Lecture 6 (Coronary Bloodflow and Angina) Flashcards

1
Q

What two molecules are key to promoting vasodilation?

A
  • Cyclic GMP and protein kinase G (PKG).
  • Anytime cGMP or PKG is unregulated in a VSM cell, the VSM will relax.
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2
Q

Low epinephrine levels cause:

High epinephrine levels cause:

A
  • low epinephrine: vasodilation via β2
  • high epinephrine: vasoconstriction via α1
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3
Q

Steps in low epinephrine levels causing vasodilation:

A
  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.
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4
Q

How does protein kinase G (PKG) cause vasodilation?

A
  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.
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5
Q

Vasodilatory factors (7):

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

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

A
  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.
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7
Q

Steps in vasoconstriction:

A
  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
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8
Q

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

A
  • vasodilation: PKG
  • vasoconstriction: PKC
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9
Q

How are SERCA channels inactivated during vasoconstriction:

A
  • PKC and arachadonic acid activate PGF2α
  • PGF2α inactivates SERCA channels
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10
Q

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

A
  • low SNS tone: norepi
  • mod-high SNS tone: norepi, epi, ATP, NPY
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11
Q

The vascular network is comprised of three functional components:

A
  • resistance (arteries and arterioles)
  • exchange (capillaries)
  • capacitance (veins)
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12
Q

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

A
  • Low pressure: low pressure baroreceptor activated; SNS tone increased.
  • High pressure: ANP released in response to volume overload. Vasodilation.
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13
Q

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

A
  • cardiac output.
  • necessary in order to maintain proper pressures.
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14
Q

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

A
  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.
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15
Q

What does increased RAP lead to?

A
  1. reduction in venous return; increased venous pressure.
  2. possibly hepatic-portal hypertension (IVC).
  3. possibly jugular vein distention (SVC).
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16
Q

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

A
  • maximal: diastole
  • minimal: systole
17
Q

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

A
  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.
18
Q

Adrenoreceptors mediating coronary VSM contraction (vasoconstriction):

A
  • α1 and α2 adrenoreceptors
  • MOSTLY α2 adrenoreceptors
19
Q

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

A
  • 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.
20
Q

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

A
  • local production of vasodilators by (healthy) vascular endothelium during contraction.
  • if impaired, SNS causes vasoconstriction, which leads to ischemia.
21
Q

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

A
  1. ventricular wall stress (i.e. systolic ventricular pressure)
  2. HR
  3. contractility (inotropic state)
22
Q

Ischemia is:

A
  • a localized anemia due to a reduction in blood supply.
23
Q

Ischemic heart disease results from:

A
  • an imbalance between O2 supply and myocardial demand
24
Q

Cause of dyspnea due to cardiac ischemia:

A
  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.
25
Two general mechanisms underlie the pathophysiology of cardiac ischemia/angina:
1. fixed vessel narrowing (e.g. atherosclerotic plaques) 2. abnormal vascular tone (e.g. VSM dysfunction)
26
Angina pecotoris is:
* chest pain/discomfort due to cardiac ischemia to one or more part of the ventricular myocardium. * resolves upon rest.
27
ECG manifestation of chronic stable angina:
1. inverted or flattened T waves 2. ST depression
28
What does the ECG show?
ST depression possible angina/cardiac ischemia
29
Steps in the cause of ischemic chest pain:
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.
30
Hypoxia due to ischemia ultimately causes what three symptoms related to angina?
1. tachycardia (SNS activation) 2. diaphoresis (SNS activation) 3. dyspnea (decreased LV function leads to pulmonary BP increase)
31
Medications for angina based on angina physiology (4):
* 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)
32
The two sodium currents of cardiac myocyte depolarization (plateau potentials):
1. early current 2. late current (INAL)
33
What sodium current is prolonged in cardiac myocyte depolarization in ischemic myocardium?
* late current (INAL)
34
How does a prolonged late current (INAL) excaberate angina/cardiac ischemia?
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.
35
What drug blocks a prolonged late current (INAL) during cardiac myocyte depolarization?
ranolazine