Cardiovascular Material - CAPS 422
What is the dyadic cleft?
space between the jSR and the T-tubule membrane (sarcolemma)
What are the steps of excitation-contraction coupling in skeletal muscle?
1. AP moves down the T-tubules 2. DHPR/Cav1.1 on the membrane of the sarcolemma senses membrane depolarization - It physically opens RyR channel on the SR 3. RyR opens to release Ca2+ from the SR to the myoplasm 4. Ca2+ moves to myofilaments and binds to troponin C and causes cross-bridge contraction 5. SERCA1a quickly uptakes Ca2+ from the myoplasm into the SR
What are the 2 mechanisms of Starling's Law?
1. Length-tension relationship --> normally cardiac muscle operates on the ascending limb because it is resistant to stretch - When venous return increases, the heart expands and moves up the length-tension relationship resulting in more efficient overlap of myofilaments and increases contraction --> Increases SV with stretch - Up to a point, won't go past the peak because cardiac muscle resistance too large 2. Increased sensitivity of Ca2+ in the myoplasm by troponin C - Increase stretch of cardiac muscle alters troponin C conformation which increases its binding to Ca2+ - Results in increases contraction force --> as sarcomeres get pulled apart, the Ca2+ concentration needed to reach half maximal force of contraction decreases
What is the Z line, A band, I band?
A band = myosin filament region I band = actin filament region Z line = borders of sarcomere
What is the fundamental unit of ECC?
A calcium spark - Dyads are independently activated by AP and produce transient spark of Ca The transient Ca smooth curve seen is a sum of all the sparks of independent dyads
What are the effects of a ventricular septal defect?
A left to right shunt occurs - Blood moves from the left ventricle to the pulmonary trunk Increased pulmonary flow Have increased load to the LV and LA due to increased pulmonary flow which moves to the LV/LA - Results in hypertrophy and eventually failure
How does muscarinic and B-adrenergic stimulation affect If opening and how do they know this is directly due to cAMP?
ACh causes decreased If activity, ISO causes increased If activity - Show a difference in activity of around 15-20 mV cAMP levels changes show a difference of around 15-20 mV - increased cAMP results in increased If activity Since both changes have similar If activity changes over the same mV range - Can say that muscarnic receptors and B-adrenergic receptors act through cAMP directly
How does ACh and NE/E affect currents in the SA node?
ACh: - Decreased If --> decreased diastolic depolarization - Increases Ik, ACh --> drops maximum diastolic potential - Reduces ICa,L --> decreased diastolic depolarization and also alters threshold to be more positive - OVERALL reduces HR NE/E: - Increased If --> increases diastolic depolarization slope - No effect on Ik, ACh - Increased Ica, L --> increases diastolic depolarization slope and shifts threshold to more (-)
What is the absolute vs refractory period?
Absolute - Time when Na+ channels are inactivated so no AP firing can occur Relative - Na+ channels are activated but K+ permeability is high so K+ is moving out of the cell - AP firing is possible but to have another firing, the Na+ influx needs to overcome K+ efflux to depolarize the cell sufficiently
At what membrane potentials are If channels activated by?
Activated by hyperpolarizations - Have large current changes at increased negative mV
How does B-adrenergic activation affect ventricular force contraction?
Activation of B receptors activates stimulatory G protein which activates AC --> increase cAMP and activates PKA PKA has various effects - It phosphorylates PLB to increase SERCA activity - It phosphorylates voltage-gated Ca channels to increase Ca influx which increases RyR2 activity - Also phosphorylates RyR2 to increase activity - Also phosphorylates troponin I which increases the off rate of Ca from troponin C --> allows relaxation to occur quicker
What are the inhibitors and activators of RyR2?
Activators - Some concentrations of Ca2+ - PKA and CaMKII phosphorylation - Low Mg2+ - NO - Low ryanodine - Caffeine Inhibitors - Some concentrations of Ca2+ - High Mg2+ - High ryanodine - PP1/PP2A --> protein phosphotases that remove the phosphate
What is the cycle of the Na+ voltage gated channel?
