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88 Cards in this Set
- Front
- Back
How many carbons are in eicosanoids?
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20 (“eicosa” Greek for 20)
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What are eicosanoids primarily produced from?
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Arachidonic acid
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T/F
Eicosanoids are local mediators (lipids) that act where synthesized or in adjacent cells. |
True!
autocrines & paracrines |
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T/F
Eicosanoids are transported in the blood. |
False!
Unlike hormones, they are not transported in the blood |
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What are the 4 major classes of eicosanoids?
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Prostaglandins, leukotrienes, thromboxanes, and lipoxins.
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T/F
Eicosanoids exert control over only a few physiological processes. |
False!
They exert control over a wide range of physiological processes. |
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Many of the effects of eicosanoids are mediated by what (2 answers)?
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Cyclic AMP or calcium second messengers
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Name the 20-carbon ω-6 FA precursor of eicosanoids.
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Arachidonic acid (AA)
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Most arachidonic acid (AA) in the human body is synthesized from what?
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Dietary linoleic acid (essential FA, 18:3 ω-6)
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What enzyme frees arachidonic acid from phospholipid molecule?
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Phospholipase A2
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alpha-Linolenic acid (ALA) is a omega-____ fatty acid.
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3
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Which is more stable: alpha-linolenic acid (ALA) or linoleic acid?
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Linoleic acid (omega-6 more stable than omega-3)
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Which FA is converted in the body to EPA (eicosapentaenoic acid) then to DHA (docosahexaenoic acid)?
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alpha-Linolenic acid (ALA)
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Which metabolites are more inflammatory: metabolites of omega-6 FAs or omega-3 FAs?
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Metabolites of omega-6 FAs
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* What is the range for the healthy ratios of omega6/omega3?
What types of oil have a healthy ratio in this this range? |
From 1:1 to 4:1
*if too much omega 6, too much prostaglandins & overreaction to stress will occur Canola and sometimes olive oil. |
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What factors can activate phospholipase A2 (PLA2)?
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Mechanical trauma (stress), histamine, cytokines, and growth factors.
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What factors can inhibit PLA2?
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Anti-inflammatories, glucocorticoids, and cortisone.
*glucocorticoids (cortisol) through the release of annexins (lipocortins) |
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T/F
Glucocorticoids' effect on phospholipase A2 will cause release of arachidonic acid from membrane lipids. |
False!
This would actually inhibit phospholipase A2, thereby inhibiting release of AA from lipids. |
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What are the enzymes in the 3 pathways that free arachidonic acid is converted to eicosanoids?
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Cyclooxygenases/COX isozymes (constitutive COX-1 and inducible COX-2)
*by most cells Lipoxygenases/LOX enzymes (5-LO, 12-LO, 15-LO) *predominantly be inflammatory cells, eisinophils, monocytes, & epithelia cells Cytochrome P450/P-450 epoxygenase |
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a) Which enzyme(s) catalyze(s) the formation of PGH2?
b) Then, cell-specific PG synthases convert PGH2 to what compounds? |
a) COX isozymes (constitutive COX-1 and inducible COX-2)
b) Prostaglandins, prostacyclin and thromboxanes. |
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Which enzyme(s) catalyze(s) the formation of:
a) LTs b) 12-HETEs c) Lipoxins (LXs) |
LOX enzymes
a) 5-LO b) 12-LO c) 15-LO |
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Which enzyme(s) catalyze(s) the formation of hydroxyeicosatetraenoic acids (HETEs) and epoxides?
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P-450 epoxygenase
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Prostaglandins can be produced from ___(how many?)____ different precursors, but the major pathway uses what as a precursor?
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3
Arachidonic acid |
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a) In the synthesis of prostoglandins and thromboxanes from arachidonic acid, what enzyme is the inital step (AA --> PGG2) catalyzed by?
b) What change is occuring at this step? (think organic chem) c) The next step is ______-specific. |
a) Cyclo-oxygenase
b) Hydroperoxy group is reduced to hydroxyl group c) Tissue |
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NSAIDs inhibit what enzymes?
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Cyclooxygenases
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Aspirin is a(n) (reversible/irreversible) inhibitor of COX-1 and COX-2.
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Irreversible
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T/F
Platelets are able to produce cyclooxygenases de novo. |
False!
Platelets cannot produce cyclooxygenases de novo. |
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____________ of the active site of COX-2 changes its catalytic activity.
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Acetylation
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When COX-2 is modified by acetylation, it converts arachidonic acid(AA) to what?
If EPA or DHA are used instead of AA, what will the modified COX2 produce? |
15R-HETE
resolvins |
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What enzyme converts 15R-HETE to lipoxins?
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Leukocyte 5-LO
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Aspirin inhibits the production of (pro/anti)-inflammatory eicosanoids, but stimulates synthesis of (pro/anti)-inflammatory eicosanoids.
