Flashcards in Ischemia/Reperfusion- Exam 2 Deck (46)
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1
Ischemia
Blood supply problem
2
Injury
cellular damage
3
Infarction (necrosis)
cell death
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What will the EKG show with myocardial ischemia?
Depressed ST segment
Inverted T wave
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What causes myocardial ischemia?
Not enough blood
atherosclerosis
vasospasm
thrombosis
embolism
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What will the EKG show for myocardial infarction?
Pathologic Q waves; permanently
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What is released with myocardial infarction?
Troponin
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What will the EKG show for myocardial injury?
Elevated ST segment
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Oxygen Free Radicals
Reactive Oxygen Species (ROS)
Altered O2 molecules created; at XC and reperfusion; reactions add unpaired electrons to outer orbit
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5 reactions leading to O2 Radical Formation
1. NADPH + O2 = Superoxide O2-
2. Superoxide Dismutase O2- -> Hydrogen Peroxide H2 O2
3. Hydrogen peroxide + myeloperoxidase= hypochlorite HOCL
4. Hydrogen peroxide + Catalase = O2 + H20
5. Hydrogen peroxide + Fe++ = Hydroxyl Radical OH
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How are reactive oxygen species created?
Xanthine oxidase releases in endothelial cells; catalyze: hypoxanthine to xanthine to uric acid
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What enzyme is important in purine breakdown path?
Xanthine oxidase
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Total depletion of O2; complete lack of O2
Anoxia
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Lack of oxygen delivered to tissues
Hypoxia
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Lack of blood supply
ischemia
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Restoration of circulation
Reperfusion; can result in inflammation and oxidative damage through inducing oxidative stress rather than restoration of normal funcion
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What abrupt biochemical and metabolic changes occur resulting in reperfusion injury?
Mitochondrial reenergization
Generative of reactive oxygen species
Intracellular calcium overload
Rapid restoration of physiologic pH
Inflammation
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What does cell death result from? (related to reperfusion injury)
Opening of mitochondrial permeability transition pore and induction of cardiac myocyte hyper-contraction
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What protects the heart from free radicals?
Antioxidant system (electron donators)
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What are the three antioxidant system components?
Superoxide dismutase
Catalase
Glutathione reductase
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What is the 5' nucleotidase system?
Converts AMP to adenosine
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When is full recovery impossible?
If adenosine nucleotide pool <50% full recovery
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What are the mediators of lethal reperfusion injury?
Oxygen paradox
Calcium paradox
pH paradox
Inflammation
Myocardial edema
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oxygen paradox
too much of a good thing: oxygen-derived free radical formation (reactive oxygen species ROS)
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calcium paradox
large influx of calcium into the cell
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pH paradox
pH moves from acidic to normal- potentiates many of hte changes
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inflammation
neutrophil activation
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What is depleted during ischemia?
Tissue stores of endogenous antioxidants
-Superoxide dismutase
-catalase
-glutathione
-glutathione peroxidase
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What factors determine the amount of oxygen free radicals produced?
Severity of ischemic injury
actiavtion and recruitment of neutrophils to myocardium
Level of O2 in the cardioplegic solution
presence of endogenous scavengers and inhibitors
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What changes are caused my oxygen free radicals?
Peroxidation of lipid components of myocellular membranes (steal electrons from lipid membranes)
Impairment of vascular endothelial function; produces vasoactive and autoinflammatory autocoids
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Autocoids
act like local hormones, act near sites of synthesis, short acting
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What are the results of oxygen free radicals? (Know this)
Postischemic dysfunction
Dysrhythmias
morphologic injury
necrosis
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How do Oxygen free radicals cause injury?
Induce opening of mitochondrial permeability transition pore
act as neutrophil chemoattractants
mediate dysfunction of SR
contribute to intracellular calcium overload
damage cell membrane by lipid peroxidation
induce enzyme denaturation
cause direct oxidative damage to DNA
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What is the mitochondrial permeability transition pore?
Nonselective channel (protein)of inner mitochondrial membrane
when open increases the permeability of molecules <1500 daltons
when open oxidative phosphorylation is uncoupled (results in decrease in atp and cell death)
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When is the mitochondrial permeability transition pore closed?
During ischemia
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When is the mitochondrial permeability transition pore open?
During reperfusion; opens in response to mitochondrial calcium overload oxidative stress, resotration of physiologic pH, and ATP depletion
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How can we combat the oxygen free radical problem?
Drugs that inhibit their formation (anesthetic agents, antiarrythmics may eliminate hydroxyl radicals, vitamin C peroxides)
Drugs that scavenge/remove them
Antineutrophil agents (decrease ischemia reperfusion injury)
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What drugs remove oxygen free radicals?
Mannitol, N-acetylcysteine
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What changes are cause by myocyte calcium influx?
Depletion of high-energy phosphate stores;
Accumulation of mitochondria kills ability to produce ATP
Activation of catalytic enzymes
Alteration of excitation-contraction coupling of actin-myosin-tropnin
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Inability to produce ATP affects what?
Ability of the cell to contract
Ability of the cell to move calcium out of hte cell or back into the SR
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What does activation of catalytic enzymes do?
increase cellular damage
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Stone heart syndrome
calcium not removed after going onto the cell causing contraction sequence; can enter by multiple pathways
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What are the three types of receptor molecules that activate neutrophils?
selectins (P, L, E)- inital binding
Beta2 integrins (CD11/CD18 complex)- firmer contact
Immunoglobulin superfamily (ICAM-1)- final surface adherance
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Diapedesis
once bound to receptor molecule, blood goes through capillaries
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What starts the activation of neutrophils?
P-selectin (endothelial cells) triggered by proinflammatory mediators (oxygen-derived free radicals/hydrogen peroxide) thrombin, complement components, histamine
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