PBL 5 - metabolism in ischaemia and hypoxia

Question 1

where does oxidative cellular metabolism occur?

Answer 1

mitochondria

Question 2

how do cardiac myofilaments generate contraction?

Answer 2

the lattice of filaments in heart cells of actin and myosin pull themselves past one another to generate shortening and to generate cardiac contraction

Question 3

how is glucose delivered to cells?

Answer 3

blood flow

Question 4

what is the main way glucose is metabolised in cells?

Answer 4

glycolysis

Question 5

describe A level glycolysis

Answer 5

glucose —ATP—> glucose-6-phosphate
—> fructose-6-phosphate 
—ATP—> fructose-1,6-diphosphate
—> 2 x triose phosphate 
—ATP and NADH2 —> intermediates 
—ATP—> PYRUVATE

Question 6

what is the aim of glycolysis?

Answer 6

to metabolise glucose from 6 cartons to 2x 3 carbon units, generating ATP. endpoint is pyruvate

Question 7

what is the lactate and pyruvate equation?

Answer 7

lactate + H+ —> pyruvate

Question 8

what happens to lactate usually?

Answer 8

it is a waste product so must be removed from the cell

Question 9

what is anaerobic metabolism?

Answer 9

glucose —>pyruvate—>lactate

Question 10

what is mitochondrial metabolism?

Answer 10

krebs cycle = major way ATP is produced (couple dozen per pyruvate molecule)

Question 11

what does the krebs cycle require?

Answer 11

oxygen

Question 12

what is glycogen?

Answer 12

backup storage form of glucose

Question 13

why does ischaemia lead to impaired metabolism?

Answer 13

can’t get rid of waste products therefore lactate stays in cell — impaired metabolism

Question 14

what are the metabolic changes in the 1st few minutes?

Answer 14

• 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)

Question 15

how is PCr used to make ATP?

Answer 15

PCr + ADP ATP + creatine

Question 16

ATP is being broken down and made at the same time so what is the net reaction of PCr?

Answer 16

PCr —> Pi + creatine (‘backup ATP’)

Question 17

what is the whole reaction for anaerobic metabolism starting with glucose?

Answer 17

glucose + ADP + Pi —> ATP + lactate + H+

Question 18

instead of glucose, what is mainly broken down in ischaemia and why?

Answer 18

blood supply is lost — glycogen broken down

Question 19

equation for glycogen break down. effects?

Answer 19

glycogen —> lactate + H+

• acidic inside cell — lactic acid made and is retained in tissue
• ATP maintained in short term

Question 20

hypoxia vs. ischaemia vs. anoxia

Answer 20

hypoxia = still some blood flow

ischaemia = no blood flow

anoxia = total absence of O2 (not really seen clinically)

Question 21

effect of defibrillator?

Answer 21

• some blood flow restored to most of body

- not to infarct zone

Question 22

what does the infarct ed myocardium not generate?

Answer 22

a normal contraction

Question 23

after 10-45 mins, what is happening in the infarcted myocardium?

Answer 23

• 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

Question 24

what is the estimated [ATP] inside cardiac cells?

Answer 24

7/8/9 10mM

Question 25

what is a rigor contracture?

Answer 25

when ATP gets really low, the actin and myosin filaments lock

Question 26

what doesn’t occur in ischaemia?

Answer 26

- 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)

Question 27

describe the infarcted zone of myocardium in late phase ischaemia

Answer 27

- [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

Question 28

difference in damage between core and outer infarcted zones

Answer 28

- 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

Question 29

describe reperfusion

Answer 29

- 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

Question 30

describe the mixture of cells in the infarct zone

Answer 30

- already necrosis (membrane integrity lost) - too damaged even to do apoptotic shutdown —> necrosis - too damaged to repair —> apoptosis - damaged but can self-repair

Question 31

what organs can sustain anoxic/ischaemic damage?

Answer 31

all… eg. : - heart (infarction) - brain (ischaemic stroke) - kidney (acute renal failure) - bowel (infarct, torsion) - muscle (crush, compartment syndrome) - pancreas (pancreatitis)

Question 32

cellular damage that compromises membrane integrity leads to what?

Answer 32

loss of cellular contents to ECF

Question 33

give examples of cellular contents lost to ECF that can be detected in the blood

Answer 33

- troponin-C (heart muscle) - myoglobin/creatine kinase (muscle) - amylase (pancreas)