Reperfusion Injury

Question 1

What happens to the cardiomyocyte during ischemia?

Answer 1

switches to anaerobic respiration (glycolysis) generating lactic acid, lowering the pH, and inhibiting myofibril contracture.

Question 2

What happens to the cardiomyocyte during reperfusion?

Answer 2

washout of lactic acid occurs and restoration of physiological pH, however this leads to uncoupling of the electron transport chain in the mitochondria, generating ROS, opening the MPTP and stimulating the SR to release excess calcium causing myofibril hypercontracture= BAD causing elevated LVEDP.

Question 3

Why is timely reperfusion necessary?

Answer 3

to reduce the accumulating infarct size that occurs as a result of ischemia

Question 4

What are some characteristics of I/R injury?

Answer 4

1. increased ROS= due to incomplete reduction of O2, uncoupled eNOS (oxidation of BH4 to BH2), or SO generation.
2. Initiate lipid peroxidation= cytokine release
3. leukocyte chemotaxis= TNFa from injured cells attracts leukocytes
4. decreased endothelial derived NO= SO combines with NO forms peroxynitrite :(

Question 5

Is INHIBITING eNOS UNCOUPLING a good thing or bad thing?

Answer 5

GOOD thing

Question 6

What is the time course of events in myocardial I/R?

Answer 6

2-5 min= endothelial dysfunction (low NO, more ROS)
10 min= upregulation of P-selectin (mediated by PCAM-1)
20 min= increased adhesion of PMNs to endothelium
30 min= PMN migration into myocardium
* AKA stop the ROS or increase the NO, ASAP

Question 7

What are the biochemical mechanism of ROS in I/R?

Answer 7

I/R sitimulates cytokine receptors, which stimulates DAG, activating PKC, which uncouples eNOS causing the oxidation of BH4 to BH2 :(

Question 8

What are the types of experimental I/R injury?

Answer 8

1. clinical I/R injury (ischemic heart disease)

2. Experimental I/R injury= acute ischemia vs. preconditioning

Question 9

What causes ischemic heart disease (IHD)?

Answer 9

coronary artery disease (atherosclerotic coronary arterial disease)

Question 10

How can we restore blood flow?

Answer 10

1. angioplasty (PCI)
2. thrombolysis
3. Coronary artery bypass and grafting

Question 11

What treatments attenuate I/R injury?

Answer 11

currently there are no therapeutics to treat this.
Experimentals:
- anti-oxidants (vitamin E) but not benefical
- NO bioavailability enhancer (inhibit uncoupled eNOS)
- Anti-inflammation

Question 12

***What is PREconditioning?

Answer 12

• PRIMING THE HEART by inducing BRIEF periods of ISCHEMIA (3 min I/R x 3) protects the organ from prolonged ischemic damage and reperfusion injury prior to reperfusion. Basically think pumping up a blood pressure cuff and releasing it 3 times to protect/prime the heart from later prolonged ischemia.
• biochemical response is mediated by PKC EPSILON ACTIVATION involving activation of mitochondrial K-ATP channels. Remember, PRIOR to prolonged ischemia!

Question 13

**What is POSTconditioning?

Answer 13

PKC EPSILON INHIBITION during REPERFUSION is associated with restoration of post-reperfused organ function; attenuates H2O2 release and enhances endothelial-derived NO bioavailability :)

Question 14

What is the role of eNOS in I/R injury?

Answer 14

eNOS normally produces NO from L-arginine with the co-factor BH4 (tetrahydrobiopterin).
However in I/R, BH4 becomes oxidized to BH2 causing eNOS uncoupling, and thus SO production instead of NO.

Question 15

What will BH4 do to cardiac function in I/R injury?

Answer 15

attenuates I/R injury :)

Question 16

What will BH2 do to cardiac function in I/R injury?

Answer 16

augment I/R injury due to more uncoupled eNOS :(

Question 17

What does SOD do and is it good or bad?

Answer 17

converts SO to O2 or H2O2 (GOOD THING).