branch can influence

Answer 90

Probably varicosities like SNS but less well characterised

Answer 91

Same: Salivary glands. Both promote salivary secretion Different: HR and force of myocardial contraction both enhanced by SNS and reduced by PNS

Answer 92

PNS for humans (other animals not always) Giving atropine to patient markedly increases HR (abolishes PNS input) but giving propranolol only slightly decreases HR (abolishes SNS input)

Answer 93

Circulating catecholamines can bind to receptors on those tissues, i.e. bronchial smooth muscle relaxes with circulating adrenaline

Answer 94

80% A 20% NA

Answer 95

Beta1 SAN increase HR, atrial muscle increase force, AVN increase automaticity, ventricular muscle increase automaticity and force M2 SAN decrease HR, atrial muscle decrease force, AVN decrease conduction velocity/AVN block, no effect on ventricular muscle

Answer 96

Beta2 dilation: muscle, veins Alpha constriction: coronary, viscera, skin, brain, erectile tissue, salivary glands, veins Para: only effects via M3 on erectile tissue and salivary glands, not on other blood vessels

Answer 97

Beta2 smooth muscle circulating adrenaline dilated | Constriction of smooth muscle and secretion of glands via M3

Answer 98

Alpha1/2/beta2: smooth muscle decreased motility, sphincters constrict M3:increase motility, dilation, secretion M1: increased gastric acid secretion

Answer 99

Beta2: relaxation Alpha1: sphincter contraction M3: contraction and sphincter relaxation

Answer 100

Pregnant: alpha contraction | Non pregnant: beta2 relaxation

Answer 101

Alpha ejaculation, M3 erection

Answer 102

Alpha pupil dilation, beta ciliary muscle relaxation | M3 pupil constriction, ciliary muscle contraction

Answer 103

Sweat gland secretion via M3 Piloerection via alpha Salivary gland secretion alpha, beta, M3 Lacrimal gland secretion M3

Answer 104

Beta1 renin secretion

Answer 105

alpha beta2 glycogenolysis, gluconeogenesis

Answer 106

Beta3 lipolysis, thermogenesis

Answer 107

alpha2 insulin sec down

Answer 108

100 million

Answer 109

Myenteric/Auerbach's plexus between longitudinal and circular muscle layers of the gut. Control GI motility. Submucosal/Meissner's plexus in gut submucosa. Regulate body fluid homeostasis

Answer 110

Passage of an impulse along an axon or muscle fibre

Answer 111

Passage of an impulse across a synaptic or neuroeffector junction

Answer 112

Local anaesthetics

Answer 113

In presynaptic terminals Enzymes to do this synthesis produced in the soma and transported to the nerve terminal cytoplasm by slow axonal transport Normally take up precursors for synthesis by transporters found in the plasma membrane of the terminal Loaded into vesicles Final steps of synthesis occur inside the vesicles

Answer 114

0.5-5mm/day Anterograde transport From soma to nerve terminal Used to take enzymes for small molecule NTs to the periphery

Answer 115

Small clear-cored vesicles 40-60nm diameter Centre clear in EM

Answer 116

Precursor peptides and enzymes for synthesis produced in the cell body of a neuron Packaged into vesicles Shuttled to nerve terminal via fast axonal transport

Answer 117

Large dense-core vesicles 90-250nm Electron-dense in electron micrographs

Answer 118

400mm/day Used to transport large dense-core vesicles containing neuropeptides from soma to peripheral nerve terminal. Move the vesicles down microtubule tracts

Answer 119

Target-derived growth factors such as nerve growth factor can reach the nucleus of a neuron where it can influence survival Viral proteins and neurotoxins hijack this mechanism Also carries things to further degrade or salvage e.g. used vesicles, degradable products

Answer 120

Enable exocytosis, protect from protease and hydrolases, stop passive leaking from pre-synaptic membrane

Answer 121

When an intracellular microelectrode is used to record the membrane potential of a muscle cell, an AP in the presynaptic motor neuron can be seen to elicit a transient depolarisation of the postsynaptic muscle fibre - an EPP 1. Spontaneous changes in muscle cell membrane potential occurs even in the absence of stimulation of the presynaptic motor neuron (MEPP). Both these and EPPs are sensitive to blockade by curare. 2. If stim the nerve to the junction under conditions of low extracellular Ca2+ (low transmitter release) the EPPS that occur were multiples of the MEPP. So ACh released in a quantal manner

Answer 122

EPP 40-50mV | MEPP 0.5mV

Answer 123

Miniature end plate potential Synchronous release of 5000 molecules ACh Maintenance of physiological responsiveness of skeletal muscle (lacks inherent tone)

