PBL 5 - metabolism in ischaemia and hypoxia Flashcards
where does oxidative cellular metabolism occur?
mitochondria
how do cardiac myofilaments generate contraction?
the lattice of filaments in heart cells of actin and myosin pull themselves past one another to generate shortening and to generate cardiac contraction
how is glucose delivered to cells?
blood flow
what is the main way glucose is metabolised in cells?
glycolysis
describe A level glycolysis
glucose —ATP—> glucose-6-phosphate —> fructose-6-phosphate —ATP—> fructose-1,6-diphosphate —> 2 x triose phosphate —ATP and NADH2 —> intermediates —ATP—> PYRUVATE
what is the aim of glycolysis?
to metabolise glucose from 6 cartons to 2x 3 carbon units, generating ATP. endpoint is pyruvate
what is the lactate and pyruvate equation?
lactate + H+ —> pyruvate
what happens to lactate usually?
it is a waste product so must be removed from the cell
what is anaerobic metabolism?
glucose —>pyruvate—>lactate
what is mitochondrial metabolism?
krebs cycle = major way ATP is produced (couple dozen per pyruvate molecule)
what does the krebs cycle require?
oxygen
what is glycogen?
backup storage form of glucose
why does ischaemia lead to impaired metabolism?
can’t get rid of waste products therefore lactate stays in cell — impaired metabolism
what are the metabolic changes in the 1st few minutes?
- no O2 —> no oxidative (mitochondrial) metabolism
- cell consumes ‘high energy phosphate’ back up = Phosphocreatine (PCr) to maintain [ATP]i
- anaerobic metabolism switches on to maintain [ATP] — produces lactate and H+
- lactate accumulates in EC space and cytosol
- contractility impaired by metabolic changes (increased Pi and reduced pHi)
how is PCr used to make ATP?
PCr + ADP ATP + creatine
ATP is being broken down and made at the same time so what is the net reaction of PCr?
PCr —> Pi + creatine (‘backup ATP’)
what is the whole reaction for anaerobic metabolism starting with glucose?
glucose + ADP + Pi —> ATP + lactate + H+
instead of glucose, what is mainly broken down in ischaemia and why?
blood supply is lost — glycogen broken down
equation for glycogen break down. effects?
glycogen —> lactate + H+
- acidic inside cell — lactic acid made and is retained in tissue
- ATP maintained in short term
hypoxia vs. ischaemia vs. anoxia
hypoxia = still some blood flow
ischaemia = no blood flow
anoxia = total absence of O2 (not really seen clinically)
effect of defibrillator?
- some blood flow restored to most of body
- not to infarct zone
what does the infarct ed myocardium not generate?
a normal contraction
after 10-45 mins, what is happening in the infarcted myocardium?
- glycolysis becoming inhibited — anaerobic metabolism has been the only thing keeping ATP levels up
- glycogen reserves depleted
- cells full of lactic acid that can’t get out
- intracellular pH now very acidic
- [ATP] falling
what is the estimated [ATP] inside cardiac cells?
7/8/9 10mM
what is a rigor contracture?
when ATP gets really low, the actin and myosin filaments lock
what doesn’t occur in ischaemia?
- no flow — so no delivery of things like glucose
- no washout
- no removal of things like: lactate + H+, K+ (channels, loss of pumping), adenosine (ATP breakdown), toxic things (eg. glutamate in stroke)
describe the infarcted zone of myocardium in late phase ischaemia
- [ATP] is now microM at best
- ion pumps have no fuel
- [Na+] and [Ca++] in cells rise
- Ca++ rise in particular triggers cell damage
- compromised mitochondria release ‘cell death trigger factors’
- some cells lose membrane integrity — even more Ca++ rise, leak cellular contents = necrosis
difference in damage between core and outer infarcted zones
- core — damage is really bad
- outer — damage is less bad — hypoxic rather than totally ischaemic, cells probably still getting some sort of O2 delivery or perfusion by collateral flow
describe reperfusion
- EC space washout
- cells can re-start metabolism… hopefully (some already dead/too damaged)
- ATP used to pump out ‘extra’ [Na+] and [Ca++] in cells — however still not much ATP
- ‘reperfusion damage’ — more Ca++, free radicals — some cells will not survive
describe the mixture of cells in the infarct zone
- already necrosis (membrane integrity lost)
- too damaged even to do apoptotic shutdown —> necrosis
- too damaged to repair —> apoptosis
- damaged but can self-repair
what organs can sustain anoxic/ischaemic damage?
all… eg. :
- heart (infarction)
- brain (ischaemic stroke)
- kidney (acute renal failure)
- bowel (infarct, torsion)
- muscle (crush, compartment syndrome)
- pancreas (pancreatitis)
cellular damage that compromises membrane integrity leads to what?
loss of cellular contents to ECF
give examples of cellular contents lost to ECF that can be detected in the blood
- troponin-C (heart muscle)
- myoglobin/creatine kinase (muscle)
- amylase (pancreas)