At RMP the inactivation gate is open but the activation gate is open - Ready for opening At depolarization threshold: the activation gate is triggered to open which causes Na+ influx - The inactivation gate is also triggered to close but closes slowly Once inactivation gate is closed, no AP can fire When repolarization occurs back to RMP: the inactivation opens and the activation gate closes so ready for next firing
What is the molecular mechanism of B2 adrenergic receptors and muscarinic receptors on SA pacemaker cells?
Both receptors are G-proteins E/NE binds to B-adrenergic receptors - Has stimulatory G protein and binding causes dissociation of By and alpha subunit - Alpha subunit activates adenylate cyclase which increased cAMP production - cAMP directly increases If activating and activates PKA which phosphorylates and activates Ica,L ACh binds to Muscarnic receptors (M2) - Has inhibitory G protein and binding causes dissociation of By and alpha subunit - Beta(gamma) subunit moves to and directly activates Ik, ACh - Alpha inhibitory subunit inactivates adenylate cyclase which decreases cAMP production and causes decreases in If and Ica, L
What are action potentials?
Brief, rapid, large changes in membrane potential where the potential actually reverses - Involves only a small portion of the total excitable membrane AP does not decrease in strength in its path
How does Cav1.2 cause opening of RyR2?
Ca2+ moves through the Cav1.2 into the cell and causes increased Ca2+ concentration locally which opens the RyR2
Why is CamKII considered a frequency transducer?
CamKII has a slow off rate for Ca, so there is always some Ca bound in normal HR but just very low When HR increases, there is increased Ca that remains bound to CamKII as not able to unbind all before next AP - Results in increased active CamKII so increases PLB phosphorylation and SERCA activity with increased HR
How can intracellular ion concentrations be measured?
Can use fluorescent indicators specific to certain ions - Small, permeable molecules that get trapped in the myoplasm once esterases hydrolyze ester bonds to make these molecules charged Upon binding with the ion the intensity of the fluorescence or the wavelength of the light can change - Allows intracellular ion concentrations to be measured
How are pressure volume loops of the heart measured?
Catheter is inserted up the femoral artery/vein up to the heart where PV is measured
What are the dihydropyridine and ryanodine receptor isoforms in cardiac muscle?
Cav1.2 --> no physical connection to RyR2 RyR2
What is the Ik?
Delayed rectifier potassium current Reversal potential = -85 mV Made of two components (IKr, IKs) - IKr = KCNH2 gene - IKs = KCNQ1 gene Both components are activated by membrane depolarization around -60 mV - However opens slowly so contributes to rate and extent of repolarization
What causes up/down deflections with ECG?
Depolarization --> moves smoothly across the heart from cell to cell through gap junctions - Upward deflection occurs when moves toward + end of lead - Downward deflection occurs when moves away from + end of lead Repolarization --> moves smoothly across cells, starting from the last cells to depolarize - Upward deflection occurs when repolarization moves away from + end of lead - Downward deflection occurs when moves toward + end of lead
What is EDPVR and ESPVR?
EDPVR = end-diastolic pressure volume relationship - What happens when you fill the heart and the heart if fully relaxed ESPVR = end-systolic pressure volume relationship - The relationship that occurs when the heart is fully contracted and filled - Contractility
What ions were related to the two currents with depolarization? What substances blocked these currents?
Early current = Na+ - Blocked by Tetraethyl-ammonium Late current = K+ - Blocked by tetrodotoxin
What do SA pacemaker cell action potentials look like?
Fire APs on their own Have specific components - Slow depolarization phase (called diastolic depolarization) - Have upstroke - Have repolarization phase
What are calcium sparks?
Flashes of Ca2+ that occur even in diastole in ventricular myocytes - Experiment show that the sparks are coming from the jSR through RyR2 opening - Result of spontaneous opening of around 10 RyR2 --> probability of opening is very low but it is not 0
How does free calcium compare to total calcium in the cytoplasm to get half maximal contractile force?
Free calcium needed around 600nm But the total calcium is much higher around 70 um because there is a lot of Ca binding sites in the cell
What is the If?
Funny current Activated by hyperpolarization around -45 mV Permeable to both Na+ and K+ but mainly Na+ inward Reversal potential is -23 mV Contributes to the slope of the pacemaker potential Coded for by hyperpolarization-activated cyclic nucleotide-modulated (HCN) channel genes
What is the structure of the HCN funny channel?
