Chapter 3 Flashcards
What are the three major types of structural cells that serve important roles in cardiovascular function?
Cardiac myocyte, vascular smooth muscle and vascular endothelial
Are cardiac myocytes striated muscle?
yes
List the primary differences between cardiac muscle and skeletal muscle
Cardiac myocytes are single nucleated, shorter in length(skeletal span the entire muscle belly), and are branched
Define the term functional syncytium.
Functional syncytium is referring to the cells of the heart functioning as one unit due to the gap junctions providing an electrical connection between cells
How does this functional syncytium affect the spread of an electrical impulse through the heart?
Ions can flow through gap junctions to start depolarization of nearby cells. This ensures the spread of the electrical impulse
What are intercalated disks?
The intercalated disks are membranes between cells and is how they are connected
What are gap junctions, what is their purpose, and how do they function?
Gap junctions are low resistance spots between cells which allow for electrical communication
Draw, identify, and define all of the primary structural components of cardiac muscle – sarcomere, myofilaments, myofibrils, Z-lines, actin, myosin, titin, myocyte, intercalated disc, troponin I/C/T, tropomyosin.
A
What are thick and thin filaments?
Actin are thin filaments and myosin are thick filaments
What percentage of the cell volume is comprised of these thick and thin filaments?
Approximately 50% of the sarcomere is comprise of actin and myosin
About how many myosin molecules are bundled together in each myosin filament?
Approximately 300 myosin molecules per thick filament
Where does myosin ATPase fit into the myosin molecule and what is its function?
Myosin ATPase is found on the myosin heads and hydrolyzes ATP
Describe the three-dimensional structure of the myosin molecule.
A
How many thin filaments surround each thick filament?
1 myosin filament is surrounded by 6 actin filaments
Describe the function of each of the three troponin subunits.
TnI: Inhibition of myosin binding to actin
TnC: Ca++ binding site
TnT: Binding to tropomyosin
How are troponins used as a clinical diagnostic biomarker?
TnI and TnT are both detected in the blood when a cardiomyocyte dies
Describe the three-dimensional structure of actin, tropomyosin, and troponin.
A
What is the function of T tubules?
The T tubules provide an ion exchange point from extracellular to intracellular
What is the sarcoplasmic reticulum?
An extensive branching tubular network within and around myofilaments
What is the function of the sarcoplasmic reticulum?
Regulate intracellular Ca++
What are the terminal cisternae?
End pouches of SR which are adjacent to T tubules
What is the function of the terminal cisternae?
Rapid Ca++ delivery
What are the “feet” located between the T tubules and the terminal cisternae?
These are electron dense regions located between the terminal cisternae and the t tubule
What is the function of these “feet”?
Sense Ca++ between terminal cisternae and t tubule
What is excitation-contraction coupling
Excitation of the myosin to bind to actin in the presence of Ca++, utilizing an ATP at the myosin head
Describe in detail the role of calcium in excitation-contraction coupling in the cardiac myocyte (see Figure 3.3 and Table 3-1).
When Ca++ enters the cell, it can trigger a larger influx of Ca++ from the SR, releasing into the myofilaments, and binding to the TnC, which reveals the myosin binding site on Actin, resulting in a cross-bridge connection
When the cardiac myocyte is depolarized, how much calcium enters the cell during the action potential through L-type calcium channels; a relatively large amount or a relatively small amount?
A relatively small amount
Does this amount change calcium concentration appreciably?
No, but is sensed in the correct areas to result in trigger the SR to release Ca++ as well
What are ryanodine receptors and what is their role in the process of excitation-contraction coupling in the cardiac myocyte?
Ryanodine receptors are on the SR side of the feet and function as Ca++ release channels for the SR
How much do intracellular levels of calcium increase when released from stores in the terminal cisternae through the calcium release channels?
100 fold
What is “trigger calcium”?
The smaller amount that results in a larger release by the SR
What is “trigger calcium”?