Answer 124

Release at the synapse between photoreceptors and bipolar neurons in the retina

Answer 125

NT release proportional to Ca2+ conc to the 3rd or 4th power

Answer 126

1. Releasable pool (within 200microseconds) | 2. Reserve pool

Answer 127

1. Uptake NT into synaptic vesicles by ATP-driven transport. Proton pump acidifies vesicle interior to give an electrochemical gradient across the synaptic vesicle membrane. This provides the energy for the uptake of NT through specific transport proteins that are specialised for the various NTs. 2. Full synaptic vesicles move to active zone of presynaptic plasma membrane 3. Dock 4. ATP-dependent prefusion reaction that primes them for Ca2+ dep release 5. Ca2+ triggers completion of fusion 6. Synaptic vesicles rapidly retrieved by clathrin-mediated endocytosis/ 'kiss and run' 7. Coated vesicles shed the coat and recycle to the interior of the synaptic terminal 8. Empty vesicles either refill immediately or pass through an endosomal intermediary sorting station. Local recycling of synaptic vesicles enables the terminals to sustain repeated rounds to transmitter release independently of the distal cell body.

Answer 128

Genetic disorders that cause muscle weakness by affecting neuromuscular transmission: - Affect AChE - Autoimmune attack of AChR - Defects in ACh due to altered synaptic vesicle traffic (impairment in endocytosis or reduced supply of vesicles from soma)--> Inadequate number of synaptic vesicles available for release during sustained presynaptic activity

Answer 129

Synaptic vesicles that are smaller in diameter but normal in number. Results in problems initiating voluntary movement

Answer 130

Occasional complication in patients with certain kinds of cancers. Evidence: intracellular recordings - number of quanta in EPPs greatly reduced, while amplitude of spontaneous MEPPs is normal. So impairs evoked NT release, but doesn't affect the size of individual quanta. Autoimmune destruction of CaV in pre-synaptic membrane. Voltage insufficient for vesicle release, leads to problems initiating voluntary movement.

Answer 131

V associated with vesicle and t associated with target. Segment in cytosolic domain called a SNARE motif - 60-70 aa and contains heptad repeats that can form coiled-coil structures.

Answer 132

Synaptobrevin is a V SNARE anchored in vesicle membrane by hydrophobic carboxy terminus. Central 70 aa residue region forms an alpha helix which complexes with SNAP25 and syntaxin (t snares). This structure is known as the core trans-SNARE complex and consists of 4 alpha helices (one synaptobrevin, one syntaxin, 2 SNAP-25). Helices lie parallel to each other and form a leucine zipper that brings the vesicle and plasma membranes close together.

Answer 133

Synaptotagmin isoforms I, II and IX. Anchored to vesicles via N-terminus. C termini contain C2A and C2B which provide the binding sites for Ca2+. In the presence of Ca2+, C2 domains bind synaxin and SNAP-25 and to membranes containing acidic phospholipids. The C2B domain is specifically able to bind to membranes enriched in PIP2.

Answer 134

``` Synaptobrevin = C Synaptotagmin = N ```

Answer 135

Proteins on the surface of vesicles that link vesicles to cytoskeleton, regulated by phosphorylation. In non-P state, synapsins bind to vesicles. When phos by PKA/CaM Kinase II vesicles dissociate. Means vesicles move to active zone. Critical for maintaining the reserve pool.

Answer 136

Synaptotagmin PKCs Low affinity binding site for Ca2+

Answer 137

Physically located in the same place as CaV - active zone. Develops a Ca2+ rich microdomain as Ca2+ is poorly diffusible.

Answer 138

NSFs using ATP

Answer 139

Ionotropic LGIC

Answer 140

Metabotropic GPCRs

Answer 141

Differences in spatial arrangement of vesicles relative to presynaptic Ca2+ channels

Answer 142

Autoinhibition

Answer 143

Preganglionic fibres of SNS and PNS Postganglionic PNS Motor Preganglionic fibres terminating in the adrenal medulla

Answer 144

Supply of choline Choline transported from ECF into cytoplasm by ChT choline transporter. Cotransports Na+. Can be inhibited by hemicholinium.

Answer 145

Clear cored = with ATP at ration 10:1 | Some cholinergic nerves have dense cored vesicles containing VIP

Answer 146

Tethered to post synaptic membrane in synaptic cleft | Also in the presynaptic terminal

Answer 147

AChE specific for ACh Butyrylcholinesterase/pseudocholinesterase BuChE - broader substrate specificity. Also breaks down local anaesthetic procaine.

Answer 148

Liver Found mainly in plasma Trace quantities in skin, gut, brain

Answer 149

Guards against accumulation of cytoplasmic ACh outside storage vesicles.

Answer 150

3 tetramers of AChE attached by disulphide bonds to a long collagenous tail that binds to a heparin sulfate proteoglycan on the basement membrane post-synaptically

Answer 151

NMJ, autonomic ganglia, adrenal medulla, CNS, some other non-neuronal cells

Answer 152

LGIC Cys-Loop family Pentamer with at least 2alpha subunits present. Each subunit 4 transmembrane M1-M4 helices M2 helix from all 4 subunits forms the pore Normal adult Nm: (alpha1)2beta1deltaepsilon Normal ganglionic Nn: (alpha3)2(beta4)3 or (alpha3)2(beta2)3 Brain: (alpha4)2(beta2)3 or (alpha7)5

Answer 153

Binds to interface between alpha and neighbouring gamma or delta subunits. Minimum 2 molecules ACh required for activation of channel.

Answer 154

Na+ K+ | (alpha7)5 Ca2+

Answer 155

