Heart rate and contractility Flashcards
What is the equation for cardiac output?
Cardiac output(CO)=Heart rate(HR) x Stroke volume(SV)
What is the sympthateic control of heart rate at SAN?
- Noradrenaline binds to beta-1 adrenoceptor
- Stimulates Galphas pathway which stimulates adenylate cyclase.
- This increases cAMP levels
- Ultimately leads to:
-Increase in If channel activity
-Increase pacemaker potential frequency
-Increase in heart rate
Overall a positive chronotropic effect
What is the parasympathetic control of heart rate at SAN?
- Acetylcholine binds to M2 receptors
- this stimulates the Galphai pathway which inhibits adenylate cyclase
- This reduces cAMP levels
- Ultimately leads to:
-Decreased If channel activity
-Decreased pacemaker potential frequency
-Decreased heart rate
Overall a negative chronotropic effect
What do beta 1 adrenoceptor blockers reduce and do?
Beta 1-adrenoceptor reduces action of sympathetic nervous system on SAN
-Reduces heart rate
What do muscarinic receptor blockers reduce and do?
Muscarinic receptor blockers (antagonists) – e.g., atropine
will reduce action of parasympathetic nervous system (vagus nerve) on SAN
-Increases heart rate
What are concerns associated with beta 1-adrenoceptor blockers?
Avoid in asthma patients (may block β2-adrenoceptor)
Not given with Ca2+ channel blockers – reduce heart rate/contractility too much
Can produce fatigue
What are concerns associated with muscarinic receptor blockers?
Muscarinic blockers are used to treat many different conditions
e.g., COPD, IBS, overactive bladder
-Muscarinic receptors increase heart rate and tachycardia increases O2 demands on heart and is significant if patients have comorbidities like COPD and angina
What needs to be decreased to reduce heart rate?
Decrease initiation and frequency of pacemaker potentials to reduce heart rate
How does decreasing initiation and frequency of pacemaker potentials reduce heart rate?
-Inhibit voltage-gated Ca2+ channels: Reduce Phase 0, slower upstroke
-Inhibit If channels: Increase Phase 4 time, slower to activate Ca2+ channels
What are calcium channel blockers and what do they do?
Drugs that sit in pore of channel - block Ca2+ entry into SAN
Reduce heart rate
Why do Ca2+ channel blockers need to be selectively targeted?
Ca2+ channels also found in cardiac myocytes (phase 2, plateau phase)
and vascular smooth muscle
Provide Ca2+ influx involved in cardiac and smooth muscle contraction
What are the 3 subtypes of Ca2+ channel blockers?
- Dihydropyridines
- Diphenylalkyamines
- Benzothiazepines
What do Dihydropyridines target and give an example?
-Vascular selective
E.g. Amlodipine
What do Diphenylalkyamines target and give an example?
-Cardiac selective
E.g. Verapamil
What do Benzothiazepines target and give an example?
-Vascular+cardiac selective
Diltiazem
Why can CCB’s make heart failure worse and eventually cause heart block?
There’s Non-selective blocking actions on Ca2+ channels in cardiac myocytes
(needed for contractility) and at AVN needed for atria-ventricle conduction which can make heart failure worse and cause heart block
What is an example of If channel blockers?
Ivabradine
What does Ivabradine inhibit?
-Selective inhibitor of If channel in the SAN
What does Ivabradine reduce?
Reduces pacemaker potential frequency
What does Ivabradine decrease?
Decreases heart rate to reduce myocardial O2 demand
What is Ivabradine used to lower?
Used to lower heart rate in heart failure patients
How does Ivabradine work?
Ivabradine decreases If channel activity
to increase phase 4 time
decrease pacemaker potential frequency
and decrease heart rate
What happens in the plateau phase of action potential in terms of VGCCs?
Plateau phase of action potential
Voltage-gated Ca2+ channels open
[Ca2+]i rise - cell shortening
What happens in the repolarization phase of action potentials in terms of VGCCs?
Repolarisation of action potential
Voltage-gated Ca2+ channel close
Reduced [Ca2+]i - cell relaxation
How is normal cardiac contraction described?
Normal cardiac contraction
is sub-maximal
How is contractility increased in cardiac contraction and what does this allow to increase, and what is this effect called?
Increase in contractility due to larger
rise in [Ca2+]i allow us to increase
stroke volume and cardiac output
-Called the Inotropic effect
Why does a rise in [Ca2+] increase contraction?
a) Myosin-actin binding sites blocked
by troponin-tropomyosin complex
b) Ca2+ displaces troponin-tropomyosin :
actin-myosin binding sites exposed and
actin-myosin cross-bridge formed
c) Myosin head flexes to move actin and Z
line towards sarcomere centre :
Contraction – ATPase activity
What is the difference between starling’s law and contractility(Inotropy effect) ?
Starling’s law:
-Increase in resting pressure/volume
-Increase in energy of contraction
Contractility(Inotropic effect):
-Same resting pressure/volume
-Increase in contractility termed inotropy
-Extrinsic control-due to rise in [Ca2+]i
What does increasing contractility increase and what does this help with?
Increasing contractility will increase stroke volume and cardiac output
Which will help maintain appropriate blood pressure
and blood flow to end organs
When is there a need for an increase in contractility?