The smaller amount that results in a larger release by the SR
Explain the sliding filament theory of muscle contraction
ATP binds to TnC, moving Tropomyosin out of the way via conformational change, allowing for Myosin to bind to Actin. Binding of Myosin to Actin results in hydrolysis of the ATP on the myosin head, releasing energy and causing the filaments to slide past each other, shortening the sarcomere
What is “ratcheting”?
The myosin filament/heads attach in a cocked position which is then used to pull on the actin, ratcheting it towards the m line
What is the role of ATP in this process?
ATP is attached at the myosin head, hydrolyzed, releasing energy and creating the cross-bridge movement. ATP is also necessary to unbind the myosin from the actin
How do intracellular calcium levels return to resting levels and how does the sarcoplasmic reticulum sequester calcium?
Towards the end of AP, Ca++ influx diminishes and the SR sequesters Ca++ via SERCA pumps(ATP dependent)
Explain what happens when intracellular calcium concentrations decline and how this relates to muscular relaxation.
When intracellular Ca++ decreases, TnC will not be bound, resulting in tropomyosin covering the Myosin binding site on Actin. This disallows a connection, resulting in no cross-bridge formation and no ratcheting availability
Is ATP required for contraction, relaxation, neither, or both?
Both
Define the term inotropy
Inotropy is the alteration of the force of a muscular contraction
List the six ways in which inotropy is regulated.
1) Ca++ entry via L type channels
2) Ca++ release by SR
3) Ca++ binding to TnC
4) Myosin phosphorylation
5) SERCA activity
6) Ca++ efflux across sarcolemma
Diagram and explain the signal transduction pathway involved with epinephrine/ norepinephrine stimulation of increased calcium entry into the cell (mention cAMP, β1- adrenoceptors, Gs, ATP, AC, L-type calcium channels).
Norepi or Epi bind to β1- adrenoceptors on sarcolemma. This receptor is coupled with a stimulatory G protein. The Gs-protein activates adenyly cyclase, hydrolyzing ATP into cAMP which activates protein kinase A. Phosphorylation of the L-type Ca++ channels increases Ca++ permeability. This results in an increase in “trigger Ca++”
Does this pathway have a positive inotropic effect or a negative inotropic effect?
Positive. It increases the force of contraction
What is the inhibitory G-protein and how does it affect this signal transduction pathway?
It is a inhibitory protein which inhibitis adenylyl cyclase (opposite of Norepi or Epi) and decreases intracellular cAMP
What receptors stimulate the formation of Gi proteins?
M2 (muscarinic) and A1 (adenosine)
What molecules can bind these receptors (M2 and A1) and where do these molecules come from?
ACH and Adenosine, parasympathetic
Does this pathway have a positive inotropic effect or a negative inotropic effect?
Negative, decreases force of contraction
Besides its effects on L-type calcium channels, what is another effect of β adrenoceptor and cAMP activation on calcium release?
Increased SR Ca++ release
What receptors are associated with Gq-proteins and what signaling molecules bind to these receptors?
a1-adrenoceptors (binds norepi), angiotensin II(AT1) and Endothelin-1 (Eta)
Diagram the Gq protein pathway for calcium release by the sarcoplasmic reticulum
Activation of these receptors stimulates phospholipase C to form IP3 (inositol triphosphate) from PIP2 (phosphatidylinositol). This stimulates release of Ca++ from SR.
What is the relationship between intracellular calcium concentration and the amount of calcium bound to TN-C?
The greater the amount of free Ca++ intracellularly, the greater amount of Ca++ bound to TnC, the greater force production
When more calcium binds to TN-C what happens to force production?
Increase in force production due to more myosin/actin cross-bridge connections
What does it mean to change the affinity of TN-C for calcium, and how does this affect inotropy?
The affinity is how attracted or accepting the TnC is to Ca++, lower affinity would result in negative inotropy
Give an example of something that can change the affinity of TN-C for calcium.
Hypoxic conditions resulting in acidosis can alter the affinity of TnC for Ca++
What is the relationship between calcium sensitivity and sarcomere length?
