Unit 1 Flashcards
Describe the functions of the CV system
- distribute dissolved gases (like O2) and nutrients
- remove metabolic waste
- maintains homeostasis (controls temp., pH, electrolytes)
Describe the series and parallel arrangement of the circulatory system, and its purposes
- right and left sides of heart arranged in series (one after another)
- systemic circulation can be parallel so that multiple organs are supplied at the same time (branching)
Describe the anatomy of the heart, including its chambers, valves, and major vessels
- epicardium: outer layer of CT and fat
- myocardium: middle layer of muscle
- endocardium: inner layer of endo cells
- pericardium surrounds entire heart; fluid filled
- four chambers: left and right atria and ventricles
- mitral valve between left atrium and ventricle
- tricuspid valve between right atrium and ventricle
- aortic valve between left ventricle and aorta
- pulmonary valve between right ventricle and pulmonary artery
- vena cava drains into right atrium
Describe the blood flow pathway through the heart
blood is oxygenated in lungs –> pulmonary vein –> left atrium –> mitral valve –> left ventricle –> aortic valve –> aorta –> body –> vena cava –> right atrium –> tricuspid valve –> right ventricle –> pulmonary valve –> pulmonary artery –> lungs to get reoxygenated
Describe the major types of blood vessels
- pulmonary vein: carry oxy blood from lungs to heart
- pulmonary artery: carry deoxy blood from right ventricle to lungs
- aorta: carry oxy blood from left ventricle to body
- vena cava: carry deoxy blood from body to right atrium
Describe the arrangement of the microcirculation
- vasculature from the first order arterioles to the venules
- site of gas, nutrient, and waste exchange
- precapillary sphincters: smooth muscle bands at junctions of arterioles and capillaries
- no smooth muscle, just endo cells and basement membrane
Describe the function of the lymphatic system
- lymph is excess interstitial fluid
- flows through lymph vessels to lymph nodes and rejoins circulatory system
- edema occurs when interstitial fluid exceeds capacity of lymphatic system
Describe the cardiac conduction system
SA node –> atria through gap junctions –> AV node (delay) –> His-Purkinje fibers
Why are arterioles so special?
- thicker than aorta and arteries
- highly innervated by autonomic nerves, circulating hormones, and local metabolites
- main site of regulation of vascular resistance by changing size of diameter
Describe the anatomy of vessels
Tunica adventitia:
- outer layer
- mostly CT with collagen and elastin
Tunia media:
- middle layer
- innervated smooth muscle
- controls diameter
Tunica intima:
- single layer of endothelial cells
What are intercalated disks?
- connect cardiac myocytes to transfer force and coordinate electrical activity
What is the relationship between pressure, flow, and resistance in the circulatory system?
- Flow is volume per unit time (Q); constant throughout system and equal to CO in CV system
Flow = Velocity*Cross-sectional Area AND Flow = pressure difference/resistance OR CO = (MAP-VP)/TPR
- analogous to I = V/R
How do changes in vascular resistance determine distribution of CO among tissues?
- if you change the diameter of a vessel through vasoconstriction or vasodilation, then according to Poiseuille’s Flow, you can drastically affect flow through that vessel
How do vascular resistance, blood viscosity, vessel length, and vessel radius affect blood flow?
Flow = pressure diffpiradius^4/(8viscositylength)
OR
Q = deltaPpir^4/(8nl)
- key point is that radius is ^4
How is the pulsatile flow of blood converted to steady flow in capillaries?
- elastic walls of aorta and arteries dampen pulsatile pressure, so by the time they reach capillaries, more like a continuous flow
- helps because pulsatile needs more work (accelerating mass vs constant vel)
What is vascular compliance?
C = deltaV/deltaP
- represents the elastic properties of vessels (if very compliant, then easily expanded, like veins but not arteries)
- compliance is opposite to elasticity
- determined by elastin fibers vs smooth muscle and collagen in vessel walls
- more compliance = lower pulse pressure (can expand more so doesn’t maintain pressure as well)
What is the relationship between vascular wall tension, transmural pressure, radius, and wall thickness?
