Lecture 6 (Coronary Bloodflow and Angina)

Question 1

What two molecules are key to promoting vasodilation?

Answer 1

• Cyclic GMP and protein kinase G (PKG).
• Anytime cGMP or PKG is unregulated in a VSM cell, the VSM will relax.

Question 2

Low epinephrine levels cause:

High epinephrine levels cause:

Answer 2

• low epinephrine: vasodilation via β2
• high epinephrine: vasoconstriction via α1

Question 3

Steps in low epinephrine levels causing vasodilation:

Answer 3

1. low epinephrine levels
2. β2 adrenoreceptors
3. epithelial nitric oxide synthase (eNOS)
4. NO
5. guanalyl cyclase
6. cGMP
7. PKG
   
   • PKG inactivates calcium channels, preventing contraction and vasoconstriction, and activates SERCA channels, calcium flows out and VSM relaxes.

Question 4

How does protein kinase G (PKG) cause vasodilation?

Answer 4

1. prevention of calcium inflow via Type-L calcium channel isoform inactivation.
2. promotion of calcium outflow via SERCA channel activation.

• decreased sarcoplasmic calcium levels causes VSM relaxation and vasodilation.

Question 5

Vasodilatory factors (7):

Answer 5

1. CO₂
2. NO
3. H+ (protons)
4. lactic acid (protons)
5. adenosine
6. thrombin
7. histamine

Question 6

Steps in vasodilatory factors (CO2, protons, etc.) causing vasodilation:

Answer 6

1. bind to specific receptors
2. epithelial nitric oxide synthase (eNOS)
3. Nitric oxide
4. guanalyl cyclase
5. cGMP
6. PKG
   
   • PKG inactivates calcium channels, preventing contraction and vasoconstriction, and activates SERCA channels, calcium flows out and VSM relaxes.

Question 7

Steps in vasoconstriction:

Answer 7

1. epi/norepi
2. α1 adrenoreceptors VSM
3. Gq proteins
4. PLC
5. PKC
   
   • PKC activates calcium channels causing calcium influx and inactivates SERCA channels via arachadonic acid/PGF2α

Question 8

Primary protein involved in vasodilation and primary protein involved in vasoconstriction:

Answer 8

• vasodilation: PKG
• vasoconstriction: PKC

Question 9

How are SERCA channels inactivated during vasoconstriction:

Answer 9

• PKC and arachadonic acid activate PGF2α
• PGF2α inactivates SERCA channels

Question 10

What causes vasoconstriction at low levels of SNS tone, and what causes vasoconstriction at moderate to high levels of SNS tone?

Answer 10

• low SNS tone: norepi
• mod-high SNS tone: norepi, epi, ATP, NPY

Question 11

The vascular network is comprised of three functional components:

Answer 11

• resistance (arteries and arterioles)
• exchange (capillaries)
• capacitance (veins)

Question 12

Right atrial response to low pressure (low RAP) and high pressure (high RAP):

Answer 12

• Low pressure: low pressure baroreceptor activated; SNS tone increased.
• High pressure: ANP released in response to volume overload. Vasodilation.

Question 13

As RAP (venous return) increases, what must also increase?

Answer 13

• cardiac output.
• necessary in order to maintain proper pressures.

Question 14

Steps in how a sick left heart leads to an increase in RAP:

Answer 14

1. reduced EF = increased LVP.
2. back pressure from LV to LA.
3. back pressure from LA to pulmonary veins.
4. Pulmonary BP increases; increased afterload on RV.
5. increased RVP.
6. back pressure on RAP; RAP rises.
7. venous return decreases; LV works harder to maintain CO.

Question 15

What does increased RAP lead to?

Answer 15

1. reduction in venous return; increased venous pressure.
2. possibly hepatic-portal hypertension (IVC).
3. possibly jugular vein distention (SVC).

Question 16

When does maximal and minimal coronary blood flow/oxygen uptake occur?

Answer 16

• maximal: diastole
• minimal: systole

Question 17

What occurs to coronary VSM in the presence of reduced flow/oxygen levels?