HCN has similar structure to potassium channels HCN has 6 transmembrane structures - 4th structure has lots of positive charges that are thought to move upon membrane potential changes - 5-6th = pore Has intracellular cyclic nucleotide binding domain that cAMP binds to cause different effects HCN forms tetramers so cAMP binds to 4 individual
How does the parasympathetic nervous system innervate pacemaker cells?
Has long pre-ganglionic neuron --> vagus nerve - Moves all the way into cardiac tissue and synapses at the cardiac ganglion - Releases ACh onto nicotinic receptors of post-ganglionic neurons Post-ganglionic neurons (short) innervate pacemaker cells and release ACh onto M2 receptors
How does the sympathetic nervous system innervate pacemaker cells?
Has short pre-ganglionic neurons that synapses at ganglion OUTSIDE the cardiac tissue - Releases ACh onto nicotinic receptors in the ganglion Long post-ganglionic neurons then synapse onto pacemaker cells - Releases NE onto B1 adrenergic receptors
What are the effects of an atrial septal defect?
Have a left to right shunt - LA to RA Results in a murmur due to turbulent flow RA and RV see increased load - Hypertrophy and eventually failure
What sort of distribution do RyR2 have on junctional SR?
Have a non uniform and variable arrangement in clusters on the SR
What is one inward rectifier that is present in SA node?
IK, ACh - Acetylcholine activated potassium current - Inwardly rectifying --> however the outward current is what is physiologically important Activated by B(gamma) released by muscarinic stimulation Coded by Kir 3.4 gene Reversal potential is -85 mV - Adding ACh will causes these channels to bring the RMP of the SA node more negative
What are the key genes for each ionic current?
INa = Nav 1.5 Ito = Kv4.2 IKur = Kv1.5 ICa, L = Cav1.2 IKr, IKs = KCHN2 and KCNQ1 IK1 = Kir 2.1
What are the primary ionic currents that underline the ventricular AP?
INa = sodium current - Phase 0 Ito = transient outward current (K current), IKur - ultra rapid delayed rectifier K current - Phase 1 ICa, L = L-type calcium current - Phase 2 IKr, IKs = rapid and slow delayed rectifier K current - Phase 3 IK1 = inward rectifier current - RMP
What is the Calcium clock hypothesis?
Idea that intracellular calcium release leads to and contributes to depolarization of the membrane potential - Evidence shows there is an increase in intracellular calcium prior to AP firing Steps: - You have early calcium release from the SR that leaks into the cytoplasm - Build up of calcium causes movement out through the electrogenic sodium calcium exchanger - It brings more sodium in (3Na+ vs 1 Ca2+) so results in depolarization of the cell - Could contribute to the late diastolic depolarization but is controversial
What are the primary ionic currents associated with each pacemaker action potential phase?
If = associated with start of diastolic depolarization ICa, T = associated with late diastolic depolarization ICa, L = associated with late diastolic depolarization and upstroke of AP Ik = associated with repolarization
How do you calculate HR on an ECG?
If the paper speed is 25 mm/sec - Then each box is 1 mm - Also it means there are 1500mm/min and each large square is 5 mm and there are 300 large squares in 1 min Can either count the small squares or large squares in an RR interval and convert to bts/min
What are the total current equations?
Ik = gk (Et - Ek) Ina = gNa (Et - Ena) Ix = current though channels --> can be measured Et = membrane voltage Ex = reversal potential for x ion --> can be experimentally determined (Et - Ex) = driving force for x ion movement through the open channel gk or gNa can be calculated
How does HR get modulated during and post light exercise?
In light exercise there is vagal input withdrawal but less sympathetic contribution After exercise, vagal input increases to lower HR quickly
How does Na or K conductance change with depolarization?
Increased depolarization magnitudes --> relate to increased Na+ (gNa) and K+ (gK) conductance but both reach a plateau
How does increased preload, contractility and after load affect the PV loop?
