CVS: Heart rate and Contractility Flashcards
What controls cardiac output?
CO = SV x HR
HR = Sympathetic and Parasympathetic nerves
SV = Preload: Stretching of heart at diastole, increases SV → Starling’s law
Afterload: Opposes ejection, reduces SV → Laplace’s law
Contractility: Strength of contraction at given resting loading, due to sympathetic nerves + circulating hormones such as adrenaline increasing [Ca2+]
How does sympathetic innervation affect heart rate and contractility?
Post-ganglionic = B1 adrenoceptors
NA binds to B1 receptors (these are Gs), stimulates AC, increases conversion of ATP → cAMP which has a positive chronotropic effect as it increases If channel activity, increases pacemaker potential frequency, therefore increases heart rate
- Positive chrontropic effect - Increased HR:
- Due to increased pacemaker potential frequency at SAN
- Positive inotropic effect - Increased contractility:
- Due to increased conduction through heart at AVN and b/w muscle cells
- Positive dromotropic effect - Increased conduction through heart at AVN and also b/w muscle cells
- Positive lusitropic effect - Increased relaxation
- Due to increased K channels /decreased VGCCs, increased SERCA
Bathmotropic effect - General increase in cardiac excitability, hence increased SNS activity can be linked to arrhythmias
How does parasympathetic innervation affect heart rate?
Pre-ganglionic - Nic receptor
Post- ganglionic - M2 receptor
Ach binds M2 (this is Gi) - Inhibits action of AC, decreased conversion of ATP to cAMP, therefore decreased If channel activity, decreased pacemaker potential frequency, decreased heart rate, so negative chronotropic effect
Describe the action of B1 adrenoceptor blockers
Blockers = antagonists
B1 blockers = bisoprolol, atenolol - prevent binding of NA, therefore inhibit SNS actions on SAN
- Lower resting heart rate - push balance in favour of parasympathetic nerves on SAN (termed vagal tone)
- Reduce heart rate from becoming too high e.g. angina, heart failure etc.
Why might B1 blockers not be prescribed?
- In asthmatic patients, they could block B2 adrenoceptors
- Not given with Ca2+ channel blockers as this could reduce HR/contractility too much
- Can produce fatigue
Describe the action of M2 blockers
M2 blockers = e.g. atropine
Reduce action of PNS (vagus nerve) on SAN by preventing Ach binding.
Remove inhibitory influence of vagal tone on HR, thereby increasing heart rate
Why might Muscarinic blockers not be prescribed?
Used to treat many conditions such as COPD, IBS, over-active bladder, but in these conditions it’s likely patients have a normal heart rate, so upon receiving this medication they may become tachycardic, which would increase O2 demands on heart.
Describe the action of Ca2+ channel blockers (CCBs)
- Drugs sit in pore of channel - block Ca2+ entry into SAN→ reduce heart rate
- But - Ca2+ channels also found in cardiac myocytes (phase 2, plateau phase) and VSMCs.
- Provide Ca2+ influx involved in cardiac and smooth muscle contraction - need to selectively target Ca2+ channels in SAN
- 3 subtypes CCBs:
- Dihydropyridines (vascular selective) - Amlodipine
- Phenylalkylamines (cardiac selective) - Verapamil
- Benzothiazepines (vascular + cardiac) - Diltiazem
- This is possible as cardiac + vascular have slightly varying Ca channel structures, therefore verapamil and diltiazem used
Why might CCBs not be prescribed?
Non-selective blocking actions on Ca2+ channels in cardiac myocytes (needed for contractility) and at AVN needed for atria-ventricle conduction, can therefore worsen heart failure, cause heart blockage
Describe the action of If channel blockers
E.g. Ivabradine
- Selective inhibitor of If channel in SAN
- Reduces pacemaker potential frequency
- Decreases HR to reduce myocardial O2 demand
- Used to lower HR in heart failure patients
How is HR lowered molecularly?
Reduce SAN firing frequency
- Inhibition of VgCa channels, reduces phase 0 = slower upstroke
- Inhibit If channels = Increase phase 4 time = slower to activate Ca2+ channels
What is inotropic effect?
Increase in contractility due to larger rise in [Ca2+], causes increase SV, therefore increased CO
How does a rise in intracellular Ca lead to contraction?
- AP upstroke (Na+ ions) depolarises T-tubules, activates VgCa channels, causes local Ca2+ influx
- Ca2+ binds to RyR located on SR → Close association with T-tubules
- RyR = ligand-gated, releases Ca2+ stored in SR
- Myosin-actin binding sites blocked by troponin-tropomyosin complex
- Ca2+ binds to troponin C, causes conformational change in shape to troponin-tropomyosin complex, displaces troponin-tropomyosin: actin-myosin binding sites exposed, and actin-myosin cross-bridge formed
- Myosin thick filament heads bind to active sites
- Myosin head ATPase activity release energy (ATP to ADP)
- Slide filaments = Contraction. Myosin head flexes to move actin and Z line towards sarcomere centre- ATPase activity
Describe the troponin-tropomyosin complex
Troponin (T):
- Composed of 3 subunits
- TnT - Binds to tropomyosin
- TnI - Binds actin filaments to hold tropomyosin in place
- TnC - Binds Ca
- Binding of Ca to TnC displaces tropomyosin and exposure of actin binding sites
- TnI and TnT important blood plasma markers for cardiac damage/death (e.g. post-MI)
What is the difference between Starling’s Law and contractility (inotropic effect)?
Starling’s law refers to the intrinsic stretch of the ventricles as resting pressure/volume and energy of contraction increases.
Inotropy - Contractility, extrinsic due to rise in intracellular Ca2+