``` Alpha = binds to ACh binding site on Nm irreversibly antagonises adult Nm. Beta = Binds to shaker type K+ channels, so localised to presynaptic membrane. PLA2 activity degrades active zone lipids ```

Answer 156

Nm: Alpha bungarotoxin Decamethonium Depolarising suxamethonium Non-depolarising d-tubocurarine/Atracurium/pancuronium Nn: Nicotine - analogous to depolarising. First stim then blocks by causing persistent depolarisation Trimetaphan - analogous to non-dep blocking agents Hexamethonium - blocks in a use dependent manner so likely to cause an open channel block. Shortens duration of current flow as open channel either becomes occluded or closes. Brain: (alpha7)5 also alpha bungarotoxin

Answer 157

1. Depolarising agents - act as agonist to Nm | 2. Non-depolarising agents - act as competitive antagonists to Nm

Answer 158

Endotracheal intubation - can provide complete muscle relaxation at lower anaesthetic doses so more rapid recovery from anaesthesia and reduce postoperative respiratory depression

Answer 159

Suxamethonium/Succinylcholine More resistant to degradation by AChE Continuous activation of nAChR Phase I: Membrane depolarises. Brief period of excitation (fasciculations) followed by flaccid paralysis. This is because Nm channels maintain cell membrane in depolarised condition, inactivating NaV, so blocking further APs. Phase II: Membrane gradually repolarises but Nm channels become desensitised. Short duration of action so much faster recovery. Due to hydrolysis by plasma cholinesterase.

Answer 160

Bradycardia due to direct muscarinic action Increased ocular pressure Increased serum K+ - can trigger ventricular dysrhythmia or cardiac arrest Malignant hypothermia Prolonged paralysis if liver disease or genetic deficiency of plasma cholinesterases

Answer 161

E.g. tubocurarine Competitive antagonists for Nm. Compete with endogenous ACh without stimulating it. Prevent dep and inhibit muscular contraction leading to flaccid paralysis.

Answer 162

AChE inhibitors to increase the conc of ACh (to compete!)

Answer 163

Selective agonists for Nn Nicotine and lobeline Epibatidine - powerful analgesic but side effects ruled it out from clinical use Varenicline partial agonist (alpha4)2(beta2)3 and full for (alpha7)5. Parial agonism allows it to stim some dopamine release in the mesolimbic dopaminergic pathway (unlike total nicotine loss) which helps in alleviating some withdrawal symptoms. Serious mental problems have been reported. Use to ease smoking withdrawal

Answer 164

M2 activation decreases transmitter release

Answer 165

Gq/11 Gq --> PLCbeta --> PIP2 hydrolysis --> IP3 and DAG --> Ca2+ activation (IP3 polar so diffuses into cytoplasm and activates ER membrane-bound IP3Rs) and PKC activation (DAG lipophilic so stays in membrane). DAG can be acted on by DAG lipase to make arachidonic acid, which may trigger a distinct Ca2+ influx pathway in some cell types, but most importantly precursor of prostaglandins and leucotrienes. PIP2 depletion also reduces K+ efflux via M current (normally PIP2 binding to their C-terminus enables activation). Brings about a late EPSP many seconds after initial fast EPSP. Peripheral and central neurons, gastric acid secretion Agonist: non-selective: ACh, carbachol, pilocarpine Antagonist: non-selective: Atropine, benzilylcholine, tropicamide, ipratropium. Irreversible: benzilylcholine mustard. Selective: pirenzipine

Answer 166

A current that raises the threshold for firing an AP. PIP2 mediated.