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inhibits proinflammatory
stimulates antiinflammatory |
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Acetaminophen and ibuprofen are (reversible/irreversible) inhibitors of COX-1 and COX-2.
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Reversible
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Salicylate is the same thing as:
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Aspirin
(Excedrin, Alka-Seltzer) |
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Para-aminophenol is the same thing as:
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Acetaminophen
(Tylenol) |
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Aryl-proprionic acid is the same thing as:
Propanoic acid is the same thing as: |
Ibuprofen (Advil, Motrin)
Naproxen (Aleve) |
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What effect does aspirin have on COX-1 & COX-2?
What is a side effect due to COX-1 inhibition? |
COX-1: Reduces platelet aggregation (TxA2).
COX-2: reduces inflammation Stomach irritation Because the prostaglandins produced in COX-1 pathway are important in production of gastric acid and gastric mucosa (overproduction of gastric acid, higher acidity, irritation) |
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What are a couple examples of specific COX-2 inhibitors?
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Celebrex/Vioxx
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What is the benefit to celebrex/vioxx over aspirin?
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They target the inflammatory response, but there is no COX-1 inhibition to produce aspirin-induced side effects (stomach irritation).
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What are the effects of PGI2, PGE2, and PGD2?(
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Increase:
vasodilation and cAMP Decrease: platelet aggregation, leukocyte aggregation, IL-1 and IL-2, T-cell proliferation, and lymphocyte migration **antagonist to PGF2 |
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What are the effects of PGF2?
What are the effects of Thromboxane A2 (TXA2)? |
(PGF2) Increases:
vasoconstriction, bronchoconstriction, & smooth muscle contraction (TXA2) Increases: vasoconstriction, platelet aggregation, lymphocyte proliferation, bronchoconstriction |
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Prostaglandins and thromboxanes are inactivated (slowly/rapidly).
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Rapidly
Half-lives range from seconds to minutes. |
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a) What are prostaglandins inactivated by (2 things)?
b) What gets excreted in the urine? c) Enzymes necessary for prostaglandin synthesis are located where? |
a) Oxidation of 15-hydroxyl group to a ketone
Reduction of double bond at carbon 13 b) Subsequent beta- and omega-oxidation of nonring portion results in dicarboxylic acid excreted in urine c) in specific cell types based on the particular prostaglandin |
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TxA2 is metabolized to what by cleavage of the oxygen bridge between carbons 9 and 11?
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TxB2
TxB2 does not have any biological activity. |
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*a) Which prostaglandin or thromboxane causes platelet aggregation (Thrombus) and vasoconstriction?
b) It is converted from PGH2 in the _________ via ___________. |
a) TXA2 (Thrombus)
b) Platelets, thromboxane synthase |
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*a) Which prostaglandin or thromboxane is involved with sleep?
b) It is converted from PGH2 in the ___________ via _________. |
a) PGD2 (Drowsy)
b) CNS, mast and fat cells; isomerase |
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*a) Which prostaglandin or thromboxane is involved with wakefulness, pain, fever, inflammation, and renal arteriolar dilation?
b) It is converted from PGH2 in _________ via __________. |
a) PGE2 (Eye opener)
b) Many cells, isomerase |
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*a) Which prostaglandin or thromboxane is involved with platelet disaggregation, vasodilation, and decreased stomach acid secretion?
b) It is converted from PGH2 in ____________ via _________. |
a) PGI2 (Inhibits aggregation)
b) Endothelial cells, prostacyclin synthase |
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*a) Which prostaglandin or thromboxane is involved with labor induction?
b) It is converted from _______ via __________. |
a) PGF2a (Fetus)
b) PGE2, reductase |
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*Which prostaglandin that we learned is the only one that isn't converted directly from PGH2?
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PGF2a
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*Which prostaglandin or thromboxane is the central intermediate?
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PGH2 (Head of pathway)
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What are the fatty compounds that simulate the proinflammatory response in asthma?
What are they produced from? |
Leukotrienes
Leukocytes (also mast cells, eosinophils, & other immunocompetent cells) |
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Leukotrienes contain what typical structure?
What do they act through? |
Triene structure - three double bonds in series
(*not cyclic like rest) GPCR |
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a) What are formed by the incorporation of an O2 molecule onto a carbon of a double bond of arachidonic acid?
b) This results in formation of a ______________ group and rearrangement of the ______________. |
a) HPETEs and HETEs
b) Hydroperoxy, double bond |
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Lipoxygenases can act on which carbons of arachidonic acid (AA)?
Lipoxygenases convert AA to HPETE's in what molecules? |
5, 12, or 15
luekocytes or platelets |
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What is occuring (think o chem) in the conversion of HPETE to HETE?
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The unstable hydroperoxy group is being converted to a more stable hydroxyl group.
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Which enzyme produces the major leukotrienes?
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5-lipoxygenase
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Which leukotrienes is 5-HPETE converted to? And where?