Increase in sarcomere length leads to increased force generation. This is via the increased sensitivity of TnC to Ca++
What is myosin light chain kinase, what reaction does it catalyze, and how does it affect inotropy?
Myosin light chain kinase is an enzyme which phosphorylates the myosin light chain head. This is associated with increased cAMP and therefore positive inotropy
How does the sarcoplasmic reticulum increase the amount of sequestered calcium?
Increased use of the SERCA pump sequesters more Ca++, but also leads to more Ca++ being released.
What effect does this have on inotropy?
Increase in Ca++ sequestered results in increases release, therefore there is a positive inotropic response
What two mechanisms lower intracellular calcium concentrations by pumping calcium out of the cell?
1) Sarcolemmal Na+/Ca++ exchange pump
2) Ca++ ATPase
What are some ways that these two can be inhibited?
Digoxin is a medication which can inhibit the NA+/K+ ATPase, increasing intracellular Na+. This affects the Na+/Ca++ exchange by supplying more of a Na+ gradient, leaving more Ca++ inside the cell. The cell will have increased positive inotropy from this.
Cellular hypoxia decreases activity of Na+/K+ ATPase and Ca++ ATPase. This is due to decreased ATP availability. Results in increased Ca++ accumulation in the cell, but reduced ATP blocks the possible benefit of having increased ATP intracellularly
How would inhibiting calcium extrusion from the cell affect inotropy?
The increased intracellular Ca++ would need to be taken up by the SR via SERCA. This would result in an increased subsequent release
Define lusitropy.
Lusitropy is the rate of myocyte relaxation
Define lusitropy.
Lusitropy is the rate of myocyte relaxation
What determines the degree of lusitropy?
The ability of the cell to rapidly reduce the intracellular concentration of Ca++ following its release from the SR
According to the text, what are four mechanisms involved with regulating lusitropy?
1) The rate at which Ca++ enters the cell
2) The rate at which Ca++ leaves the cell via sarcolemmal Ca++ ATPase and Na+/Ca++ ATPase
3) The activity of the SERCA pump
4) The binding affinity of TnC and Ca++
What is the relationship between lusitropy and SERCA activity?
Lusitropy can be increased by increased SERCA activity. Phosphoralation of phospholamban increases SERCA
What is phospholamban and what is its action?
A regulatory protein associated with SERCA
What is the effect of phospholamban phosphorylation?
Inihitibition of SERCA activity
How does β adrenoceptor stimulation affect phospholamban?
Β adrenoreceptor stimulation -> increased cAMP and PK-A -> PK-A phosphorylates phospholamban
How can calcium binding to TN-C be modulated?
PK-A phosphorylation of TnI will increase dissociation between TnC and Ca++
What are the effects of some inotropic drugs on lusitropy?
Increased inotropy may result in decreased lusitropy because of the TnC and Ca++ having a much tighter bond
Do cardiomyocytes have a low, moderate, or high metabolic rate?
high
What cellular organelle is abundant in cardiomyocytes that helps them produce large amounts of ATP?
mitochondria
How long could the cardiac myocyte contract in the absence of oxygen?
About 1 minute
What is the anaerobic capacity of cardiac myocytes?
limited
Following an overnight fast, what are the primary substrates utilized for energy production?
60% fatty acids and 40% carbohydrates
How would this change after eating a high- carbohydrate meal?
Will adapt to using carbohydrates almost exclusively
What other substrates can be utilized by the heart?
Amino acids and ketones
What happens to cardiomyocyte ATP use and oxygen consumption when there is an increase in heart rate or contractility?
Increased dramatically
List, define, and describe the three layers of large blood vessels
Intima: Single layer of epithelial cells
A separation layer of basal lamina between intima and media
Media: Where the vascular smooth muscle cells exist within a matrix of collagen, elastin and various glycoproteins. % of matrix is dependent on location and function of the vessel. The aorta is under higher pressures and requires more elastin. Vascular smooth muscle cell arrangement depends upon the size of the vessel. Arranged so that contraction reduces vessel diameter.