Increased preload - Have increase in diastolic filling and end-diastolic volume - Have increase in SV - Increase in force of contraction because preload increases length-tension relationship and troponin C affinity for Ca - No chance in contractility or ESV Increased contractility - Increase in ESPVR - Increase in SV - Decrease in ESV - EDV stays the same Increased after load - Have increased diastolic and systolic BP - Decreased SV - Increase in end-systolic volume but same end-diastolic volume Sympathetic NS --> increases all these parameters
How does time and amount of Ca added affect RyR2 and what does this mean?
Increased time of adding Ca2+ results in lower opening of RyR2 - High amounts of Ca2+ also result in lower opening of RyR2 This is because RyR2 has an activation site and an inactivation site for Ca2+ - Slower Ca2+ is added, the higher the probability it binds to the inactivation site as quickly as the activation site - The faster it is added, the increased probability it binds to the activation site first - Same with Ca2+ levels, higher levels results in more binding to the inactivation site
How does lumen SR Ca2+ levels regulate RyR2 activation?
Independent of myoplasmic Ca2+ levels Lower Ca2+ results in decreased sensitivity of the RyR2 channels to myoplasmic Ca2+ levels - A way to regulate that as Ca2+ levels in the SR decreases, have less opening of the RyR2 --> reduces positive feedback
What are the intrinsic and extrinsic mechanisms that regulate heart force of contraction?
Intrinsic - Starling's Law of the Heart - HR dependent variations in Ca2+ valance Extrinsic - Hormones, NE/E from adrenal medulla stimulate B1 receptors - Cardiac nerves also release ACh and NE -> Very little PSNS innervation of cardiac muscle other than SA and AV node
How does age affect intrinsic HR?
Intrinsic HR decreases over age (not including autonomic input)
What are 4 ways cardiac muscle can change the force of contraction?
Intrinsic and extrinsic mechanism Changing the amount of Ca2+ in the myoplasm and the rate at which it changes Change the sensitivity of the myofilaments to Ca2+ Build more muscle
How does autonomic input affect intrinsic heart rate?
Intrinsic heart rate is around 100-110 Vagal input contributes to lower HR Sympathetic contributes to raise HR In light exercise - There is vagal withdrawal with less sympathetic contribution
What part of the IK1 is important and why does this difference show?
Inward rectifier potassium current - Shows strong inward current at very negative membrane potential --> physiologically these membrane potentials dont occur The important region is the region below 0 but above -80 mV where there is outward current that helps repolarization - The outward current isn't as large as inward current The difference in current is due to Mg2+ and Spermidine binding that bind stronger to the channel and block it at positive membrane potentials - At negative membrane potentials Mg2+ and Spermidine bind weakly to the intracellular part and inward current can happen - At more positive ones they can bind stronger to the intracellular part and eventually fully block outward K+ current
What is the reversal potential of If channels, why?
It is around -25 mV - The reason it is more positive than potassium channels is because it is permeable to potassium and sodium
Why is RyR2 difficult to study?
It is not on the surface membrane but in the junctional SR Its large size also makes it hard to express and manipulate
What is the ICa,L?
L-type calcium current Activated by membrane depolarization (around -35 mV) Inactivates quickly (slower than Na+ channels) Contributes to late pacemaker potential and to threshold and upstroke of AP Permeable to Ca2+ - Reversal potential is +64 mV Coded for by Cav1.x genes
What are the polarities of the three bipolar leads?
Lead I: +LA, -RA Lead II: +LL, -RA Lead III: +LL, -LA
What is a bipolar lead?
Lead where the potential difference is measured between 2 recording electrodes --> one positive and one negative
What is the morphology of SA pacemaker cells?
Long and spindly Have a lack of organized contractile system
What are murmurs? What does a murmur mean if it is only in systole vs only in diastole?
Murmur --> sound heard other than the normal heart sounds due to turbulent blood flow Assuming no ASD or VSD If murmur heard only in systole - Could be due to stenosis of either the aortic or pulmonary valve - Also could be incompetence of the mitral or tricuspid valves --> regurgitation If murmur only heard in diastole - Could be due to stenosis of mitral/tricuspid valves - Also due to incompetence of pulmonary and aortic values --> regurgitation since PAP and AP are greater than ventricular pressure in diastole
How does Na and K permeability change in an AP?