Answer 167

Gi/o Inhibition of AC --> inhibit cAMP and PKA production --> decreased phosphorylation of CaV --> decreases their open probability --> decreases Ca2+ influx --> decreased NT release + decreased excitability of heart cells. Second mechanism in heart: Beta gamma subunit of Gi/o opens S (G protein coupled inwardly rectifying K+ channels) in the SAN and AVN. Triggers K+ efflux, hyperpolarisation, negative chronotropic. Heart, presynaptic nerve terminals Agonist: non-selective: ACh, carbachol, pilocarpine Antagonist: non-selective: Atropine, benzilylcholine, tropicamide, ipratropium. Irreversible: benzilylcholine. Selective antagonist = gallamine, tripitramine.

Answer 168

Gq/11 Gq --> PLCbeta --> PIP2 hydrolysis --> IP3 and DAG --> Ca2+ activation (IP3 polar so diffuses into cytoplasm and activates ER membrane-bound IP3Rs) and PKC activation (DAG lipophilic so stays in membrane). Smooth muscle contraction due to Ca2+i. Vascular endothelial cells, Ca2+i --> CaM --> eNOS (arginine--> citrulline+) --> NO --> diffuses into underying vascular smooth muscle --> activates soluble GC --> cGMP --> PKG --> relax the vascular smooth muscle. Agonist: non-selective: ACh, carbachol, pilocarpine. Selective = cevimeline Antagonist: Non-selective: Atropine, benzilylcholine, tropicamide, ipratropium. Irreversible antagonist: benzilyl choline mustard. Selective antagonist: darifenacin

Answer 169

1. Choline esters like ACh and carbachol, bethanechol | 2. Naturally occurring cholinomimetic alkaloids e.g. pilocarpine

Answer 170

`Ester and basic group like ACh, but also a bulky aromatic group replacing the acetyl moiety

Answer 171

1. Naturally occurring alkaloids - atropine and scopolamine 2. Their semi-synthetic derivatives - ipratropium 3. Synthetic agents - pirenzipine, darifenacin Compete for ACh binding site on mAChR Most non selective, a few selective (pirenzipine M1, tripitramine M2, darifenacin, solifenacin M3)

Answer 172

Alpha 1 = dil M3 = constrict So can use M3 antagonist atropine (but duration v long) so normally use short acting agents like tropicamide Or adrenoceptor agonists - phenylephrine

Answer 173

Darifenacin M3 antagonist

Answer 174

10,000 molecules/sec/active site

Answer 175

Widespread | Liver, skin, brain, GI smooth muscle, soluble in plasma

Answer 176

Physiologically don't know | Hydrolyses butyrylcholine more rapidly than ACh, ester-type local anaesthetics e.g. procaine, and suxamethonium

Answer 177

Active site at base of deep and narrow cavity called aromatic gorge At entrance to gorge there is a PAS peripheral anionic site Base of gorge catalytic anionic site

Answer 178

Peripheral anionic site Recognising ACh as the substrate - weak pi-cation interaction between heteroaromatic ring of W279 tryptophan on AChE and the charged quaternary nitrogen of ACh

Answer 179

Gorge lined with 14 conserved aromatic residues which can also form pi-cation interactions with ACh Also an electrostatic gradient

Answer 180

Catalytic anionic site Cation-pi interaction between another tryptophan W84 and quaternary nitrogen atom of ACh critical Binds in the acyl pocket

Answer 181

F330 and Y121 two aromatic sidechains Smaller now than AChE Indicates protein must undergo considerable conformational changes locally to widen the gorge and let the substrate through

Answer 182

Binding in the CAS and acyl pocket Catalytic triad glu, hist, ser. Residues arranged so hist (+) and glu (-)donate elecrons in a charge-relay system, making the hydroxyl group of the serine highly reactive as a nucleophile. Serine forms a covalent bond with ACh, forming a tetrahedral intermediate with the acetyl moiety.

Answer 183

Oxyanion (ser bound to acetyl) stabilised by interactions with backbone amide groups in area called oxyanion hole. Here ACh bond is broken, releasing choline and leaving acetyl-serine. Serine-acetate bond spontaneously hydrolysed by water to release acetate and regenerate the enzyme.