Wall tension = transmural pressureradius/wall thickness
OR
T = deltaPtmr/u
- Wall tension is the circular tension that exists around/on the wall of a vessel
What is Fick’s Principle and how can it be used to determine transcapillary efflux?
- Fick’s principle: the amount used is the equal to the amount that enters minus amount that leaves
x_used = xi-xo = Q*([x]i-[x]o)
for myocardial O2 consumption:
mVO2 = CO*([O2]arterial-[O2]venous)
How does the balance between hydrostatic and oncotic pressures in a capillary bed determine direction of transcapillary transport?
- hydrostatic pressure is difference between capillary blood pressure and interstitial pressure and typically results in stuff going out of vessel into interstitium (because pressure there is basically 0) –> filtration
- oncotic pressure is due to osmotic force by proteins; more proteins in blood, so fluid comes into vessel –> reabsorption
Flux = k[(Pc-Pi)-(pic-pii)]
- Arterial side of capillaries, Pc is higher and pic is lower; opposite for venous side
What is transmural pressure?
- Difference in pressure between inside and outside of a vessel (across the wall)
Where does pressure fall the most?
- Arterioles
What is the total blood volume? Where is most of the blood volume found?
- about 5L
- Mostly in venous system
Describe resistance, flow, and pressure in parallel and in series
Parallel:
- 1/Rtot = 1/R1+1/R2+….
- deltaP1 = deltaP2 = …
- total res is lower than individual paths
- changing one res pathway doesn’t affect total res that much
- pressure diff is same across all branches
- flow is proportional to 1/Ri
Series:
- Rtot = R1+R2+….
- Q1=Q2=….
- total res is sum of res (most res in arterioles)
- flow is constant, but pressure diff is different between segments
Difference between laminar and turbulent flow
- Laminar: smooth, efficient, slowest at edge, fastest in center
- Turbulent: irregular; needs more pressure for same avg velocity; occurs with large diameter, high velocity, low viscosity, changes in diameter; creates shearing force that damages endo cells
What is mean arterial pressure?
diastolic pressure + 1/3(systolic press-diastolic press)
OR
1/3systolic press + 2/3diastolic press
- basically like this because more often in diastole than in systole –> changes with heart rate
What is bulk transport?
- cargo from point A to point B in the CV system; can use to measure O2 consumption
rate = flowconc
OR
x=Q[x]
What are the unique properties of cardiac muscle?
- striated
- autonomic (doesn’t need neural input)
- interconnected mono-nuc cells in weaved collagen
- longer repol than skeletal muscle
- ATPase activity slower than skeletal
- **thin-filament regulated (as opposed to thick for smooth muscle)
- mechanical and electrical coupling between cells (desmosomes provide mech coupling, gap junctions for electrical)
- lots of mitochondria
Describe the cross bridge cycle
- resting muscle: low Ca in cell, TN-TM complex inhibits actin-myosin binding; action potential leads to release of Ca from SR to increase Ca in cell; TN binds Ca and moves TM out of the way so actin and myosin can bind
1) ATP binds and hydrolyzes to ADP and Pi to activate myosin; Pi leaves and myosin strongly binds to actin
2) ADP released and myosin head pivots
3) ATP binds to myosin head and detaches
4) reactivate myosin head with hydrolysis of ATP
Describe the length tension (Frank-Starling) relationship in cardiac muscle
- increase in preload –> increase in SV
- length-tension relationship (some optimal length where if you lengthen the sarcomere, get a better overlap, better Ca sensitivity, and inc Ca release and a better contraction –> increased preload stretched the sarcomeres)
Relate myocyte mechanics to ventricular function
- inc in volume –> inc in ventricular circumference –> inc in length of individual myocytes
- T=P*r/u
Identify sarcomeric changes associated with heart failure
- hypertrophy: concentric cell growth; changes mainly in Ca sensitivity
- Dilation: eccentric cell growth; changes in force output
What is cardiac output?