Na permeability increases at threshold and decreases at AP peak K permeability increases at AP peak
What are the approximate Na+ and K+ ECF and ICF concentrations? What is the Nernst equation?
Na+ - In = 10 mM - Out = 140 M K+ - In = 5 mM - Out = 160 mM Nernst E = RT/zF ln (K outside/Kinside) - Can replace K with whatever the ion is
How do adult and newborn pacemaker cells differ in sensitivity to TTX?
Only a small fraction of adult pacemaker cells (10%) are sensitive to TTX - Means they have voltage-gated Na+ channels In newborns, a large fraction (50%) are sensitive to TTX - Means they have voltage-gated Na+ channels, more compared to adults
What is Po?
Open probability - Sum of the all the times the channel was open dividd by the total time of the recording It is the likelihood of finding the channel open at any time point
What is the histology of the SA node?
Overall it is a small region of tissue - Appears lighter - Pacemaker cells are embedded in connective tissue
How do the pressures on the right side of the heart compared to the left side?
Overall the pressures on the right side are lower than the pressures on the left side
What do the components of ECG correspond to in the heart?
P = atrial depolarization QRS = ventricular depolarization T = ventricular repolarization
How is PR and QRS interval measured and what is normal?
PV interval --> atrial conduction - from start of P wave to the start of first deflection after the P wave (could be Q or R) - normal is around 2-5 squares QRS interval --> ventricular conduction - from start of first deflection after P wave to the end of S wave - normal is < or equal to 3 squares
How do ventricular APs differ from pacemaker APs?
Pacemaker APs - shape is different --> have no broad plateau - Have a higher maximum diastolic potential (MDP) --> -65 mV vs -80 or -90 mV in ventricular cells - Have slow diastolic depolarization
What is the SA node?
Pacemaker of the heart --> Sino atrial node is situated at the top of the right atrium next to the superior vena cava -Its AP corresponds to the P-wave AV node also pacemaker but slower
What are the phases of ventricular action potential?
Phase 0: activation --> inward Na current Phase 1: rapid repolarization --> early outward K currents Phase 2: plateau --> activation of Ca current and late Na current Phase 3: repolarization --> decay of Ca current and activation of delayed K current RMP: determined by inwardly rectifying potassium current
How are Cav1.1 and RyR1 connected?
Physically coupled Cav1.1 opens, doesn't need Ca2+ to flow through it, but physically pull the RyR1 open
What is positive lusitropic effect and why is it important>?
Positive lusitropic effect --> increased rate of relaxation that occurs with increased HR - Very important and is due to increased SERCA activity and increased Ca off rate of troponin C The capillaries of the ventricular myocytes only have blood flow in diastole and get O2 - So need increased relaxation with increased HR to ensure 2/3 of time is in diastole to ensure enough O2 delivery
What is pulse pressure, MAP and MSP?
Pulse pressure = systolic pressure - diastolic pressure MAP = mean arterial pressure - It is the pressure required to get enough perfusion of the organs - Calculated as diastolic pressure + 1/3 pulse pressure MSP = mean systemic pressure - Around 7 mmHg - It is the pressure that will occur in the vasculature if the blood flow is stopped and is based on total vessel diameter and blood volume
What are the 3 ways skeletal muscle can change the force of contraction?
Recruit more motor units - Motor units consist of a motor axon and several muscle fibers - Muscle fibers are electrically isolated so recruitment of more motor units means more muscle cells contracting and increased strength Summation and tetanus - Each AP causes enough Ca2+ release for complete TnC saturation but SERCA removes Ca2+ before full contraction can be reached - But adding another AP before tension reaches baseline will add to the peak tension and if enough stimulation it will cause RyR1 to open frequently to overpower SERCA so constant contraction Building more muscle - Individual cell hypertrophy
What is the function of the mitochondrial Ca2+ uniporter in cardiac muscle?
Regulates flow of Ca2+ into the mitochondria and is sensitive to Ca2+ levels in the cytoplasm - Increase Ca in the cytoplasm means increased Ca entry to the mitochondria and increased ATP production as increases activity of Ca2+ sensitive enzymes in oxidative phosphorylation Method to match energy production to demand
What are all the chambers and great vessels of the heart?
