First year Flashcards
Intropic effects of PKA
• Leads to phosphorylation of phospholamban:
○ Normally phospholamban is an endogenous inhibitor of SERCA Ca2+ ATPase pump
○ Phosphorylation removes this inhibition
○ This increases activation of the pump → more Ca2+ enters the SR during repolarisation → more is able to be released into the cytoplasm during the next action action potential
○ As in a normal beat, the rise in Ca2+ concentration only produces a factor of the intrinsically available tension, thus releasing more Ca2+ increases the binding to troponin C and therefore increass the number of cross-bridges formed
• As well as this, the PKA also leads to phosphorylation of LTCC (L-type calcium channel)- this leads to a greater open probability, so there is more calcium interest due to calcium-induced calcium release
○ LTCC is responsible for the excitation-contraction coupling of skeletal, smooth, cardiac muscle and for aldosterone secretion in endocrine cells of the adrenal cortex
In cardiac myocytes, the LTCC passes inward Ca2+ current and triggers calcium release from the sarcoplasmic reticulum by activating RyR2
Physiological positive inotropes
Hypercalcaemia
NA/A as part of flight or flight
Angiotensin II during exercise
Physiological negative inotropes
Other than parasympathetic activity, most are pathophysiological:
- ischaemia
- chronic cardiac failure
How can hypercalcaemia be a positive inotrope?
- leads to decreased activity of NCX (which removes calcium from the cell)
- more calcium is simply able to enter the LTCCs due to the increased gradient
- More CICR
- More contractility
How may ischaemia lead to a decrease in contractility?
The fall in mitochondrial oxidative metabolism leads to a decrease in the energy reserves of the cell and therefore leads to an increase in anaerobic metabolism leading to the production of lactic acid. This leads to lactic acidosis and therefore a rise in the concentrations of H+ions in the cell. This has a majorly negative inotropic effect, thought to occur as the H+ ions bind to the troponin I subunit leading to a conformational change in the troponin C subunit, reducing its affinity for calcium ions.
What features of chronic cardiac failure lead to a decrease in contractility?
Reduced SERCA expression
Impaired ryanodine receptor II channels, which are leaky so the SR store isn’t maintained.
Upregulation of the NCX
These all mean that the Ca2+ transient is impaired and reduced and slower, leading to a fall in contractility.
List pharmacological inotropes
Catecholamines/synthetic beta1 agonists
Phosphodiesterase III inhibitors
Calcium sensitisers
Digoxin
Describe dobutamine
Synthetic beta1 agonist that doesnt activate DA receptors (otherwise leading to the release of NA- vasopressor)
Can be useful in other conditions when ischaemia is the problem - as vasopression actually creates a greater afterload and more work for the heart
Describe phosphodiesterase III inhibitors
Give example
- prevent breakdown of cAMP intracellularly, amplify effects of beta stimulation
Milirone
What do calcium sensitizers do?
Increase the sensitivity of troponin C to Ca2+
What does digoxin do?
§ Inhibits the Na+/K+/ATPase transporter meaning that the increasing Na+ within the cell decreases the gradient of the NCX exchanger. This means less Ca+ is extruded and so more remains intracellularly, available for contraction.
§ This increases cardiac contractility, with little increase in oxygen demand.
§ However the therapeutic dose is very close to the toxic dose. (narrow therapeutic idex)
This therefore can lead to risks of dysrhythmia should an overdose be given
Draw an SAN pacemaker action potential and describe what is happening
See OneNote
Describe sympathetic effect on chronotropy
- Gs - alphas activates AC, ATP to cAMP, amplification
- cAMP has many effects:
○ Interacts directly with if channels to increase their open probability - rise in current accelerate pacemaker potential decay and chronotropic effect
○ cAMP activates PKA, phosphorylation of LTCCs, increases the open probability, accelerates decay and chronotropic effect
○ PKA phosphorylates delayed rectifier K+ channels. Increase in outward current contributes to the shortening of ventricular AP, allows more APs to happen per min - deactived/ reactivated quicker
○ PKA phosphorylates phospholamban - more Ca2+ by SERCA - faster relaxation
○ Intracellular cAMP is not only dependent on AC but also degradation by phosphodiesterase. Agents that inhibit, such as caffeine and theophylline raise intracellular cAMP.
○ Long-term beta-adrenergic stimulation may also activate another kinase - Ca2+/calmodulin dependent kinase II (CaMKII). This phosphorylates phospholamban at a different site and maintains the effect of beta-adrenergic stimulation- Results in increase HR (chronotropic effect), increased AVN conduction velocity (dromotropic effect), inotropic effect and increased rate of relaxation
- This pathway is long and slow so the response to sympathetic stimulation is slow
Describe parasympathetic effect on chronotropy
• Slows down heart
• Parasympathetic predominates at rest
• Cardiac parasympathetic fibre from the dorsal vagal motor nucleus and nuclei ambiguus of brainstem, fibres travel in long right and left vagus nerves
• Preganglionic neurones synapse with postganglionic neurones within the myocardium, mostly around SA and AV nodes. Vagus nerve also innervates ventricle to an extent - in humans, this innervation is modest but functionally significant - the vagus can depress ventricular contraction when heart rate is held constant
• Mechanism:
○ ACh binds to M2 receptors on myocyte membrane
○ Gi inhibits AC, decrease in cAMP and PKA activity
○ Reduced activity of if and LTCCs- reduce the rate at which pacemaker potential decays
○ Alpha subunit - inhibitory effect on AC - less cAMP - reduction of funny current
○ Reduction in PKA activity, reduces activity of If channels and LTCCs, reduces steepness of phase 4
○ βγ subunit activates inward rectifier - KACh channel - resulting in increase in K+ current shifts membrane Nernst higher - causing hyperpolarisation - meaning the depolarisation takes even longer, reducing HR
Pharmacological manipulation of chronotropy
• Beta blockers:
○ Propanolol = non-selective, atenolol = selective
○ Used to treat hypertension (also cause decreased renin release from kidneys via B1), angina (reducing oxygen demand improves demand/supply ratio) and heart failure
○ Side effects are bradycardia, hypotension and bronchocontriction (non-selective beta blockers)
• Funny channel blocker:
○ ivabradine blocks pacemaker if current which reduces the rate of pacemaker . The attendant slowing of the heart rate reduces myocardial O2 demand, so ivabradine is used to treat stable angina
• Calcium channel blockers:
○ Verapamil
○ Act on LTCCs slow pacemaker potential
• Cardiac glycosides:
• Increase vagal efferent activity to the heart - possibly via sensitization of baroreceptors in the carotid sinus
• The parasympathomimetic action of digitalis reduces SAN firing rate
• Used to treat some arrhythmias - e.g. atrial fibrillation and flutter, reduces conduction in the AV node, blocking some impulses so that fewer reach the ventricles and ventricular rate fails
Positive chronotropes are most adrenergic agonists, atropine, dopamine