CO = stroke volume*heart rate
What factors control stroke volume?
- Preload: length-tension; higher preload = higher force
- Afterload: pressure that ventricle needs to overcome; usually aortic pressure
- Contractility: force that heart contracts with; norepinephrine regulates
What are the proteins involved in contraction?
- Myosin: 2 heavy and 4 light chains
- Actin: binds tropomyosin and troponin
- Thin filament regulatory proteins:
- TN-C: contains one Ca binding site
- -TN-I: regulated by phosphorylation/PKA sites; actin cannot bind myosin when in the way
- -TN-T: binds tropomyosin
- -Tropomyosin: lays over actin in the myosin binding sites
Describe titin
- giant protein
- functions as an elastic spring
- resting tension of myocyte
- N2B is stiffer and shorter than N2BA
Define cardiac output
- CO is the volume of blood pumped per min by the left ventricle
CO=SV*HR
- usually about 5L/min at rest
What are the four phases of the cardiac cycle and describe changes in pressure and volume in each chamber accordingly
1) Diastole:
- LA filled with oxy blood and mitral valve is open so LV fills with blood passively
- LA contracts and builds atrial pressure
- mitral valve is open and blood starts to fill in LV and also increase pressure in LV
2) Isovolumetric contraction:
- LV contracts as pressure increases really quickly
- volume stays same because mitral valve closed when filled enough and aortic valve not open yet
3) Ejection phase:
- LV contracts and aortic valve opens
- LV starts to relax and ejects blood so pressure starts to decrease and volume decreases
- aortic valve stays open for a little bit due to inertia of blood moving while LV relaxes
4) Isovolumetric relaxation phase:
- aortic and mitral valves closed and LV continues to relax so volume is same, but pressure decreases until so low that mitral valve opens again
Define systolic and diastolic pressure-volume relations and ventricular function curves
End diastolic pressure-volume relationship (EDPVR):
- represents the preload on the heart
- curve representing pressure-volume relation while passive, before contracting (at the end of diastole)
Systolic pressure-volume relationship (SPVR):
- curve representing pressure-volume relation at peak of contraction
- depends on afterload (aortic pressure)
Describe the Frank-Starling Law of the Heart
1) if increase in EDV, then increase in force of contraction
2) healthy heart functions on ascending limb of Starling curve
3) CO must equal venous return; CO from LV and RV must match
- titin is stiff
- as sarcomeres are stretched, more Ca binding sites, so more contraction
- closer lattice spreading
Describe relative changes in pressure and volume through the cardiac cycle (PV Loops)
1) Filling phase:
- ESV is bottom left; lowest pressure and lowest volume right after systole
- LV relaxes and fills with blood passively from LA with little change in pressure
- end volume is end diastolic volume
2) Isovolumetric contraction phase:
- LV contracts, mitral valve closed, but aortic valve alos closed since LV pressure not high enough to over come yet, so volume stays same
3) Ejection phase:
- LV pressure exceeds aortic pressure so aortic valve opens
- blood leaves so volume decreases
- pressure increases because blood cannot leave aorta as fast as it enters
- pressure starts to fall as LV starts to relax
4) Isovolumetric relaxation phase:
- LV pressure below aortic pressure, aortic valve closes, still relaxing so mitral valve still closed
Define stroke volume, ejection fraction, stroke work, and pulse pressure, and to identify them graphically on a PV Loop diagram
Stroke Volume:
- amount of blood pumped per beat
- EDV-ESV = SV
Ejection Fraction:
- fraction of EDV ejected during systole
- SV/EDV = EF
Stroke Work:
- energy per beat
- area of PV loop
Pulse Pressure:
- systolic pressure - diastolic pressure
Define preload, afterload, and contractility, and describe how altering these variables changes ventricular function
Preload:
- EDV; the amount that initially stretches the LV
- *ventricular compliance: dec compliance = more stiff (hypertrophy) = lower EDV at given pressures (shifts EDPVR left)
- if you inc preload, you immediately increase SV (Starling’s law) bc EDV increases but ESV stays same and stroke work inc
- next beats are same SV because ESV is same
Afterload:
- ~aortic pressure
- wall thickness and radius affect
- inc afterload, decrease in SV because less time for ejection (since need to reach higher pressure before aortic valve opens), also less pressure due to dec shortening velocity and lower ejection velocity
- EDV is same, EF dec, ESV inc, SV dec
Contractility:
- strength of contraction indep of preload or afterload
- new Startling curves
- regulated by drugs and NS
- if inc inotropy, shift Starling curve to left (greater systolic pressure at any vol); see inc SV, dec ESV, inc EF
How do HR and SV affect CO?