Answer 184

65% homology 3 aromatic residues of AChE PAS missing in BuChE PAS (2 different amino acid residues) - means BuChE has weaker affinity than that of AChE for ACh and other drugs. 6 of 14 conserved aromatic residues in AChE gorge are replaced by aliphatic amino acids in the gorge of BuChE. BuChE thus more flexible and can accommodate a wider range of substrate than AChE.

Answer 185

Anticholinesterases!

Answer 186

Neostigmine

Answer 187

Mechanism of inhibition: 1. Reversible a) non-covalent Edrophonium, tacrine b) covalent Physostigmine, neostigmine, rivastigmine 2. Irreversible Organophosphates e.g. Dyflos, parathion, ecothiophate

Answer 188

Short acting = edrophonium, tacrine Intermediate acting = physostigmine, neostigmine, rivastigmine Long acting = organophosphates

Answer 189

Strength of anionic site interaction

Answer 190

PAS may serve as pathological chaperone for amyloid beta peptides, and promoting the formation of insoluble oligomer or amyloid plaque that is neurotoxic. Donepezil spans the gorge to interact with the PAS and the CAS. Also shown to have inhibitory effect on protein aggregation.

Answer 191

Rivastigmine - rest charged and so only act peripherally. Rivastigmine = lipophilic so useful in mild to moderate dementia.

Answer 192

Medium acting covalent reversible anticholinesterase | Used orally to treat myasthenia gravis with a longer action than neostigmine

Answer 193

Organophosphorous compounds - pentavalent phosphorous atom connected to either 3 O or 2 O 1 S along with a labile group like fluoride (dyflos DFP) or organic group (ecothiophate, parathion) Labile group released then serine hydroxyl group phosphorylated Extremely stable

Answer 194

In long acting anticholinesterases like dyflos and ecothiophate/parathion, the oxygen-phosphorous bond can undergo spontaneous rearrangement in favour of stronger bonding between enzyme and inhibitor. Once this has occurred, the duration of AChE inhibition is increased even further, so organophosphate inhibition is essentially irreversible.

Answer 195

Interacts with anionic site of AChE Used to treat poisoning by irreversible anticholinesterases Brings oxime group into close proximity of phosphorylated serine Oxime group very strong nucleophile and causes the phosphate to transfer to the oxime, freeing the serine hydroxyl group. Limited to within a few hours of exposure as phosphorylated AChE undergoes aging that renders the phosphorylated group unsusceptible to nucleophilic attack.

Answer 196

Atropine to counteract symptoms (can cross BBB) | Praloxime to reactivate enzyme

Answer 197

Catechol aromatic ring with two proximal hydroxyl groups and amine flanked by a two carbon linkage that often has an alcoholic -OH at beta position (but not dopamine)

Answer 198

L-tyrosine pumped in cotransported with Na+ Tyrosine hydroxylase (Rate limiting step) DOPA DOPA decarboxylase Dopamine Stored in vesicles VMAT2 driven by proton gradient Dopamine beta-hydroxylase Noradrenaline In adrenal medulla: PNMT Phenlyethanolamine N-methyltransferase Adrenaline

Answer 199

Synthetic derivative of NA used experimentally

Answer 200

Dopamine NA L-histidine to histamine L-tryptophan to serotonin

Answer 201

Used in vesicles to make NA from dopamine So released with NA Not rapidly degraded or susceptible to any uptake mechanism Conc in plasma and body fluids used as index of overall sympathetic nerve activity

Answer 202

Failure of NA synthesis | Severe orthostatic hypotension

Answer 203

Cortisol produced by surrounding adrenal cortex through the adrenal portal system Reduction in cortisol levels reduces Adr:NA ratio Also regulates DBH levels

Answer 204

alpha-methyltyrosine: competitive inhibitor TOH L-DOPA: can cross BBB so used to bypass rate limiting step and boost DA synth in Parkinson's Combine with carbidopa/benserazide which inhibits peripheral decarboxylase and so blocks some of the unwanted side effects of L-DOPA. Disulfiram: inhibit DBH by chelating Cu2+ (its cofactor) or attacking sulphur-handling system of the methyl donor. Inhibition aldehyde dehydrogenase, so used in dealing with alcohol addiction. Methyldopa: false transmitter. Antihypertensive. Less active than NA at alpha1, more active at alpha2 --> decreased alpha1 mediated constriction, more alpha2 mediated negative feedback. Primarily acts on alpha2 adrenoceptors in CNS where reduces NA outflow. Clonidine: as alpha-methylNA. Reserpine: inhibit VMAT by binding to amine binding site.