A separation layer of external elastic lamina between media and adventitia
Adventitia: Contains collagen, fibroblast, blood vessels, lymphatics and autonomic nerves
About how big are vascular smooth muscle cells?
5 – 10 micrometers in diameter and 50 – 300 micrometers in length
Draw and identify all of the primary anatomical structures of smooth muscle cells.
Actin/Myosin not organized in distinct bands
What is the function and/or purpose of each of these major anatomical structures?
Dense band: Structure on the inner surface of membrane which anchors actin/myosin
Dense body: Structures within the cell which anchor and join actin/myosin groups
Calveolae: Cell membrane invaginations which increase the surface area
How are contractions in smooth muscle cells different than contractions in cardiac myocytes?
Slow and sustained, usually in a partially contracted state, initiated by electrical, chemical or mechanical stimuli
In the blood vessels, is smooth muscle normally completely relaxed, partially contracted, or maximally contracted?
Partially contracted, the resting tone
Describe how electrical stimuli cause smooth muscle contraction
Opening of voltage-dependent Ca++ channels initiating ion concentration change
Describe how chemical stimuli cause smooth muscle contraction
Binding to specific receptors on the vascular smooth muscle cell. The different signal transduction pathways converge to increases intracellular Ca++
Describe how mechanical stimuli cause smooth muscle contraction.
Passive stretching of some arteries can cause a contraction
Define the term myogenic response
A contraction initiated by the passive stretching of the vessel resulting from stretch-induced activation of ion channels, leading to Ca++ influx
Describe the mechanism by which an increase in intracellular calcium stimulates vascular smooth muscle contraction (mention calmodulin, myosin light chain kinase, myosin light chain).
Free Ca++ binds to Calmodulin (a special calcium binding protein), which activates myosin light chain kinase which phosphorylates myosin light chains in the presence of ATP. This leads to cross-bridge formation and contraction
Diagram and describe in detail the three signal transduction mechanisms that regulate intracellular calcium contraction in vascular smooth muscle (see Figure 3.10).
1) IP3 via Gq-protein activation of phospholipase C
2) cAMP via Gs-protein activation of adenylyl cyclase
3) Cyclic guanosine monophosphate (cGMP) via Nitric oxide (NO)
Describe the anatomical structure of vascular endothelial cells
Flat, single nucleated and elongated cells with different types of intercellular junctions(tight or gapped) depending on the type and the location of the vessel
According to the text, what are the four primary functions of the vascular endothelium?
1) A barrier for exchange of fluid, electrolytes, macromolecules and cells between intravascular and extravascular space
2) Regulation of smooth muscle function through synthesis of vasoactive substances (NO, PGI2 and Endothelin-1)
3) Modulation of platelet aggregation (through biosynthesis of NO and PGI2)
4) Modulation of leukocyte adhesion and transendothelial migration through biosynthesis of NO and expression of surface adhesion molecules
When do endothelial cells produce nitric oxide?
Continuously
According to the text, what are three ways that nitric oxide production can be enhanced?
1) specific agonists binding to endothelial receptors
2) Increased shearing forces acting on the endothelial surface
3) Cytokines (such as TNF and IL’s) released by leukocytes during inflammation and infection
What happens to nitric oxide after it has been synthesized in the endothelial cell?
Rapid diffusion out of endothelial cells to cause smooth muscle relaxation or inhibit platelet aggregation in the blood. From increased cGMP formation
What are the three primary functions of nitric oxide after it has diffused out of the endothelial cell?
Inhibition of expression of adhesion molecules involved in attaching leukocytes to the endothelial surface, smooth muscle relaxation or inhibit platelet aggregation in the blood. From increased cGMP formation
What is endothelin-1 and how does it affect smooth muscle function?
ET-1 is a powerful vasoconstrictor. Binds to Eta receptors on vascular smooth muscle, causing Ca++ mobilization and smooth muscle contraction
What is prostacyclin and how does it affect smooth muscle function?
PGI2 (a product of arachidonic acid metabolism in endothelial cells) has two effects on smooth muscle function. Smooth muscle relaxation and inhibition of platelet aggregation