CO=HR*SV
- HR is highly regulated by autonomic NS
- HR can change more than SV so can influence CO more
- high HR means less time for filling –> lower stroke volume
- SV affected by preload, afterload, and contractility
What is active tension?
- the difference in force between peak sys press and dia press curves
- basically the tension developed purely by contraction, indep of preload
- presented by Starling Curve
Describe the differences between fast and slow cardiac APs graphically
Slow APs:
- Phase 0: rising phase due to Ca channels
- no Phase 1 or 2
- Phase 3: repol due to IKr and IKs (delayed rectifier K channels)
- Phase 4: steady depol from If
Fast:
- Phase 0: rising phase due to Na channels
- Phase 1: IKto gives a partial repol and makes Ca entering more favorable
- Phase 2: plateau phase where L type Ca channels open
- Phase 3: delayed rectifier IKr and IKs channels open to repol
- Phase 4: flat, some inward rectifier
Which cells are fast and slow cardiac APs found in respectively?
Fast:
- atrial muscles
- ventricular muscles
- Purkinje fibers
Slow:
- SA nodal cells
- AV nodal cells
Describe the properties of ion channels that underlie fast and slow cardiac APs
Fast APs:
- Phase 0: rapid depol of entry of Na ions
- Phase 1: partial repol due to inact of Na gates and act of IKto
- Phase 2: plateau where L-type Ca channels are open influx are balance by IKr and IKs
- Phase 3: Ca gates start to inact and act of IKr and IKs
- Phase 4: IKr and IKs deact and IK1 holds Vm near Ek
Slow:
- Phase 0: upstroke due to Ca channels and not as fast as Na
- no phase 1 or phase 2
- Phase 3: IKr and IKs cause repol
- Phase 4: slow depol that brings cell back to threshold automatically due to funny current –> activated by hyperpolarization after IKr and IKs –> brings in Na and out K, but mainly in Na so depols slowly
Describe the ionic mechanisms that account for the ability of pacemaker cells to generate firing without neural input
- repetitive slow APs due to If causing a slow depolarization naturally
Describe the significance of IK1 channels in myocardial cells with fast APs
- maintain resting membrane potential around EK after AP
Describe the significance of If or Ih currents in cells with slow APs
- causes the slow depol that allows cells in SA and AV node to fire automatically
Discuss the mechanism and significance of overdrive suppression
- Overdrive suppression is when AV node cells reach APs with a higher frequency than naturally because of signals from the SA node, which generates APs faster than the AV does naturally
Define the absolute refractory period
- 2nd AP cannot be initiated until most of Na inactivation is removed (during repol phase)
Define the relative refractory period
- threshold is elevated for an AP until after repol phase due to compete removal of Na inactivation and complete deactivation of IKr and IKs)
Describe Na channels
- ## depol causes rapid activation then voltage-dep inactivation
Describe Ca channels
- similar to Na channels
- L type: long; high depol causes rapid activation then voltage-dep and cytoplasmic Ca-dep inactivation; mainly in cardiac muscle
- T type: transient; low depol activated then inactivate
Describe time-dep K channels
IKto:
- transient outward
- depol leads to act and inact slower than Na channel
- Phase 1 of fast APs
IKr and IKs:
- rapid and slow delayed rectifier
- depol leads to activation
- Phase 3 of fast and slow APs
Describe the inward rectified K channels
IK1:
- conduct inward K current when VmEk
- hold cells near Ek between APs
Describe the funny current
- turned off at depol and turned on at hyperpol
- permeable to both Na and K (Erev = -30)
What is HERG?