Answer 205

4:1 (nb ACh was 10:1)

Answer 206

ACh: Vesamicol NA: Reserpine

Answer 207

Guanethidine and bretylium - displace amine from storage sites so can transiently stimulate the release of NA. Compete with NA for Uptake1/NET so potentiates exogenously applied NA. Repeated low doses, or in the aftermath of a large dose, block release of NA evoked by APs, but spontaneous release unaffected --> so vesicle release processes unaffected

Answer 208

Indirectly acting sympathomimetic amines e.g. tyramine, dextroamphetamine, ephedrine Not adrenoceptor agonists themselves NET1 VMAT Displace NA from vesicles Pumped into synaptic space by reverse transport of NET (and partly metabolised by MAO. After this there is no stimulation with vesicle release (as they contain tyramine)

Answer 209

``` Tyramine = substrate Dextroamfetamine = weak inhibitor ```

Answer 210

Ritalin/methylphenidate and MDMA (but MDMA also acts on 5HT2 receptors)

Answer 211

Repeated administration produces less and less response

Answer 212

Reserpine - destroy the transmitter stores

Answer 213

1. Modify synthesis 2. Modify storage 3. Directly bock adrenergic neurons 4. Indirectly acting sympathomimetic amines 5. Stimulating presynaptic receptors

Answer 214

Blocking alpha 2 --> reduces the inhibitory effect of alpha2 on presynaptic nerve terminals

Answer 215

Autoreceptors: Alpha2 - reduces Beta2- enhance Other: M2, deltaopioid, prostaglandin EP3 - decrease NA release P2Y1 G1 sympathetic neuron presynaptically, facilitate NT release by inhibiting M current. A current that raises the threshold for firing an AP. PIP2 mediated.

Answer 216

GIRK opening by betagamma subunit Gi/o --> hyp

Answer 217

Uptake 1 and 2 | Uptake 1 more important

Answer 218

``` Neuronal cells High affinity Low capacity NET transporter Na+ dep Blocked by cocaine, tricyclic antidepressants including imipramine and amitriptyline. Blocked by phenoxybenzamine at 10x higher conc than blocks uptake 2. 75% so primarily responsible for termination of transmitter action NA repackaged into vesicles ```

Answer 219

``` Non-neuronal cells Low affinity High capacity ENT transporter Not Na+ dep 25% NA Inhibited by normetanephrine (NA metabolite), corticosteroids, and phenoxybenzamine irreversibly ```

Answer 220

``` MAO and COMT MAO oxidative deamination amine to aldehyde, then alcohol dehydrogenase metabolises to corresponding carboxylic acid. COMT methylates aromatic hydroxyls. PNS: MAO then COMT --> VMA --> urine CNS: MOPEG ```

Answer 221

Outer mitochondrial membrane Noradrenergic nerve terminals - metabolises NA leaking from vesicles Liver, intestinal epithelium - inactivates circulating monoamines carried in the portal venous blood from the gut.

Answer 222

MAO-A: degrades serotonin, NA, DA. Moclobemide used in depression (serotonin) MAO-B: degrades DA more rapidly. Selegyline used in Parkinson's (DA). Non-selective MAO inhibitors = tranylcypromine, isocarboxazid, phenelzine.

Answer 223

Cytosol in liver and adrenal medulla. NOT NA nerve terminals.

Answer 224

Marked increase in urinary excretion VMA

Answer 225

L-DOPA, can cross BBB and reach CNS. Converted to dopamine. Also need to take carbidopa to inhibit peripheral DDC to stop L-DOPA metabolism in the periphery. Also take entacaptone to inhibit COMT in the periphery (also less L-DOPA metabolism).

Answer 226

Gq/11 PLCbeta--> PIP2--> DAG and IP3 --> increase Ca2+ and PKC Na>A>>Iso Agonist: Phenylephrine, oxymetazoline Antagonist: Prazosin, doxazosin (tamsulosin silodosin selective alpha-1A) Postsynaptic effector cells esp smooth muscle 1A: bladder. Contraction of trigone and sphincter muscles of urinary bladder 1B: Vasoconstriction (blood vessels to viscera, brain, skin) Also: Mydriasis Salivary secretion Decreased GI motility and tone due to relaxation of smooth muscles Localised secretion of sweat Piloerection Ejaculation Increased glycogenolysis and gluconeogenesis

Answer 227

Gi/o Inhibit AC, inhibit cAMP, decrease Ca2+ channels, increase K+ channels. A>NA>>ISO Agonist: Clonidine partial, methylnoradrenaline Antagonist: Yohimbine Presynaptic nerve terminals, platelets, lipocytes, smooth muscle Inhibit NT release Platelet aggregation Vasoconstriction Inhibit insulin release from pancreatic beta cell

