The molecular and ionic basis of cardiovascular control

Question 1

How is force of contraction of cardiac muscle regulated

Answer 1

Intrinsic regulation – starlings law, increased contractility, longer and stronger (more cross bridges, more of everything)
Extrinsic regulation – sympathetic stim, faster and stronger, not longer duration, extant cross bridges work harder and faster

Question 2

how do sarcomeres link to starlings law

Answer 2

EDV inc – inc force of contraction

Increased overlap of thin and thick filaments (inc overlap – inc force generators so more of everything)

Question 3

how is HR controlled autonomically

Answer 3

Isolated or denervated heart rate about 100 bpm
The normal resting HR is due to tonic ps stimulation (about 60 bpm)
HR determined mostly by slope of the pacemaker potential

Question 4

how does sympathetic affect HR

Answer 4

NA – inc If (net inward current)
Pacemaker channels, inc slope of pacemaker potential, via B1 receptor
Also nodal and ventricular
NA inc Ca current (inc force of contraction)
NA inc K current
Delayed rectifier, shortens AP duration, allows faster HR

Question 5

What is the funny current

Answer 5

Net current is inward 
Technically conducts Na and K
Non specific monovalent cation channel
Reversal potential of -10mV
HCN channel opens when membrane gets more negative, controls slope of pacemaker potential (Na/Ca exchange)
Inc by sympathetic stimulation

Question 6

what do a1 receptors do

Answer 6

PLC - PIP3 to IP3 and DAG - Ca2+ - vasoconstriction in most organs, sweat

Question 7

what do B receptors do

Answer 7

Adenylyl-cyclase ATP to cAMP - inc contractility (B1), HR (If), skeletal muscle perfusion and bronchodilation(B2)

Question 8

how does the vagus nerve affect HR

Answer 8

Parasympathetic – slower
Ach inc K current (hyperpolarises membrane, dec slope of pacemaker potential)
Ach activated K channel (G protein coupled, muscarinic)

Question 9

How is HR slowed

Answer 9

Atropine blocks vagal slowing of HR (acts on M2 to stop ATP to cAMP IN SA and AV node)

Question 10

how does the muscarinic receptor affect HR

Answer 10

Muscarinic Receptor slows HR

Question 11

what K+ channels are found in cardiomyocytes

Answer 11

Delayed rectifiers
Inward rectifiers
Ach sensitive K channels

Question 12

what happens during hyper polarisation

Answer 12

K+ permeability inc and Na+ dec, membrane potential closer to EKMore negative due to delayed rectifiers

Question 13

Why voltage in after hyperpolarisation is more negative than at rest

Answer 13

Both delayed and inward rectifiers are open early during AHP
Inward open when membrane more negative than -70mV and delayed rectifiers slow to close
Leads to refractory period

Question 14

What does the refractory period do

Answer 14

When it becomes nearly impossible to start a new action potential
In cardiomyocyte, lasts for duration of AP
Protects heart from unwanted extra Aps between SA node initiated heart beats - could start arrythmias

Question 15

what are the t tubules and terminal cisternae

Answer 15

A system for strong and releasing calcium in response to Vm

Question 16

what are t tubules

Answer 16

invaginations of plasma membrane into myocyte

Question 17

what do t tubules and terminal cisternae do

Answer 17

Triad – 1 t tubule surrounded by terminal cisternae
membrane currents can be near contractile machinery
Contiguous with extracellular fluid
Adjacent to SR
T tubule depolarises
Terminal cisterna detects it and sends throughout SR

Question 18

what are terminal cisternae

Answer 18

enlarged area of SR

Contiguous with SR, specialised for storing and releasing calcium

Question 19

what is excitation contraction coupling

Answer 19

The link between the depolarisation of the membrane (with tiny influx of Ca) and consequent huge inc in cytosolic Ca that leads to contraction
Excitation – when a neuron stimulates a muscle cell
Diffusion of free Ca into cytoplasm – voltage change – contraction