- anti-target for new drugs
- IKr is a tetramer of HERG and important for repol in both fast and slow APs
- altered HERG can lead to arrhythmias
How do electrical impulse spread from cell to cell
- through gap junctions between cells, there are connexins that let ions pass
Describe the cardiac conduction pathway
starts in SA node in high RA –> RA –> LA (P wave) –> AV node b/w tricuspid and mitral valves b/w atria and ventricles (junction) –> delay before entering ventricles –> bundle of His –> left and right bundle branches –> Purkinje fibers
Compare ventricular AP to an ECG
- Phase 0 = QRS
- Phase 2 = ST segment
- Phase 3 = T wave
- Phase 4 = isoelectric segment
What is T wave and QRS in the same direction but repol and depol not?
- Endocardium depol earlier than epicardium, but repol later than epicardium
- so repol going away from the electrode looks like a positive deflection
Describe the components of the ECD
- P wave = atrial depol
- QRS = ventricular depol
- T wave = ventricular repol
- PR interval = index of conduction time across AV node
- QT interval = total duration of depol and repol
What happens with SA node abnormality?
- slow sinus rate
- taken over by other pacemakers that can be too fast or too slow
Describe the types of AV block
1st degree: conduction delayed but all P waves conduct to ventricles
2nd degree: some P waves conduct
3rd degree: no P waves conduct; ventricular pacemaker takes over
Describe the different bundle branch blocks
Right bundle blocked: wide QRS w/ delayed conduction to right ventricle
Left bundle blocked: wide QRS w/ delayed conduction to left ventricle
Left fascicles blocked: shifts in depol, but no wide QRS
What are the 3 common mechanisms leading to arrhytmia?
1) abnormal reentry pathways:
- unidirectional block and slowed conduction
2) ectopic foci:
- focus of myocardium acquires automaticity and rate is faster than SA node
3) triggered activity:
- afterpolarizations due to preceding AP
Describe the gene defects and molecular basis of long QT syndrome
- mutations in cardiac ion channels
- AD form (Romano-Ward syndrome): 200+ mutations mainly in IKs, IKr, and Na channels
- AR form (Jervell-Lange-Nielson syndrome): mutations in IKs also have deafness
- mutations in K channel subunits (LQT1) –> reduce number of K channels expressed –> reduced size of IKr and IKs current –> weaker repol –> longer plateau
- mutations in Na channels (LQT3) prevent them from inactivating completely –> prolong phase 2 due to more depol
List the cardiac ion channels and the phases of the slow and fast responses that are targeted by the various antiarrhythmic drugs
Ion channel targets:
- Na channels
- Ca channels
- K channels (IKr and IKs)
- beta-adrenergic receptors
- Na channel blockers for LQT3 due to elongated phase 2
- K channel openers for LQT1 or LQT2 but none currently exist
Describe the cellular mechanism of triggered (early and delayed) afterdepolarizations
EAD:
- during late phase 2 and phase 3
- re-activation of Ca channels due to elevated Cai from prolonged phase 2
DAD:
- during early phase 4
- inc Cai –> inc Na/Ca exchange (3 Na in/1 Ca out) –> depol due to Incx
Describe how a re-entrant, or circus, arrhythmia originates
- two requirements:
1) uni-directional conduction block
2) conduction time around the circuit is longer than refractory period
-
Describe the basis of use-dependent block of Na channels by class I antiarrhythmic drugs
- drugs target cells that are over-active with high firing rates or that are abnormally depolarized
- this targets defective cells and prevents affecting normal cells
- hydrophilic drug enters pore when channel is open
Describe how class I antiarrhythmics increase Na channel refractory period, whether or not they prolong phase 2 of the fast response
- drug initially blocks and enter channel during open state, but have a higher affinity during closed state and stabilize that closed/inact state and prolong the time the channel spends in the inact state
- class Ia and Ic drugs block K channels to delay repol and prolong phase 2 –> more Na channels are inact –> longer refractory period
Describe how beta-adrenergic receptor blockers help suppress arrhythmias