Answer 228

Gs AC cAMP PKA MLCK phos relax smooth muscles ISO> NA> A Agonist: dobutamine, xamotterol Antagonist: Atenolol, metoprolol, nebivolol Postynaptic effector cell in heart, presynaptic nerve terminals, juxtaglomerular apparatus of renal tubes, ciliary body Increase force of myocardial contraction + inotropy, increased HR + chronotropy

Answer 229

Gs AC CAMP PKA Phos and inhibit MLCK relax smooth muscles ISO> A> NA Sabutamol, salmeterol, formoterol, indacaterol None clinically useful (but butoxamine we do have, not useful) Postsynaptic effector cells, especially cardiac and smooth muscle Relax bronchial and tracheal smooth muscle, relax smooth muscle of vessels supplying hear and skeletal muscle, relax uterine smooth muscle (if non-pregnant), hepatic glycogenolysis

Answer 230

Gs AC cAMP - NO? ISO > NA=Adr Agonist: mirabegron No selective antagonist On posysynaptic effector cells, esp lipocytes and heart Lipolysis, thermogenesis, relaxation bladder detrusor muscle.

Answer 231

Nebivolol Metabolite is a beta3 agonist NO production up Vasodil

Answer 232

Want to relieve bronchospasm | Adr has higher efficacy than NA on beta2 receptors (present on smooth muscle of bronchus and trachea)

Answer 233

1. Peripheral excitatory Constrict blood vessles to skin, kidney and mucous membranes alpha1 2. Peripheral inhibitory Relax gut alpha1 Relax bronchial tree - breathe more beta2 Relax blood vessels to skeletal muscle beta2 3. Cardiac excitatory + ino and chrono beta1 4. Metabolic actions. Enhanced glycogenolysis and liberation FFAs from adipose beta2 and 3 5. Endocrine actions Endocrine modulation insulin secretion, renin secretion, pituitary hormones alpha2 6. CNS actions (resp stim, increase in wakefulness and psychomotor activity, reduction in appetite) 7. Prejunctional actions to inhibit mainly release NT alpha2

Answer 234

Beta1: + ino + chrono --> increased HR Alpha1: Constricts arterioles in skin, mucous membranes and viscera --> increase peripheral resistance Beta2: Vasodil skeletal muscle vascular bed --> decrease peripheral resistance So cumulative increase systolic BP slight decrease diastolic BP. slight decrease TPR. Increase HR

Answer 235

Alpha1: strong effect. Rise in TPR due to intense vasoconstriction most vascular beds. Increases both sys and dias BP to an extent high enough to stim baroreceptors --> vagal activity --> reflex bradycardia. If + atropine, stim of beta1 --> tachycardia. Beta2: doesn't induce compensatory vasodil So greater total vasoconstriction than Adr and large increase peripheral resistance. Increase sys and dias BP, decrease pulse rate.

Answer 236

Only acts on beta adrenoceptors Beta1: tachycardia Beta2: vasodil - decrease diastolic BP - Large drop BP

