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48 Cards in this Set
- Front
- Back
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State the functions of NO |
- Vasodilation therefore lowers BP - Anticoagulant - Antiatherogenic - Smooth muscle relaxation - Cytotoxic agent used in immune cells - Neurotransmitter - Reduced vascular permeability - Anti-leukocyte adhesion (prevent E-selectin mediated neutrophil recruitment therefore anti-inflammatory) |
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NOS-III is aka? Also what are its properties? |
aka eNOS (endothelial NOS) - Constituative (always present) - Requires Ca and calmodulin - Requires co-factors (NADPH, FAD, FMN and BH4) -Produces short pulses of NO (pM range) |
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NOS-II is aka? Also what are its properties? |
aka iNOS (inducable/immune NOS) - Inducable (not always present) - High amounts of NO released (micromolar range, cytotoxic) - Does not require Ca or calmodulin - Requires co-factors (NADPH, FAD, FMN and BH4) |
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NOS-I is aka? Also what are its properties? |
-Constituative (always present) - Requires Ca and calmodulin - Requires co-factors (NADPH, FAD, FMN and BH4) - Produces small amounts of NO for cell signalling |
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What effect does superoxide anion have on NO? |
NO is a free radical gas that reacts with superoxide anions to produce reactive nitrogen species (RNS) inactivating the NO |
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What does NO cause to smooth muscle K channels? |
Causes Ca efflux, leading to K influx causing hyperpolarization preventing further Ca influx. Preventing contraction. |
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What is the enzyme that forms arachadonic acid from membrane phospholipids? |
Phospholipase A2 |
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In the COX pathway, what is formed directly from the catalysis of arachadonic acid with COX? |
Cyclic endoperoxidases |
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What is the main function of TXA2? |
Vasoconstriction and Pro-thrombrotic agent Released from platelets |
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What is the main function of PGI2? |
aka Prostacyline Vasodilation and anti-thrombrotic agent (opposite to TXA2) A type of endothelium derived relaxation factor |
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What is meant by the omega number of a fat? |
How many carbons away from the non-carboxyl end of the fat is the first double bond |
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What is the omega number of arachodonate and what series of prostoglandins are produced? |
Aracodonate = omega 6 - produce the 2 series prostanoids |
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What series of prostanoids are produced by a person who has a diet high in omega 3 fatty acids? What is the significance of this? |
Omega-3 fatty acids will produce a different series of prostanoids (prostaglandins and thromboxanes) it will produce series 3 prostanoids instead of series 2 (with arachidonic acid) e.g. TX3 and PGI3 TX and PGI involved in control of platelet aggregation and blood vessel diameter TX-2 is a potent vasoconstrictor and potent pro-aggregatory agent where PGI-2 is a vasodilator and antiaggregatory agent However, TX-3 is a far less potent vasoconstrictor and pro-aggregatory agent and PGI-3 is a far more potent vasodilator and antiaggregatory agent, which is far healthier, and this is why omega-3 oils are considered better for you (due to using an omega-3 fatty acid as opposed to arachidonic acid in eicosanoid production |
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The main effects of PGD2 are: |
- Vasodilator - Decreased gastric acid secretion |
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The main effects of PGE2 are: |
- Vasodilator - Decreased gastric acid secretion |
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The main effects of PGF2 are: |
- Bronchoconstriction |
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The main effects of LTB4 are? |
Chemotactic agent used in neutrophil recruitment |
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The main effects of LTC4 are? |
- Bronchoconstriction (MOST POTENT) |
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The main effects of LTD4 are? |
- Bronchoconstriction |
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The main effects of LTE4 are? |
- Bronchoconstriction |
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How does asprin have anti-coagulant properties but other NSAIDs do not? |
Aspirin causes irreversible COX inhibition via acetylation COX is responsible for producing PGI2 (anti-aggregatory) and TX2 (pro-aggregatory) and therefore you would think aspirin would have no effect and that it would balance out But the effect comes from where abouts the prostanoids are made. PGI2 is generated in the endothelium (it is an endothelium derived relaxation factor) and the TX2 is generated in the platelets The endothelium can generate new enzymes and respond much faster to the inhibition when compared to the platelets and therefore there is a net anti-aggregatory effect |
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Describe histamine sythesis |
Histadine --> Histamine via histadine decarboxylase |
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Describe how histamine is stored |
w/ heperin mostly in white blood cells (mast cells and basophils) but also in histaminocytes within the stomach and presynaptic knobs within neurones |
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How is histamine release stimulated? |
- C3a + C5a - Or cross-linking Fc-Epsilon R1 IgE molecules with antigen - Increase in cAMP inhibit histamine release e.g. beta agonist |
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How is histamine metabolised? |
via histaminase or imidazole N-methyl transferase |
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What is the role of the H1 receptor |
Histamine binds, causing smooth muscle contraction and increased vascular perimability |
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Fexofenidine, Loratadine and Cetirazine are examples of: |
2nd generation H1 receptor antagonist |
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Chlorphenamine, Promethazine and Diphenhydramine are examples of: |