When stroke volume and Cardiac output is too low in instances such as:
-Hypovolemia
-Acute heart failure
-Chronic heart failure
How does stimulating beta1-adrenoceptors increase contractility?
1.Beta1-adrenoceptor on atrial/ventricular myocytes is activated by noradrenaline/adrenaline which stimulates Galphas pathway.
2. Adenylyl cyclase will increase levels of cAMP which increases PKA.
3. Levels of PKA also increased by the phosphorylation of VGCC’s which causes an influx of Ca2+
4. PKA phosphorylates RyR on Ca2+ stores that cause an increase in calcium induced calcium release. This increases [Ca2+]i
5. This Ca2+ interacts with troponin-tropomyosin system and sliding filament mechanism
6. This increases contractility causing the inotropic effect
What does stimulation of beta1-adrenoceptors induce and how?
Induces relaxation
1. Beta1-adrenoceptor on atrial/ventricular myocytes is activated by noradrenaline/adrenaline which activates GalphaS pathway
2. Adenylyl cyclase causes the increase in cAMP which causes an increase in PKA
3. PKA will act on SERCA on Ca2+ stores which increases Ca2+ reuptake into SR
4. PKA will also phosphorylate K+ channels on the membrane which results in hyperpolarisation, switching off VGCC’s. This decreases Ca2+ influx.
5. This results in an overall decrease in [Ca2+]i and overall relaxation. This is known as the lusitropic effect.
What are drug targets to increase contractility (inotropic agents)?
Targets:
-Gs-coupled receptor agonists
-PDE inhibitors
-Other ca2+ rising processes
How does a beta1-adrenoceptor or glucagon receptor work?
- Beta1-adrenoceptor or glucagon receptor stimulate GalphaS pathway which results in adenylyl cyclase increasing cAMP levels.
- PDE3 will work on cAMP to convert cAMP to AMP
- cAMP will also work to increase PKA
- PKA will phosphorylate Ca2+ channels on membrane which will result in an increase in Ca2+ influx
- This Ca2+ will act on RyR on SR and increase CICR
- This increases overall Ca2+i which interacts with the troponin system. This will increase number of actin-myosin interactions.
- Will overall increase contractility(inotropic effect)
What are examples of beta1-adrenoceptor agonists and what are they used in?
e.g., Adrenaline, dobutamine, dopamine
Used in acute heart failure, e.g., cardiac arrest, anaphylaxis, sepsis
What are examples of other Gs-coupled agonists that are not beta1-adrenoceptors and what are they used in?
e.g., Glucagon – glucagon receptors expressed in heart muscle
Used in acute heart failure conditions where a patient is taking β-blockers, meaning prescribing beta1-adrenoceptor agonists would not work
Why are Gs agonists not used in chronic heart failure?
Gs agonists not used in chronic heart failure – this would increase heart rate and
increase myocardial work + O2 demand – worst outcome
What are examples of PDE3 inhibitors, how do they work and when are they used?
e.g., Amrinone – phosphodiesterase III inhibitor (PDE3 is heart specific)
Causes build up of cAMP, activation of PKA, increase VGCCs/Ca2+ influx/CICR
Only used in severe and chronic cases – e.g., waiting for heart transplants
What is an example of cardiac glycosides and how do they work?
Cardiac glycosides, e.g. digoxin, increases contractility by reducing Ca2+ extrusion – but high toxicity
What is the mechanism of action of digoxin?
- Digoxin inhibits Na+/K+ ATPase
- This causes a build up of [Na+]i
- Less Ca2+ extrusion by Na/Ca exchanger
- More Ca2+ uptake into stores and greater CICR leading to greater contraction
What are problems with Gs-coupled agonist-induced rise in Ca2+i?
Increase need for Ca2+-ATPase – to reuptake more Ca2+ into SR stores
More O2 consumption, stresses the heart
Why are Gs coupled agonists pro-arrhythmogenic?
Gs pathways increase heart rate – pro-arrhythmogenic
what is a potential solution to pro-arrhythmogenic Gs-coupled agonists and why?
Ca2+ sensitizers
-These drugs would not increase O2 consumption, or be pro-arrhythmogenic
What is the mechanism of action for Ca2+ sensitizers?
These drugs 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
What is levosimendan and what is its mechanism of action?
-Ca2+ sensitizer
-Bind to troponin C, increase binding of Ca2+ to Trop C
What is omecamtiv what is its mechanism of action?
-Ca2+ sensitizer
-Increases actin-myosin interactions (in absence of rise in Ca2+)
What does a high external K+ concentration cause and why?
Causes hyperkalemia
-Raising K+ from normal 3.5-5 mM to 7-8mM stops the heart beating
Causes depolarisation of membrane potential,
reduces onset time/amplitude/shorter action potentials as Na+ channels become inactivated
What does increased H+ concentration cause and why?
Increased H+ concentration (lower pH)
H+ compete for Ca2+ for troponin C binding sites
Impairs contraction
What do low O2 levels lead to and impar and what does this cause?
Hypoxia leads to local acidosis – impairs contraction due to raised H+ levels
Also, effects ion channels – causing depolarised membrane potential,
smaller/shorter action potentials – poor contraction
