The molecular and ionic basis of cardiovascular control Flashcards
What is the effective refractory period?
A period of time when it becomes nearly impossible to start a new action potential. In a cardiomyocyte, the ERP lasts for the duration of the AP. It protects the heart from unwanted extra action potentials between SA node initiated heart beats. This reduces the chance of arrhythmias due to re-entry (circus movements)
What do troponin and tropomyosin do, and how are they structurally put together?
Troponin and tropomyosin together are regulatory proteins that make contraction in skeletal and cardiac muscle dependent on cytosolic calcium. Tropomyosin is a protein that resides on thin filaments (mostly double helical F-actin); when the muscle cell is relaxed, the tropomyosin sits at the interaction site for myosin (in the groove between helices), and it physically prevents the myosin from interacting with actin. When muscle is about to contract, the tropomyosin is moved out of the way. The tropomyosin is connected to troponin, and it is the troponin that is both calcium sensitive and that moves tropomyosin out of the way. The four peptides are organised in the following order: TnI (the inhibitory subunit of troponin) is connected to the actin, TnC (the calcium sensitive subunit of troponin) sits between TnI and TnT, and TnT connects to the tropomyosin.
What is digoxin AND how does it work?
Digoxin is a drug used in cardiac medicine as a positive inotropic agent (ie it increases the force of contraction of the heart). It used to be used as a front-line treatment for heart failure, but other agents have been shown to improve prognosis, whereas digoxin has not (although it typically improves symptoms). It works by blocking some of the activity of the Na/K pump, which results in a build up of intracellular Na+, and this leads to a build up of cytosolic Ca2+, as well as slower calcium removal during diastole (because this is normally done by a Na/Ca exchanger, which works less efficiently if there is higher intracellular Na+). This activity of digoxin also slows the heart rate, making it useful for atrial fibrillation – where what the patient needs is for the heart rate to be slow (ie normal rate), combined with increased contractility (because the atrial fibrillation reduces preload and thus decreases cardiac output).
Isolated heart beats at a frequency of about 100 beats per minute – why is the normal resting heart rate slower than that?
Tonic vagal (parasympathetic) drive, mediated by acetylcholine
During cardiomyocyte contraction, what protein releases calcium from intracellular stores in the sarcoplasmic reticulum, and what protein pumps the calcium back into the stores?
Release: ryanodyne receptors
Pump back: SERCA, smooth endoplasmic reticulum calcium atpase
In a cardiomyocyte what pathology can happen if calcium overload occurs?
Ectopic beats
Risk of arrhythmia
(afterdepolarisations)
In a healthy cardiomyocyte what is the name of the molecular process that links the action potential to the beating of the cell and what process does calcium-induced calcium release contribute to?
Excitation contraction coupling
What are the normal physiological processes that increase and decrease the force of contraction of a sarcomere twitch?
In skeletal muscle it is recruitment of additional fibres and tetany. Neither of these is relevant for the heart because in a healthy heart every fibre should contract on every beat and there should never be tetany in a cardiac myocyte (as it would probably lead to an arrhythmia or prevent diastole from occurring). Instead, the heart varies its contractility by increasing the force of contraction generated by each individual myocyte. This is done in two ways: extrinsic regulation via autonomic (sympathetic and parasympathetic) stimulation, and intrinsic regulation via the Frank-Starling principle.
What cardiac changes would result from a drug that blocks a percentage of cardiac sodium channels (e.g. class I antiarrhythmic).
This would slow down the depolarisation of almost all atrial and ventricular action potentials, as well as the action potentials in the His-Purkinje conduction system. It would have much less of an effect on nodal action potentials because their depolarisation is driven by calcium entry.
So the primary effect would be a slowing of conduction speed, with a potential either reducing OR increasing the risk of arrhythmia (depends on the background problems of the myocardium before adding the drugs)
The two graphs show the same typical tension vs time relationship for a ventricular cardiomyocyte’s contraction (labelled “T”, coloured grey), and each graph also shows the same cardiomyocyte after an intervention (labelled X, coloured blue). One intervention (X, blue) is sympathetic stimulation and the other is increased preload (i.e. Starling’s law). Which is which, and how can you tell?
A is sympathetic stimulation. There is more contractile drive due to increased calcium activity (earlier and more tension), but it ends earlier (due to increased K currrent repolarising AP.
B is preload because there is more force generated earlier, during the peak and at the end due to increased increased actin-myosin crossbridge overlap
How does the heart pump the blood forward?
The exits to the chambers of the heart are guarded by one-way valves, which open when the pressure behind them exceeds the downstream pressure in front of them. When a heart chamber contracts (via a form of “wringing”), it causes an increase in pressure, which is followed by a decrease in volume when the valve opens. Contraction is mediated at the molecular level by ATP-consuming actin-myosin interactions that are organised in the form of sarcomeres.
What is excitation contraction coupling?
E-C coupling is the molecular process linking the depolarisation of the membrane (with a tiny influx of calcium) to the consequent huge increase in cytosolic calcium that then leads to actin-myosin interaction and contraction
How is the heart able to adjust its output (about 5 litres/minute at rest) to the needs of the body (e.g. up to 25 litres/minute during heavy exercise)?
The heart can increase its rate and its stroke volume (via an increase in force generation and thus pressure). Both of these are mediated by sympathetic drive. Chronotropic increases are due primarily to steeper pacemaker potentials in the pacemaking cells (sympathetic activity increases the funny current). Inotropic activity is primarily driven by increased intracellular free calcium during systole.
How is the balance between the outputs of pulmonary and systemic circulations maintained?
The systemic circulatory flow must match the flow of the pulmonary circulation or there would be a net build up (or loss) of blood in one of them. The Frank-Starling mechanism means that if increased blood volume returns to one chamber, the stretching of the chamber would lead to an increased force of contraction, and thus to increased output.
Explain the molecular basis of the Frank-Starling law.
The molecular basis of the Frank-Starling law depends on the size of sarcomeres. The quantity of overlap of thick and thin filaments determines the potential force of contraction. In particular, if sarcomeres are shorter, the interaction of myosin heads with their matching thin (actin) filaments will be interfered with by thin filaments from the opposite side of the sarcomere. (A drawing can be shown here).
