Flashcards in Ischemia/Reperfusion- Exam 2 Deck (46)
Blood supply problem
What will the EKG show with myocardial ischemia?
Depressed ST segment
Inverted T wave
What causes myocardial ischemia?
Not enough blood
What will the EKG show for myocardial infarction?
Pathologic Q waves; permanently
What is released with myocardial infarction?
What will the EKG show for myocardial injury?
Elevated ST segment
Oxygen Free Radicals
Reactive Oxygen Species (ROS)
Altered O2 molecules created; at XC and reperfusion; reactions add unpaired electrons to outer orbit
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
How are reactive oxygen species created?
Xanthine oxidase releases in endothelial cells; catalyze: hypoxanthine to xanthine to uric acid
What enzyme is important in purine breakdown path?
Total depletion of O2; complete lack of O2
Lack of oxygen delivered to tissues
Lack of blood supply
Restoration of circulation
Reperfusion; can result in inflammation and oxidative damage through inducing oxidative stress rather than restoration of normal funcion
What abrupt biochemical and metabolic changes occur resulting in reperfusion injury?
Generative of reactive oxygen species
Intracellular calcium overload
Rapid restoration of physiologic pH
What does cell death result from? (related to reperfusion injury)
Opening of mitochondrial permeability transition pore and induction of cardiac myocyte hyper-contraction
What protects the heart from free radicals?
Antioxidant system (electron donators)
What are the three antioxidant system components?
What is the 5' nucleotidase system?
Converts AMP to adenosine
When is full recovery impossible?
If adenosine nucleotide pool <50% full recovery
What are the mediators of lethal reperfusion injury?
too much of a good thing: oxygen-derived free radical formation (reactive oxygen species ROS)
large influx of calcium into the cell
pH moves from acidic to normal- potentiates many of hte changes
What is depleted during ischemia?
Tissue stores of endogenous antioxidants
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
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
act like local hormones, act near sites of synthesis, short acting
What are the results of oxygen free radicals? (Know this)
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
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)
When is the mitochondrial permeability transition pore closed?
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
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)
What drugs remove oxygen free radicals?
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
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
What does activation of catalytic enzymes do?
increase cellular damage
Stone heart syndrome
calcium not removed after going onto the cell causing contraction sequence; can enter by multiple pathways
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
once bound to receptor molecule, blood goes through capillaries
What starts the activation of neutrophils?
P-selectin (endothelial cells) triggered by proinflammatory mediators (oxygen-derived free radicals/hydrogen peroxide) thrombin, complement components, histamine