The molecular and ionic basis of cardiovascular control Flashcards
How is force of contraction of cardiac muscle regulated
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
how do sarcomeres link to starlings law
EDV inc – inc force of contraction
Increased overlap of thin and thick filaments (inc overlap – inc force generators so more of everything)
how is HR controlled autonomically
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
how does sympathetic affect HR
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
What is the funny current
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
what do a1 receptors do
PLC - PIP3 to IP3 and DAG - Ca2+ - vasoconstriction in most organs, sweat
what do B receptors do
Adenylyl-cyclase ATP to cAMP - inc contractility (B1), HR (If), skeletal muscle perfusion and bronchodilation(B2)
how does the vagus nerve affect HR
Parasympathetic – slower
Ach inc K current (hyperpolarises membrane, dec slope of pacemaker potential)
Ach activated K channel (G protein coupled, muscarinic)
How is HR slowed
Atropine blocks vagal slowing of HR (acts on M2 to stop ATP to cAMP IN SA and AV node)
how does the muscarinic receptor affect HR
Muscarinic Receptor slows HR
what K+ channels are found in cardiomyocytes
Delayed rectifiers
Inward rectifiers
Ach sensitive K channels
what happens during hyper polarisation
K+ permeability inc and Na+ dec, membrane potential closer to EKMore negative due to delayed rectifiers
Why voltage in after hyperpolarisation is more negative than at rest
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
What does the refractory period do
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
what are the t tubules and terminal cisternae
A system for strong and releasing calcium in response to Vm
what are t tubules
invaginations of plasma membrane into myocyte
what do t tubules and terminal cisternae do
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
what are terminal cisternae
enlarged area of SR
Contiguous with SR, specialised for storing and releasing calcium
what is excitation contraction coupling
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
E-C coupling in skeletal muscle
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
E-C coupling in cardiac myocytes
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
how does calcium lead to calcium release
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
what results from excess calcium
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
what are the different types of calcium channel blockers
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
what does verapamil do
not a DHP, antiarrythmia
blocks heart more than vessel
slows nodal cells
protects V from rapd A rhythms (slow conduction to AV node)
what does diltiazem do
not a DHP, antianginal and antiarrythmia
heart and vessel channels
slow nodal rate, vasodilator CAs, prevents angina (dec WL, inc perfusion)
what is digoxin
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
how is BP controlled locally
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
What does MLCK do
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
how are VSMCs relaxed
dephosphorylating myosin by phosphatase activated by NO induced enzyme cascade
In peripheral skeletal muscles – B2 stimulation phosphorylates K channels leading to relaxation
how are core organs and GI tract contracted
A1 stimulation phosphorylates MLCK – VSMC contraction
How do nitrates act as
GTN degrades to produce NO
rapid vasodilation
continuous administration - tolerance
what are bradykinins
Peptide hormone – loosens capillaries and BVs, constricts bronchi and GI tract smooth muscle
what do bradykinins do
Vasodilator – endothelium dependant, stimulates NO production in endothelium
Increases capillary permeability eg inc saliva production
what are the biomarkers in plasma
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
how are bradykinins affected by ACE inhibitors
ACE inhibitors prevent degradation of bradykinin which causes dry cough associated with ACE inhibitors