Answer 17

1. oxidative phosphorylation and generation of ATP impaired.
2. formation of ADP, AMP, and ultimately adenosine.
3. adenosine blocks Ca2+ entry into VSM.
4. vasodilation.

Question 18

Adrenoreceptors mediating coronary VSM contraction (vasoconstriction):

Answer 18

• α1 and α2 adrenoreceptors
• MOSTLY α2 adrenoreceptors

Question 19

Effect of SNS tone on coronary VSM in healthy and non-healthy hearts:

Answer 19

• healthy: SNS binding to α2 adrenoreceptors does not cause vasoconstriction. Vasodilation occurs due local vasodilatory metabolites (CO2 and protons) produced via myocardium work.
• non-healthy: local vasodilatory metabolites not produced at sufficient levels. SNS tone causes vasoconstriction of coronary VSM and ischemia.

Question 20

During physiologic conditions, how do the coronary arteries maintain a state of relative vasodilation?

Answer 20

• local production of vasodilators by (healthy) vascular endothelium during contraction.
• if impaired, SNS causes vasoconstriction, which leads to ischemia.

Question 21

The major determinants of myocardial O2 requirements in order of demand:

Answer 21

1. ventricular wall stress (i.e. systolic ventricular pressure)
2. HR
3. contractility (inotropic state)

Question 22

Ischemia is:

Answer 22

• a localized anemia due to a reduction in blood supply.

Question 23

Ischemic heart disease results from:

Answer 23

• an imbalance between O2 supply and myocardial demand

Question 24

Cause of dyspnea due to cardiac ischemia:

Answer 24

1. impediment in coronary blood flow.
2. localized anemia.
3. decreased oxygen levels.
4. impaired LV function.
5. increased LVP; increased LAP; increased pulmonary BP.
6. dyspnea.

Question 25

Two general mechanisms underlie the pathophysiology of cardiac ischemia/angina:

Answer 25

1. fixed vessel narrowing (e.g. atherosclerotic plaques)
2. abnormal vascular tone (e.g. VSM dysfunction)

Question 26

Angina pecotoris is:

Answer 26

• chest pain/discomfort due to cardiac ischemia to one or more part of the ventricular myocardium.
• resolves upon rest.

Question 27

ECG manifestation of chronic stable angina:

Answer 27

1. inverted or flattened T waves
2. ST depression

Question 28

What does the ECG show?

Answer 28

ST depression

possible angina/cardiac ischemia

Question 29

Steps in the cause of ischemic chest pain:

Answer 29

1. hypoxia due to ischemia.
2. hypoxia decreases ATP production and increases lactic acid.
3. decreased ATP compromises Na+/K+ ATPase and increases adenosine.
4. increased lactic acid causes local acidosis.
5. sarcolemma integrity compromised and myocardial injury occurs.
6. adenosine and injured myocardium compounds bind to nociceptors.

Question 30

Hypoxia due to ischemia ultimately causes what three symptoms related to angina?

Answer 30

1. tachycardia (SNS activation)
2. diaphoresis (SNS activation)
3. dyspnea (decreased LV function leads to pulmonary BP increase)

Question 31

Medications for angina based on angina physiology (4):

Answer 31

• angina is due to cardiac ischemia:
  
  1. vasodilator (NO)
  2. beta-blocker (negative inotrope; decrease oxygen demand)
  3. calcium channel blockers (vasodilate and decrease HR)
  4. ranolazine (impairs prolonged late Na+ current)

Question 32

The two sodium currents of cardiac myocyte depolarization (plateau potentials):

Answer 32

1. early current
2. late current (I_NAL)

Question 33

What sodium current is prolonged in cardiac myocyte depolarization in ischemic myocardium?

Answer 33

• late current (I_NAL)

Question 34

How does a prolonged late current (INAL) excaberate angina/cardiac ischemia?

Answer 34

1. more Na+ enters myocytes.
2. NCX function impaired, more Ca2+ in myocytes.
3. increased Ca2+ levels impairs LV relaxation.
4. LV wall tension increases.
5. LV oxygen demand increases.

Question 35

What drug blocks a prolonged late current (INAL) during cardiac myocyte depolarization?

Answer 35

ranolazine