1st generation H1 receptor antagonists |
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Ranitadine, cimeridine and famatidine are examples of: |
H2 receptor antagonists |
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Describe the distribution of 5HT |
Majority in the enterochromaffin cells (around 90%) which run alongside epithelial cells that are released around food causing smooth muscle contraction. If the food is bad more serotonin will be released which increases motility rapidly causing an increase in G.I. motility and therefore diarrhea. If too much serotonin is released before platelets can take it up it will lead to binding with 5HT3 receptors in the brain stimulating vomiting.Central 5HT is usually from the Raphe nuclei within the medial portion of the reticular formation in the mid brain. Some found in myenteric plexus (excitatory neurotransmitter) Can enter platelets via active trasport, stimulating aggregation (5-HT leaves as aggregation occurs) |
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Describe the pathway for 5HT formation |
Tryprophan → 5-hydroxytryptophan via tryptophan hydroxylase → 5-HT via dopa decarboxylase |
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State a 5HT1D receptor antagonist and its use |
Sumatriptan (decrease cerebral vasoconstriction in migraine) |
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State a mixed 5HT3 antagonist/5HT4 agonist |
Metoclopromide for sickness |
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What is the most significant endothelin receptor, where is it present and what effect does it have? |
ET-A in smooth muscle Leads to broncho and vasoconstriction Leads to aldosterone secretion and therefore sodium and water retention Affinity: ET-1 = ET-2 > ET-3 |
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Describe the synthesis of endothelin |
Pre-Pro-Endothelin → Endothelin (via ECE endothelin converting enzyme) |
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State how endothelin release can be stimulated |
Activated platelets Thromboxane Angiotensin-II Hypoxia Low shear stress |
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State how endothelin release can be inhibited |
Endothelium derived relaxation factor (NO or PGI2) Atrial natriuretic peptide (powerful vasodilator) High shear stress |
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What is the intracellular mechanism of ET? |
Activated PLC - Increase DAG and IP3 therefore increase Ca release - Increasing smooth muscle contraction |
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What is rate limiting step in prostanoid synthesis? |
PLA2 mediated liberation of membrane phospholipid |
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Describe prostanoid synthesis, stating functions of major products (stating major roles of COX-1 and COX-2) |
1. Liberation of membrane phospholipids (e.g. phosphotidylcholine) via PLA2 to form AA (PAF byfactor, released by platelets, is pro-aggregatory, pro-inflammatory and spasmodic in bronchioles) 2. COX-1 (constuative) and COX-2 (inducible) convert AA into intermediary cyclic endoperoxidases (namely PGG2 and PGH2) 3. Family of synthase enzymes (e.g. prostacyclin synthase, thrombroxane synthase) then determine what prostanoids are formed Effects of prostanoids depend on the prostaglandin/thrombroxane receptor expressed (e.g. what G-protein is coupled) e.g. PGE2 binds to prostaglandin receptors on parietal cells of the stomach, leading to activation of Gi protein, which decreases gastric acid secretion) e.g. PGE2: Decreased GA secretion and vasodilation PGI2: Vasodilation and inhibition of platelet aggregation COX-1: – Gastric cytoprotection – Haemostasis – Regulation of platelet aggregation – Renal function COX-2:
– Inflammation + allergy states (therefore COX-2 mediated inhibition is preferable) |
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State a few uses and names of prostanoid-mimetics |
• Relief of gastric irritation/ulceration in NSAID therapy– E.g. misoprostol (PGE1 analogue) |
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eNOS is selectively inhibited by
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L-NIO |
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Describe pathophysiology linked with inadequate supply of NO
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Atherogenesis Vasospasm Thrombosis Essential hypertension Erectile dysfunction Achalasia Hypertrophic pyloric stenosis |
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Describe pathophysiology linked with over supply of NO |
Hypotension (in circulatory/ septic shock) Neuronal destruction (in senility) Ischaemic stroke Huntington’s disease Migraine Rheumatoid arthritis Osteoarthritis Asthma Psoriasis Crohn’s disease Type 1 diabetes mellitus |
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Describe modulation of NO signalling (increase and decrease in signalling
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Increase by: - Increased NO production by NOS E.g. by raising L-arginine or BH4, reducing ADMA or overexpressing NOS gene - Reduced inactivation of NO E.g. using antioxidants that scavenge superoxide anion, e.g. superoxide dismutase (SOD), tempol, ascorbate - Increased production of cGMP E.g. by directly activating sGC with e.g. ataciguat, YC-1 - Reduced inactivation of cGMP E.g. by inhibiting PDE V with e.g. sildenafil, tadalafil, vardenafil *Providing exogenous NO with NO donors / nitrovasodilators Decrease by: - Reduced NOS mediated NO production with NOS inhibitors e.g. L-NIL (iNOS specific) or L-NIO (eNOS specific) - Increased inactivation of NOS by increasing scavengers e.g. cobinamide and Hb - Reduce production of cGMP by inhibiting sGC w/methylene blue |
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How many types of endothelin are there? How many receptors are there |
ET-1, ET-2 and ET-3 (ET-1 most significant) ET-A and ET-B receptors (A most significant) |
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State some biological roles of 5-HT |
- Microvascular control - Gut motility - Emesis - Sleep (ARAS) - Mood - Pain perception - Visceral smooth muscle contraction - Appetite - Platelet aggregation - Pro-inflammatory |
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State which intracellular mechanism 5-HT1, 5-HT2, 5-HT3 and 5-HT4-7 receptors use
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5-HT1: Gi coupled 5HT-2: Gi coupled 5HT-3: Ligand gated ion channel 5HT-4: Gs coupled |