Right Atrium Right ventricle Left atrium Left ventricle Superior vena cava Inferior vena cava Pulmonary artery Pulmonary trunk Pulmonary vein Aorta
What are 3 ways a wide QRS can occur?
Right bundle branch block - No conduction occurs through the right bundle branch, only to the left ventricle - electrical conduction slowly moves from left ventricle to right ventricle --> widens Left bundle branch block - Same as right bundle but blockage is on left bundle branch Ventricular ectopic - Ventricular myocytes, due to pathological conditions, start to depolarize spontaneously and occurs faster than the SA and AV node - Takes control of heart rhythm --> fast rhythm but wide QRS
What are the heart sounds?
S1: closure of the mitral and tricuspid valves - Start of systole S2: closure of the aortic and pulmonary valves - End of systole
What is the electrical conducting system of the heart?
SA node has pacemaker cells that spontaneously depolarize and - wide diameter with lots of gap junctions so depolarization travels quickly - moves to LA through Bachman's bundle - moves to AV node through intranodal pathways AV node --> smaller diameter with less gap junctions so travels slower - conducts to bundle of His --> right and left bundle branches --> purkinje fibers --> ventricular myocytes
What is the SERCA isoform in cardiac muscle and what is the important regulator?
SERCA2a Associated with regulator PLB = phospholamban PLB is associated with SERCA2a --> when it is connected there is slow Ca2+ influx PKA and CaMKII can phosphorylate PLB - If one phosphorylates then PLB physically moves away and have medium activity of SERCA2a - If both phosphorylate in any order, have maximal movement away and have maximal activity of SERCA2a
What is a voltage clamp set up?
Set up that allows to current to be measured when voltage of the cell/axon is clamped at a certain value
What is Ca2+ ATPase role in cardiac muscle?
Sits on the sarcolemma of the cells Has a minor role in Ca2+ extrusion in these cells
How does AP, Ca2+ transient and muscle contraction compare between skeletal muscle and cardiac muscle?
Skeletal muscle - Few mSec AP - Ca2+ follows and then muscle twitch Cardiac muscle - Longer AP - Followed by Ca2+ influx and then contraction - Amplitude of Ca2+ transient is variable - Time course of all three is variable too
What is NCX and its role in cardiac muscle?
Sodium and Calcium exchanger - Moves 3Na+ for 1 Ca2+ --> electrogenic Forward = 3Na in and 1 Ca out Reverse = 3Na out and 1 Ca in Direction of movement depends on factors - Transmembrane Na+ ion concentration gradient - Transmembrane Ca2+ ion [] gradient - membrane potential Reversal potential is -45 mV NCX is in reverse mode for upstroke of AP (moves Ca2+ and positive charge out to bring back to reversal potential) NCK is in forward mode to move Ca2+ out until next AP NCK is the MAIN FACTOR for removing Ca2+ from cardiac myoplasm
What are some important components of the PV loop of the heart?
Starting from lowest pressure and lowest volume Have diastolic filling after the mitral valve opens - Then the mitral valve closes and the volume at this point is called end-diastolic volume --> preload Isovolumetric contraction occurs and SLAP valves open - When SLAP valves opens this is diastolic blood pressure --> after load Have contractor of ventricles and ventricular ejection - Highest pressure point is systolic BP SLAP valves close and then have isovolumetric relaxation - Down to end-systolic volume Difference in volume between isovolumetric contraction and relaxation - Stroke volume
Where does systole and diastole occur on a wiggers diagram?
Systole occurs when you have increase in ventricular pressure and ends when the aortic valve closes Diastole has two phases - Early diastole occurs when the aortic valve closes and ventricular pressure is dropping - Late diastole is characterized by low ventricular and atrial pressure
What is the ICa, T?
T-type calcium current Activated by membrane depolarization of -55mV Inactivate quickly Contributes to the latter portion of pacemaker potential Permeable to Ca2+ - Reversal potential is around +65 mV Coded for by Cav3.x genes
What are the cordae tendinae?
Tendons that connect the valves to the papillary muscles of the ventricular walls - When ventricles contract, papillary muscles contract and pull the chordae tendinae to ensure valves don't open
How do heart valves work? When do the valves open?