- reduce If, ICa, and IKs current –> reduce rate of diastolic depol in pacemaker cells, reduce upstroke rate, and slow repol –> pace rate is reduced and refractory period is prolonged
- AV nodal re-entry terminated
- control ventricular rate during afib
- dec phase 4 slope –> dec rate of firing –> dec automaticity
- prolonged repol of AV node –> inc effective refractory period –> dec re-entry
Describe how class III drugs increase refractory period
- block IKr channels
- leads to prolonged phase 2 and prolonged refractory period
- inc effective refractory period –> dec re-entry
Describe how class IV antiarrhythmic drugs (Ca channel blockers) reduce re-entry via effects on conduction velocity through the AV node and refractory period of the AV node
- block Ca channels –> slows Ca upstroke in slow AP cells –> slows conduction velocity in AV node –> dec re-entry
- prolong refractory period –> dec re-entry
- also, since reduced peak Ca upstroke, you have reduced K repol
Describe how increasing refractory period may help suppress re-entrant arrhythmias
- tissue in refractory period cannot generate an AP so the re-entrant arrhythmia would be extinguished
Describe how some antiarrhythmic drugs can suppress arrhythmias by decreasing cardiac automaticity
- class II beta blockers block If so that rate of depol during diastole is reduced and rate of firing (decreasing cardiac automaticity) is decreased –> slows conduction velocity –> dec re-entry
Describe how adenosine can help suppress cardiac arrhythmias
- through GPCR (similar mechanism to beta blockers), can inc K current, and dec Ca and If currents
- dec If and ICa –> dec diastolic depol and weaker upstroke –> slowed conduction velocity
- adenoside binds to receptor –> activated G protein –> inhibits cAMP –> reduces cAMP –> reduces PKA –> reduces phosphorylation of Ca channels –> closes Ca channels –> smaller Ca current –> smaller upstroke
- G protein binds to IKado –> inc in K current –> faster hyperpol
What happens in long QT syndrome?
- prolongation of the plateau phase 2 of fast AP cells in ventricular myocytes –> ventricular tachycardia (torsades de pointes) –> ventricular fibrillation –> syncope –> sudden cardiac death
What is Brugada syndrome?
- form of congenital arrhythmia
- ventricular fibrillation occurs
- 30+ different mutations in Na channels –> reduce peak inward Na current
What happens in Finnish familial arrhythmia?
- beta-adrenergic receptors upregulate Ca channels, but not K channels
- yotiao normally targets PKA of Ca and K channels by binding to them
- however binding to K channels is impaired –> diminished beta receptor upreg of K channels
- with sympathetic activity, Ca depol, but not enough K repol
What are the two sources of arrhythmias?
1) inappropriate impulse initiation in SA nodes:
- ectopic foci (SA node too slow or ectopic foci too fast)
- EADs (depol during phase 2/3 from Ca)
- DADs (depol during phase 4 from Ca and NCX)
2) disturbed impulse conduction in nodes, conduction (Purkinje) cells, or myocytes:
- conduction block (1, 2, 3 degree)
- re-entry (requires uni-directional conduction block and conduction time around circuit is longer than refractory period)
What is the primary mechanism of class I drugs?
- blocking voltage-gated Na channels (slower upstroke)
- affect fast response cells mainly
- decrease conduction rate and increase refractory period
- block Na channels –> dec phase 0 upstroke velocity –> dec conduction velocity –> dec re-entry
- inc effective refractory period –> dec re-entry
Describe class Ia Na channel blockers
- slowed upstroke (block of Na channels due to class I)
- delayed repol (block of K channels due to class III)
- prolonged refractory period
Describe class Ib Na channel blockers
- slowed upstroke (block of Na channels due to class I)
- prolonged refractory period
- phase 2 NOT prolonged, actually shortened
- purest form of class I (because only Na channel block and not K channel)
Describe class Ic Na channel blockers
- most pronounced slowed upstroked
- prolonged phase 2
- powerful prolongation of refractory period
What are two mechanisms to terminate re-entry?