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To LTA4
(which can then be converted to LTC4 or LTB4. LTC4 is then converted to LTD4 & LTE4) In leukocytes and mast cells |
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What does zyflo inhibit?
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5-lipoxygenase, and therefore leukotriene synthesis
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Which leukotriene(s) increase(s) vascular permeability, T-cell proliferation, lymphocyte aggregation, INF-y, IL-1 and IL-2?
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LTB4
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Which leukotriene(s) increase(s) bronchoconstriction, vascular permeability, and INF-y (contributing to asthma & edema)?
What does Singular do? |
LTC4 and LTD4
*LTC4, LTD4 & LTE4 = cysteinyl luekotriens (all contain Cys) Singular blocks LTD4 receptors, prevents smooth muscle contstriction in airways, treats asthma |
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Name the series of anti-inflammatory mediators that are short-lived nonclassic eicosanoids.
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Lipoxins
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Which 2 enzymes help form lipoxins?
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15-LOX and 5-LOX
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Which lipoxin acts to oppose some leukocyte responses to leukotrienes?
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LXA4
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a) Which action(s) of LTB4 does LXA4 inhibit?
b) Which action(s) of LTD4 does LXA4 inhibit? |
a) Chemotaxis and degranulation of polymorphonuclear leukocytes.
b) Vasoconstriction |
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How is 15-epi-LXA4 (ATL) produced?
What is the effect of ATL? |
ATL (aspirin triggered lipoxin) is formed when aspirin modifies COX-2 & redirects catalytic activity
(^this can be prevented via NSAIDS) ATL has an inhibitory effect on inflammation & carcinogenesis |
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Anandamine is produced from:
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Phosphatidylethanolamine
(which is originally AA, AA is transferred to amino group of ethanolamine) |
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What enzyme releases anandamine?
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Phospholipase D
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Anandamine promotes what type of an effect?
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Analgesic effect
via Cannabinoid receptors |
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What enzyme degrades anandamine?
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Hydrolase
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Which eicosanoids are increased in chronic inflammatory conditions?
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PGs and LTs
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Granulocytes, macrophages, neutrophils, platelets, mast cells and endothelial cells are involved in eicosanoid production during what?
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Inflammation
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What 5 things do eicosanoids act as during inflammation? (also, for each one, what is the eicosanoid(s) performing the action)
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Proinflammatory molecules (PGH2)
Chemoatractants (LTB4) Platelet aggregating factors (TXA2) Contractors of smooth muscle (CysLTs) Modifiers of vascular permeability (LTs) |
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Which eicosanoids can act as both proinflammatory and anti-inflammatory mediators depending on the array of EP (E-prostanoid) receptors with different signal transduction pathways?
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PGs
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In (white/gray) matter, there is a higher proportion of omega-6 than omega-3 PUFAs.
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White
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T/F
Normal endothelium supports platelet adhesion or blood coagulation. |
False!
Normal endothelium does NOT support platelet adhesion or blood coagulation. It has antithrombotic properties. |
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Normal endothelium produces what to inhibit thrombosis?
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Prostacyclin or prostaglandin I2 (PGI2)
Nitric oxide, also known as endothelium derived relaxing factor (EDRF) Heparin sulfate and thrombomodulin |
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What is the action of prostacyclin or prostaglandin I2 (PGI2)?
What is the action of EDRF? |
Prevents platelets aggregation
stimulates smooth muscle relaxation |
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What is the action of heparin sulfate and thrombomodulin?
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Both inhibit thrombin action
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Hemostasis is the process of blood clotting & subsequent clot dissolution. What are the 4 major events
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1. Vascular phase
2. Platelet phase 3. Coagulation phase 4. Fibrinolytic phase |
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What leads to the activation of PLA2 and activation of platelets?
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Binding of platelets to exposed collagen + Ca2+
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Activation of PLA2 → release of _________________ → production of ___________________.
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Arachidonic acid and thromboxane A2 (TXA2)
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Contents of granules are secreted in response to what?
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Platelet activation
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What do granules contain which promotes platelet aggregation, degranulation, and vasoconstriction?
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TXA2
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What does prostacyclin (PGI2) cause in endothelial cells? and platelets?
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Endothelial cells - increased cAMP/vessel smooth
muscle relaxes. Platelets - increase in cAMP and decreased aggregation |
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What does TxA2 cause in endothelial cells? in platelets?
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Endothelial cells - increased Ca2+/vessel smooth muscle constricts
Platelets - increase in Ca2+ and increased aggregation |
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Platelet aggregation is controlled by what 3 things?
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By the balance in production of TXA2 and PGI2
By drugs NSAIDs (aspirin) By dietary intervention |
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How can platelet aggregation be controlled by NSAIDs (aspirin)?
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Platelets lack nucleus; cannot replace COX – production of TXA2 is preferentially inhibited.
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How can platelet aggregation be controlled by dietary intervention?
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Supplementation of omega-3 reduces production of proinflammatory eicosanoids.
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