Molecular and ionic basis of CVD Flashcards
Intrinsic regulation of the force of contraction of cardiac muscle.
Frank-Starling relationship.
The more the cardiac cells are stretched, the greater force of contraction produced.
Increased overlap of thin + thick filaments= greater force generated.
Extrinsic regulation of the force of contraction of cardiac muscle.
Controlled by sympathetic regulation- release of noradrenaline.
Increased sympathetic stimulation increases Ca2+ conductance= stronger cardiac muscle contraction.
Vagal control of heart rate
Tonic parasympathetic stimulation keeps the HR around 60 bpm.
Neurotransmitter: acetylcholine.
ACh acts on ACh-activated K+ channels.
This system increase K+ conductance which hyperpolarizes the cells and makes the pacemaker potential slope less steep.
What determines heart rate
Pacemaker potential.
The steeper the slope, the quicker the HR.
Sympathetic control of HR
Noradrenaline increases Na conductance via the funny current.
Conductance of Ca2+ and K+ also increased.
NADR and the funny current
Sympathetic control of HR- leads to a faster HR, via Beta-1 receptors.
Increases net inward current in funny current- Na+.
NADR and K+ in pacemaker cells
Increases conductance in delayed rectifier K+ channels.
This shortens AP duration as repolarisation occurs at a quicker heart rate.
Funny current
A non-specific monovalent cation channel present in nodal cells.
Net current of Na+ inwards with small amount of K+ outwards.
The HCN channel opens when membrane becomes more negative.
This current increases with sympathetic stimulation.
ACh-activated K+ channels
A muscarinic G-protein coupled channel.
Contains receptor for ACh
K+ conductance increases with vagal stimulation- decreases pacemaker potential slope by hyperpolarising membrane.
Inward rectifying K+ channels
G-protein coupled channels- activated by ACh
ACh binds to M2 receptors- interacting with Gi protein to decrease cAMP.
K+ flow out of cell and hyperpolarise it- slowing down action potential generation.
They open when neural Vm is below -60 mV.
M2 muscarinic receptor
Activated by ACh– slows down HR.
- ACh binds to M2 receptor.
- Interacts with Gi protein- causes G-alpha to dissociate from beta-gamma complex.
- This decreases cAMP produced= increased chronotropy and dromotropy.
Atropine
A drug that blocks M2 receptors- increases HR, dilates pupils, reduces saliva and other exocrine secretions.
After hyperpolarization
Occurs when Vm is below resting potential in neurones.
The delayed-rectifier K+ channels are slow to close which makes membrane more negative.
The inward rectifier are open at the start of AHp but close when Vm is below -70mV.
When potential returns to rest, delayed rectifiers close.
Effective refractory period
The period where it is nearly impossible to start a new AP.
- Lasts for the duration of an AP in cardiomyocytes.
Protects the heart from unwanted extra APs between SAn initiated heart beats- extra APs= arrhythmias.
T-tubules
Invaginations in myocyte plasma membrane- adjacent to the SR.
Contiguous with extracellular fluid.
Connected to terminal cisternae which detects when the T-tubules depolarises
Terminal cisternae
Enlarged area of SR connected to the T-tubules.
Detects depolarisation from T-tubules.
Excitation coupling
The link between the molecular process of depolarisation of the membrane and the consequent huge influx of cytosolic Ca2+- leading to depolarisation.
Dihydropyridine receptor calcium channel
L-type Ca2+ channels
Channel that allows influx of Ca2+ from extracellular environment to intracellular environment.
In skeletal muscle cells.
Ca2+ influx through L-type channels trigger conformational change in RyR channels in terminal cisterna- opening them.
Influx of Ca2+ from SR to sarcolemma.
Excitation-contraction coupling in cardiac myocytes
There are L-type Ca2+ channels in the T-tubule envaginations.
When the cell is depolarised, L-type channel opens and allows Ca2+ into cardiomyocyte.
Depolarisation of L-type channels directly touch ryanodine receptors in SR membrane and transmit signals to cause conformational change- triggering further release of Ca2+.
SERCA
Smooth endoplasmic reticulum calcium ATPase
Pumps Ca2+ back into the SR, using ATP.
Calcium induced calcium release
Calcium is detected by Ryanodine channels.
This opens the RyR channels and causes influx of Ca2+ into the cytosol from the SR.
Positive feedback loop.
Calcium overload
Occurs when there is too excessive intracellular calcium.
Due to excessive release of Ca2+ from SR.
Risk: ectopic heartbeats and arrythmias
Exacerbated by fast HR and sympathetic drive
Diltiazem
A non DHP Ca2+ blocker for heart and blood vessels.
Used as antianginal and antiarrhythmic.
Vasodilates coronary arteries.
Slows SAN rate.
Verapamil
A non DHP Ca2+ blocker
Anti antiarrhythmic agent.
Affects nodal cells and slows conduction through AVN.
Digoxin
Positive inotropic agent- cardiac glycoside.
Inhibits Na+/K+ pump.
Increases Ca2+ in cytosol:
Increases SV and heart contractility.
Slows HR by stimulating vagus nerve.
Was used for HR.
Myosin Light Chain kinase
Myosin is phosphorylated by MLCK in order to allow it to contract in cardiac muscle cells.
(troponin and tropomyosin control phosphorylation in skeletal muscle)
Calcium-calmodulin activates MLCK.
NO-activated phosphatase dephosphorylates myosin= relaxation.
GTN
Glyceryl trinitrate- a nitrate drug
Prodrug- taken in an inactive form and degrades into NO.
Causes vasodilation rapidly but has short term effects.
Continuous administration can cause tolerance.
Bradykinin
Peptide hormone:
Loosens capillaries and BVs
Constricts bronchi and GI SMs.
Vasodilator:
Stimulates NO production.
Increases capillary permeability.
Troponin as a biomarker
Tn is released by cardiomyocytes during necrosis.
Therefore elevated during:
Heart failure
Acute myocardial infarction
Not elevated during unstable angina.
Creatine kinase as a biomarker
CK/CPK is released from myocytes during necrosis
C reactive protein (CRP)
Increases in response to inflammation.
An acute phase protein that predicts risk of cardiovascular disease.
Made in the liver