The cardiac valves only open in one direction - Open when the pressure behind the valve is greater than the pressure in front Tricupsid valve: RAP>RVP Pulmonary valve: RVP>PAP Mitral valve: LAP>LVP Aortic valve: LVP > AP
What is Starling's Law of the heart?
The further the cardiac cells are stretched by incoming blood, the greater the strength of the contraction - Up to a certain point the greater the preload the increased CO without any change in other factors --> mediated by SV
What are intercalated discs?
The junctions between adjacent cardiac cells - Have lots of gap junctions which are low electrical resistance conduits and allow for current to flow between the cells - Skeletal muscles don't have these
What is the Ito?
The transient outward delayed rectifier potassium current of ventricles Has reversal potential of -85 mV Kv4.2 or KCND2 gene Activated by membrane depolarization -60 mV Contributes to the initial phase of repolarization of the ventricular AP Unsure of contribution in SA node
What is functionally important about the times when both the mitral and aortic valve are closed?
These are times of isovolumetric contraction and relaxation - Contraction is when both valves are closed at the start of systole and the pressure in the ventricle is increasing due to contraction - Relaxation: both valves closed so no volume change but muscles relaxing so have decreased ventricular pressure
What are the lipid bilayer experiments?
They fractionate the cell, isolate jSR, insert the jSR into the artificial lipid bilayer - Can also purify RyR2 and add to lipid bilayer Can alter the solution of either side of the bilayer
When depolarization occurred at a specific clamped voltage, what two characteristics currents were seen? How did this change at larger depolarizations?
Transient inward current = represents ions flowing in - Was early Delayed outward current = represents ions flowing out - Was late At increased depolarizations: - The late current was extended and higher but the early inward current decreased and eventually was a outward blip
What are the values of the heart?
Tricupsid valve Mitral valve Pulmonary valve Aortic valve
What is the IKur?
Ultra-rapid delayed rectifier potassium current Reversal potential -85 mV Activates more quickly compared to other rectifier potentials IKr, IKs Kv1.5 or KCNA5 gene Activated by membrane depolarization, -60 mV Contributes to the initial phase of repolarization of the ventricular action potential Unsure of contribution in the SA node
What are the consequences of having abnormal diastolic RyR2?
Underlies inherited and acquired heart disease - Genetic disease --> CPVT - Acquired disease --> heart failure Decreased SR content --> less Ca2+ in systole so less force of contraction Elevated diastolic Ca --> slows the diastolic Ca2+ decline so less time for filling and less SV Reverse operation of NCX --> have Ca2+ release in diastole, normally in diastole NCX is in forward motion so increased Ca2+ release means more activity of NCX Requires more ATP
What is the experimental set up used to determine how RyR2 responds to calcium?
Used Purkinje cells that don't have T-tubules Then put in water bath whose solution mimicked intracellular ion concentrations - Hooked up cell to tension transducer Stripped off the sarcolemma to provide access to the cell and to RyR2 Added mineral oil around the cell to minimize the volume Added inflow and outflow pipettes to control Ca concentration around RyR2 - Started with basal (100nm) Ca2+ and then switch to known concentration quickly and then back to basal levels before contraction occurred - Controlled amount of Ca2+ added and how quickly it was added
What type of axon did Hodgkin and Huxley use for their studies?
Used a squid axon and put an electrode directly into it
What is the difference between voltage-gated Na and K channels?
Voltage-gated Na+ channels - Have two gates --> Inactivation gate and activation gate Voltage-gated K+ channels - Have an activation gate but may also have an inactivation gate that closes slowly
What is the frequency-dependent regulation of heart contraction?
When there is an increase in HR --> initially have decrease in contraction but then increase in contraction above previous When there is a decrease in HR --> initially have increase in contraction but then decrease contraction below previous Increase HR - Initial decrease is due to RyR2 inactivation - Then increased AP frequency results in increased Na+ intracellular concentration which alters the reversal potential of NCX and reduces its activity --> Less Ca2+ is removed from myoplasm --> Increases SERCA substrate and increase Ca2+ in the SR - Also increased Ca2+ causes increased activation of CamKII which phosphorylates PLB and increases SERCA turnover rate --< increases Ca2+ in the SR