1) slow AP conduction velocity –> reduce upstroke rate –> more likely to fail to propagate through depressed region –> convert to bi-directional block
2) prolong refractory period –> refractory tissue will not generate an AP
What is the paradox in combating re-entry?
- try to slow conduction velocity, but this means that the signal being propagated is less likely to be shorter than the refractory period, meaning that it will be able to excite tissue since they will no longer be in the refractory period
What is so special about Amiodarone?
- class III antiarrhythmic but has class I activity
- reduces conduction velocity because blocks Na channels
- also dec rate of diastolic depol (phase 4) in pacemaker cells
- dec conduction velocity –> dec re-entry
- dec rate of firing –> dec automaticity
How do you treat paroxysmal supraventricular tachycardia?
acute: adenosine (short half-life)
chronic: AV node blockers (class II, class IV, class II, digoxin), cather ablation of ectopic foci
How do you treat atrial fibrillation?
acute: AV node blockers, electrical cardioversion
chronic: AV node blockers with anticoag (warfarin), cardioversion with maintaining sinus rhythm with drugs (class III, class Ic)
How do you treat ventricular tachycardias/fibrillation?
prevent sudden cardiac death
acute: amiodarone, lidocaine, pocainamide
chronic: beta-blockers, mabye amiodarone
What is the half-life of class II esmolol?
10 min
What is the half-life of class II amiodarone?
13-100 days
What is the half-life of adenosine?
What are class I antiarrhythmic drugs?
block Na channels
What are class II antiarrhythmic drugs?
beta blockers
What are class III antiarrhythmic drugs?
block K channels
What are class IV antiarrhythmic drugs?
block L-type Ca channels
Describe the mechanisms by which PKA-mediated phosphorylation of Phospholamban, L-type Ca channels, RyRs, and troponin I affect inotropy and lusitropy
Phospholamban:
- PB inhibits SERCA
- when phos, PB dissociates from SERCA, so SERCA reuptakes more Ca into SR
- inc lusitropy (better relaxing)
- inc inotropy by inc SR Ca load
L-type Ca channels:
- phos of these channels slows inactivation so more CICR and inc inotropy
RyRs:
- when phos, more sensitive to Ca (less Ca for same Ca release)
- inc inotropy
Troponin:
- normally, TnI inhibits interaction between actin and myosin
- when phos, decrease sensitivity of Ca –> faster dissoc of Ca –> inc lusitropy –> heart fills more quickly
Describe how HCN, L-type Ca, RyRs, and GIRK channels contribute to autonomic control of heart rate
HCNs (hyperpolarization-activated cyclic nucleotide-gated channels):
- symp stim: inc cAMP –> cAMP bind directly to HCN channels to make them more likely to open –> more If to inc rate of diastolic depol –> inc heart rate
- para inh: dec cAMP –> HCN less likely to open –> less If to dec diastolic depol –> dec heart rate
L-type Ca:
- symp stim: cAMP activates PKA –> phos L-type Ca channel –> slows inactivation –> inc Ca current –> inc heart rate
- para inh: dec cAMP –> PKA less activated –> less phos of LTCCs –> no slowing of inact –> dec/normal Ca current –> dec heart rate
RyRs/NCX:
- symp stim: inc SR Ca load when PKA phos PB, RyRs, and LTCCs –> more Ca release –> diastolic depol with more inward current from NCX –> inc heart rate
- para inh: less Ca release –> less diastolic depol with less inward current from NCX –> dec heart rate
GIRK (G-protein couple inwardly-rectifying K):
- para inh: beta/gamma Gsubunit binds to GIRK –> activated IKACh –> keep Vm near EK –> slow firing freq –> dec heart rate