CVS: Contractility Flashcards
Describe sympathetic control of the heart at the SAN to form a chronotropic effect
Describe parasympathetic control of the heart at the SAN to form a chronotropic effect
Describe and evaluate B1 adrenoreceptor antagonists
β1-adrenoceptor blockers – e.g. atenolol, bisoprolol reduce action of symp NS on SAN and instead favours vagal tone. HR/contractility is prevented from increasing.
This reduces work / O2 demands on the heart which helps treat angina
Concerns: Avoid in asthma patients (may block β2-adrenoceptor). Not given w Ca2+ channel blockers bc these reduce HR/contractility too much. Can produce fatigue
Describe muscarinic receptor antagonists
Muscarinic receptor blockers e.g. atropine reduce parasymp (vagus nerve) action on SAN
Less inhibitory vagal tone on heart rate, so HR increases
Eg: muscarinic receptor blockers increase HR following MI-induced bradycardia to create more stable cardiac output
Concerns: Muscarinic blockers treat many conditions e.g. COPD, IBS, over-active bladder. Can cause tachycardia in these patients which increases O2 demands on heart
Describe Calcuim channel blockers acting on the SAN
CCBs= drugs that sit in pore of Ca channel and block Ca2+ entry into SAN, reducing HR
But, Ca2+ channels are also in cardiac myocytes (phase 2, plateau phase) and vsmcs. They give Ca2+ influx for contraction
So, you must selectivity target Ca2+ channels in SAN:
- Dihydropyridines (vascular selective) – Amlodipine
- Diphenylalkyamines (cardiac selective) – Verapamil✅
- Benzothiazepines (vascular+cardiac) – Diltiazem✅
Concerns: Non-selective Ca2+ channel blocking in cardiac myocytes (for contractility) and at AVN needed for atria-ventricle conduction can worsen heart failure and cause heart block
Describe If channel blockers
e.g. Ivabradine: Selective inhibitor of If channel in the SAN decreases If channel activity.
This increases phase 4 time, slower to activate Ca2+ channels, reduces depolarisation at resting membrane potential
Decreases HR to reduce myocardial O2 demand in heart failure
What is the inotropic effect?
Normal cardiac contraction is sub-maximal. Force of contraction proportional to rise in [Ca2+]i
- Normal systole [Ca2+]i ~ 1 mM
- Max systole, e.g. vigorous exercise or hypovolemia [Ca2+]i ~ 10 mM
Ability to increase contractility due to larger rise in [Ca2+]i allow us to increase stroke volume and cardiac output= the INOTROPIC EFFECT
How does stimulating b1-adrenoceptors increase Contractility?
Beta-1 is Gs coupled. NA bind, Gs subunit stimulates AC. This increased cAMP = increases PKA.
PKA phosphorylates VGCCs = Ca influx in T tubules = more CICR = more cross bridge formation = increased contractility
PKA also acts on ryanodine receptors in the SR to release Ca2+= more CICR
Greater rise in [Ca 2+]i = more sites exposed= more crossbridges= greater contractility
Stimulation of b1-adrenoceptors also induces relaxation, how and why?
As HR/contractility increases, the symp ns also needs to increase rate of relaxation to keep up.
NA/adr acts on K+ channels in atrial/ventricular myocytes to cause hyperpolarisation. Hyperpolarisation switches off VGCCs. Hay less Ca2+ influx, so less CICR.
NA/Adr acts on a B1receptor linked to GaS, producing AC, cAMP, PKA. This activates Ca2+ ATPase (SERCA) which increases Ca2+ reuptake into SR. This quicker lowering of Ca2+= quicker relaxation, less contractility.
This= Lusitropic Effect
Explain simply the effect of increased sympathetic stimulation on the heart
Positive chronotropic effect – Increased HR from increased pacemaker potential frequency at SAN
Positive inotropic effect – Increased contractility from increased VGCCs/Ca2+ influx and increased RyR/CICR
Positive dromotropic effect – Increased conduction at AVN and also between muscle cells
Positive lusitropic effect – Increased rate of relaxation from more K channels, SERCA
Outline drugs which increase heart rate and contractility
β1-adrenoceptor agonists e.g. Adrenaline, dopamine. For acute HF, e.g. cardiac arrest, anaphylaxis, sepsis. Wont work if patient is taking β-blockers
Other Gs agonists e.g. Glucagon receptors in heart muscle. Used in acute HF where a patient is taking β-blockers. Not used in chronic HF as this would increase HR and O2 demand
PDE inhibitors e.g. Amrinone (PDE3 is heart specific). Causes cAMP buildup, activation of PKA, increase VGCCs/Ca2+ influx/CICR. Only used in severe, chronic cases – e.g. awaiting transplant
What are cardiac glycosides
eg Digoxin inhibits Na+/K+ ATPase. Remember this removes 3 Na+ and brings 2 K+ ions into the cell. If this is blocked, hay Na+ buildup
Less Ca2+ removal by Na/Ca exchanger (NCX)
More Ca2+ uptake into stores and greater CICR – greater contraction
Give problems with Gs-coupled agonist-induced rise in Ca2+ to increase contractility
These drugs increase need for Ca2+-ATPase – to bring Ca2+ back into SR stores for relaxation.
The more calcuim levels you have, the more ATP you will need to bring it back down for relaxation.
More ATP demand increases O2 consumption, which stresses the heart
Also, Gs pathways increase heart rate – pro-arrhythmogenic
Gs-coupled agonist-induced rise in Ca2+ to increase contractility also increase demands on the heart. What is a potential solution for this?
Ca2+ sensitisers: have no effect on Ca2+ levels but increase the contractile apparatus sensitivity (e.g. troponin) to Ca2+. Contraction now works better at lower Ca2+ levels
These drugs would not increase O2 consumption, or be pro-arrhythmogenic
- Levosimedan - Bind to troponin C, increase binding of Ca2+ to Trop C
- Omecamtiv – Increases actin-myosin interactions (in absence of rise in Ca2+)
Describe how hyperkalaemia can cause a negative ionotropic effect
High external K+ concentration - hyperkalaemia
hyperkalemia decreases the resting potential (makes it less negative) and partially depolarises the membrane. However, w prolonged depolarization, the cell membrane will become more refractory and less likely to fully depolarize.
Causes shorter a.potentials as Na+ channels become inactivated- more of a plateau effect can’t fire any action potentials. Heart stops beating