Question 20

E-C coupling in skeletal muscle

Answer 20

During contraction – most Ca comes from the sarcoplasmic reticulum (next to myocytes actin and myosin)
the membrane depolarises and calcium channels undergo a conformational change, calcium release channel in SR undergo a conformational change that opens them so Ca can flow in

Question 21

E-C coupling in cardiac myocytes

Answer 21

Ryanodine receptor (RyR)
In SR membrane, channel that releases Ca, triggered by intracellular Ca inc, positive FB loop
SERCA in SR membrane, pumps Ca2+ back into SR (req ATP)
Sympathetic stimulation – inc EC coupling which may cause calcium overload

Question 22

how does calcium lead to calcium release

Answer 22

Initially Ca enters the cell from the outside
Calcium detected by calcium release channels in SP (intracellular), RyR open to allow Ca from SR to cytosol
Positive feedback loop
Close after a time delay
SERCA pumps Ca back into SR

Question 23

what results from excess calcium

Answer 23

Excessive intracellular Ca (also possibly xs Ca in SR)
Can cause risk of ectopic beats and arrythmias
Ca may spill out of SR into cytosol at inappropriate times in cardiac cycle, made worse by fast rates and sympathetic drives

Question 24

what are the different types of calcium channel blockers

Answer 24

On vessels – vasodilate, oppose hypertension (eg Amlodipine, a dihydropyridine)
On heart – anti-anginal and antiarrhythmic agents by reducing nodal rates and conduction through AV node but makes HF worse

Question 25

what does verapamil do

Answer 25

not a DHP, antiarrythmia blocks heart more than vessel slows nodal cells protects V from rapd A rhythms (slow conduction to AV node)

Question 26

what does diltiazem do

Answer 26

not a DHP, antianginal and antiarrythmia heart and vessel channels slow nodal rate, vasodilator CAs, prevents angina (dec WL, inc perfusion)

Question 27

what is digoxin

Answer 27

Positive intropic agent – inc SV and contractility Works by slightly inhibiting Na/K pump on membrane (inc Ca in cytosol) also stimulates Vagus (slows HR and inc AV delay) Was used for HF (improves symptoms but not mortality, BB preferred) Use now controversial, sometimes used for AF

Question 28

how is BP controlled locally

Answer 28

myogenic control Endothelium detects stretch and plasma factors Produced NO Local hormones can affect the SM outside of endothelium Endothelium controls vascular tone and clotting, responds to/makes Bradykinin and NO

Question 29

What does MLCK do

Answer 29

Vascular smooth muscle cell contraction initiated by MLCK In SM, myosin must be phosphorylated to contract (instead of control by troponin and tropomyosin) MLCK can phosphorylate myosin (at its light chain), activated by calcium-calmodulin Relaxation occurs by dephosphorylating myosin, done by phosphatase activated by NO induced enzyme cascade

Question 30

how are VSMCs relaxed

Answer 30

dephosphorylating myosin by phosphatase activated by NO induced enzyme cascade In peripheral skeletal muscles – B2 stimulation phosphorylates K channels leading to relaxation

Question 31

how are core organs and GI tract contracted

Answer 31

A1 stimulation phosphorylates MLCK – VSMC contraction

Question 32

How do nitrates act as

Answer 32

GTN degrades to produce NO rapid vasodilation continuous administration - tolerance

Question 33

what are bradykinins

Answer 33

Peptide hormone – loosens capillaries and BVs, constricts bronchi and GI tract smooth muscle

Question 34

what do bradykinins do

Answer 34

Vasodilator – endothelium dependant, stimulates NO production in endothelium Increases capillary permeability eg inc saliva production

Question 35

what are the biomarkers in plasma

Answer 35

Troponin (Tn) – released from cardiomyocytes during necrosis Elevated during AMI, HF and many others not elevated during unstable angina Creatine Kinases (CK or CPK) – released from myocytes during necrosis C reactive protein (CRP) – increases in response to inflammation Acute phase protein

Question 36

how are bradykinins affected by ACE inhibitors

Answer 36

ACE inhibitors prevent degradation of bradykinin which causes dry cough associated with ACE inhibitors