Answer 237

``` Alpha: Agonist Xylometazoline, methoxamine, Antagonist: Phentolamine, phenoxybenzamine Beta: Agonist: Isoprenaline Mixed: Propranolol, Agonist: Adr NA Antagonist: Labetalol, carvedilol mixed alpha1/beta ```

Answer 238

COPD and asthma Blockade of beta2 in bronchial smooth muscle can exacerbate condition and lead to a serious crisis. Diabetic receiving insulin Blockade of beta2 --> decreased glycogenolysis and decreased glucagon secretion (can lead to hypoglycaemia)

Answer 239

ATP and ACh Biphasic/twin-peaked First peak abolished by suramin (ATP antagonist) Late peak blocked by prazosin alpha1 adrenoceptor antagonist Completely abolished when both are present ACh in vas = erection

Answer 240

Need higher conc of Ca2+ to elicit release of peptide transmitters, so they are preferentially released at high rates of neural stim

Answer 241

Purinoceptors ATP ADM AMP Adenosine receptors P1/adenosine receptors A1 A2A A2B A3: Adenosine>AMP>ADP>ATP. GPCR P2: ATP>ADP>AMP>Adenosine Divided into P2X1-7: Ligand gated. Homo/heterotrimeric ATP-gated cation channels P2Y1,2,4,6,11-14: GPCR Gq. some don't know natural agonists yet.

Answer 242

Either from cytosol through large membrane channels e.g. pannexins Or from vesicles via Ca2+ dep exocytosis Or via NtT nucleotide transporters

Answer 243

Ectonucleotidases to ADP to Adenosine | Adenosine deaminase Adenosine to inosine

Answer 244

NsT nucleoside transporters

Answer 245

Non selective cation channels (equal Na+ K+ and with significant Ca2+ perm) ATP opens Homo or heterotrimer Each subunit comprises two transmembrane segments TM1 and TM2 separated by an ectodomain containing 10 conserved cysteine residues that form disulphide bonds. Disruption of these can sometimes impair trafficking of these proteins to the plasma membrane. Projects on an axis of symmetry projecting as a perpendicular from the cell membrane. ATP binding site formed between 2 adjacent subunits, so each receptor binds 3 ATPs.

Answer 246

P2X1 smooth muscle i.e. sympathetic to vas deferens, blood vessels. Fast response. Example - mice lacking P2X1 receptor gene have drastically reduced fertility because of much reduced sperm count. Maybe target as contraceptive? Also parasympathetic to urinary bladder fast response. P2X2,4,6 postsynaptic neurons. ATP released from urothelial cells when bladder distended, P2X3 mediate the nerve responses to distension, providing mechanosensory feedback involving both the micturition reflex and pain. Maybe target in pain and detrusor instability?

Answer 247

Dipyridamole - blocks NsT so indirectly increases the concentration of extracellular adenosine Methotrexate, unsure how.

Answer 248

Stressful conditions (Hypoxia, ischaemia) --> endothelial cells, neutrophils, cardiomyocytes, smooth muscle cells, glial cells release ATP through pannexins/connexions --> dephos to adenosine by ectonucleotidases

Answer 249

``` A1 Gi/o. Slows rate and force of contraction in the heart. So used to terminate supraventricular tachycardia. Presynaptic inhibitory effects on release of excitatory NT in CNS and periphery. A2A Gs A2B Gs - both 2A and 2B relaxation vascular smooth muscle cells. A3 Gi/o Ischaemic preconditioning Potentially anti-inflammatory act via cAMP Some also via PLC and thus Ca2+, MAPK Can alter KV and CaV ```

Answer 250

Caffeine competitive antagonist A1 | theophylline

Answer 251

1. Neuronal NOS: CNS and NANC nerves 2. Inducible NOS: induced in macrophages and other cells by bacterial LPS and other inflammatory cytokines ie IFNgamma 3. Endothelial NOS: expressed in platelets and endothelial cells

Answer 252

Shear stress (force exerted on blood vessel wall by movement of blood past it) Protein kinase B/Akt (ca2+ independent) NO diffuses activates sGC via interacting with haem moiety of the enzyme cGMP PKG Relaxation smooth muscle Tonic release NO needed for maintenance of a normal BP NO also inhibits platelet aggregation NO also activates some K+ channels, esp KCa, which hyperpolarises the vascular smooth muscle NO inhibits monocyte adhesion and migration, adhesion and aggregation of platelets, and smooth muscle and fibroblast proliferation Summary: antiatherosclerotic and antihyeprtensive

Answer 253

cGMP present in absence of light Binds to and activates cGMP gated ion channel Na+ and Ca2+ influx (dark current) Depolarises outer segment of photoreceptors

Answer 254

Upper airways, GI tract, male sexual organs GI: NO regulates muscle tone of sphincter in the lower oesophagus, pylorus, sphincter of Oddi, anus. Accommodation reflex fundus. Peristaltic reflex of intestine. nNOS disorders may be responsible for motility disorders in the GI tract.

Answer 255

Diabetes Type I - reduced sec insulin - reduced nNOS protein in enteric neurons - inadequacy in NO-mediated NANC transmission - distended stomach and pyloric hypertrophy

Answer 256

Oesophagus cannot move food down | Loss of nitrergic neurons supplied to oesophageal sphincter muscles

Answer 257

NPY NA | VIP cholinergic

Answer 258

Dense-cored granules do not cluster at the active zone | Requires a more generalised increase in intracellular Ca2+

Answer 259

Not rapidly removed from ECF - their action terminated by diffusion or by extracellular peptidases.

Answer 260

Purinergic Nitrergic Neuropeptides

Answer 261

N EPSP M2 IPSP M1 slow EPSP Peptides late slow EPSP

Answer 262

Substance P CCK VIP

Answer 263

Leucine encephalin alpha-endorphin Dynorphin A

Answer 264

Vasopressin Oxytocin ACTH

Answer 265

TRH LHRH (LH) Somatostatin (GHIH)

Pharmacology of Peripheral NT Flashcards

(295 cards)