Lecture 6 (Coronary Bloodflow and Angina) Flashcards
What two molecules are key to promoting vasodilation?
- Cyclic GMP and protein kinase G (PKG).
- Anytime cGMP or PKG is unregulated in a VSM cell, the VSM will relax.
Low epinephrine levels cause:
High epinephrine levels cause:
- low epinephrine: vasodilation via β2
- high epinephrine: vasoconstriction via α1
Steps in low epinephrine levels causing vasodilation:
- low epinephrine levels
- β2 adrenoreceptors
- epithelial nitric oxide synthase (eNOS)
- NO
- guanalyl cyclase
- cGMP
- PKG
- PKG inactivates calcium channels, preventing contraction and vasoconstriction, and activates SERCA channels, calcium flows out and VSM relaxes.
How does protein kinase G (PKG) cause vasodilation?
- prevention of calcium inflow via Type-L calcium channel isoform inactivation.
- promotion of calcium outflow via SERCA channel activation.
- decreased sarcoplasmic calcium levels causes VSM relaxation and vasodilation.
Vasodilatory factors (7):
- CO2
- NO
- H+ (protons)
- lactic acid (protons)
- adenosine
- thrombin
- histamine
Steps in vasodilatory factors (CO2, protons, etc.) causing vasodilation:
- bind to specific receptors
- epithelial nitric oxide synthase (eNOS)
- Nitric oxide
- guanalyl cyclase
- cGMP
- PKG
- PKG inactivates calcium channels, preventing contraction and vasoconstriction, and activates SERCA channels, calcium flows out and VSM relaxes.
Steps in vasoconstriction:
- epi/norepi
- α1 adrenoreceptors VSM
- Gq proteins
- PLC
- PKC
- PKC activates calcium channels causing calcium influx and inactivates SERCA channels via arachadonic acid/PGF2α
Primary protein involved in vasodilation and primary protein involved in vasoconstriction:
- vasodilation: PKG
- vasoconstriction: PKC
How are SERCA channels inactivated during vasoconstriction:
- PKC and arachadonic acid activate PGF2α
- PGF2α inactivates SERCA channels
What causes vasoconstriction at low levels of SNS tone, and what causes vasoconstriction at moderate to high levels of SNS tone?
- low SNS tone: norepi
- mod-high SNS tone: norepi, epi, ATP, NPY
The vascular network is comprised of three functional components:
- resistance (arteries and arterioles)
- exchange (capillaries)
- capacitance (veins)
Right atrial response to low pressure (low RAP) and high pressure (high RAP):
- Low pressure: low pressure baroreceptor activated; SNS tone increased.
- High pressure: ANP released in response to volume overload. Vasodilation.
As RAP (venous return) increases, what must also increase?
- cardiac output.
- necessary in order to maintain proper pressures.
Steps in how a sick left heart leads to an increase in RAP:
- reduced EF = increased LVP.
- back pressure from LV to LA.
- back pressure from LA to pulmonary veins.
- Pulmonary BP increases; increased afterload on RV.
- increased RVP.
- back pressure on RAP; RAP rises.
- venous return decreases; LV works harder to maintain CO.
What does increased RAP lead to?
- reduction in venous return; increased venous pressure.
- possibly hepatic-portal hypertension (IVC).
- possibly jugular vein distention (SVC).
When does maximal and minimal coronary blood flow/oxygen uptake occur?
- maximal: diastole
- minimal: systole
What occurs to coronary VSM in the presence of reduced flow/oxygen levels?
- oxidative phosphorylation and generation of ATP impaired.
- formation of ADP, AMP, and ultimately adenosine.
- adenosine blocks Ca2+ entry into VSM.
- vasodilation.
Adrenoreceptors mediating coronary VSM contraction (vasoconstriction):
- α1 and α2 adrenoreceptors
- MOSTLY α2 adrenoreceptors
Effect of SNS tone on coronary VSM in healthy and non-healthy hearts:
- 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.
During physiologic conditions, how do the coronary arteries maintain a state of relative vasodilation?
- local production of vasodilators by (healthy) vascular endothelium during contraction.
- if impaired, SNS causes vasoconstriction, which leads to ischemia.
The major determinants of myocardial O2 requirements in order of demand:
- ventricular wall stress (i.e. systolic ventricular pressure)
- HR
- contractility (inotropic state)
Ischemia is:
- a localized anemia due to a reduction in blood supply.
Ischemic heart disease results from:
- an imbalance between O2 supply and myocardial demand
Cause of dyspnea due to cardiac ischemia:
- impediment in coronary blood flow.
- localized anemia.
- decreased oxygen levels.
- impaired LV function.
- increased LVP; increased LAP; increased pulmonary BP.
- dyspnea.
Two general mechanisms underlie the pathophysiology of cardiac ischemia/angina:
- fixed vessel narrowing (e.g. atherosclerotic plaques)
- abnormal vascular tone (e.g. VSM dysfunction)
Angina pecotoris is:
- chest pain/discomfort due to cardiac ischemia to one or more part of the ventricular myocardium.
- resolves upon rest.
ECG manifestation of chronic stable angina:
- inverted or flattened T waves
- ST depression
What does the ECG show?
ST depression
possible angina/cardiac ischemia
Steps in the cause of ischemic chest pain:
- hypoxia due to ischemia.
- hypoxia decreases ATP production and increases lactic acid.
- decreased ATP compromises Na+/K+ ATPase and increases adenosine.
- increased lactic acid causes local acidosis.
- sarcolemma integrity compromised and myocardial injury occurs.
- adenosine and injured myocardium compounds bind to nociceptors.
Hypoxia due to ischemia ultimately causes what three symptoms related to angina?
- tachycardia (SNS activation)
- diaphoresis (SNS activation)
- dyspnea (decreased LV function leads to pulmonary BP increase)
Medications for angina based on angina physiology (4):
- angina is due to cardiac ischemia:
- vasodilator (NO)
- beta-blocker (negative inotrope; decrease oxygen demand)
- calcium channel blockers (vasodilate and decrease HR)
- ranolazine (impairs prolonged late Na+ current)
The two sodium currents of cardiac myocyte depolarization (plateau potentials):
- early current
- late current (INAL)
What sodium current is prolonged in cardiac myocyte depolarization in ischemic myocardium?
- late current (INAL)
How does a prolonged late current (INAL) excaberate angina/cardiac ischemia?
- more Na+ enters myocytes.
- NCX function impaired, more Ca2+ in myocytes.
- increased Ca2+ levels impairs LV relaxation.
- LV wall tension increases.
- LV oxygen demand increases.
What drug blocks a prolonged late current (INAL) during cardiac myocyte depolarization?
ranolazine
