Week 4 - Cellular and Molecular Events in the CVS Flashcards
How is the resting membrane potential generated?
It is largely due to K+ permeability of the cell membrane at rest
- Leaky K+ channels are open at rest
- Only small permeability to other ions
- K+ ions move out of the cell, down their concentration gradient
- This small movement of ions makes the inside negative with respect to the outside
- This negative charge can attract K+ ions, so they will not leave the cell
- As charge builds up, an electrical gradient is established
- There is a net outflow of K+ until Ek+ is reached
Na+/K+ ATPase establishes the gradient, but it doesn’t set it
How do cardiac muscles cell cause contraction?
They are electrically active
- They fire action potentials
- The action potential triggers an increase in cytosolic [Ca2+]
- A rise in calcium is required to allow actin and myosin interaction, which generates the contraction
Explain the changes in membrane potential of ventricular cells over the cardiac cycle
- Resting membrane potential (about -75mV) is due to background K+ channels
- Increase (to about +30mV) is due to opening of voltage-gated Na+ channels and hence an influx of Na+
- Initial repolarisation (to about +10mV) is due to transient outward K+ channels, and hence an efflux of K+
- The decrease in membrane potential plateaus due to the opening of voltage-gated Ca2+ channels and hence an influx of Ca2+, which is balanced with K+ efflux (to about -20mV)
- Repolarisation (to RMP) is due to efflux of K+ through voltage-gated K+ channels and others. At this stage, Ca2+ channels have been inactivated
Explain the changes in membrane potential of pacemaker cells over the cardiac cycle
Pacemaker potential
- Initial slope to the threshold (gradual depolarisation)
- Activated by membrane potentials more negative than -50mV (the more negative it is, the more it activates)
- Uses HCN channels (and voltage-gated Na+ channels), so there is an influx of Na+
Upstroke
- Opening of voltage-gated Ca2+ channels (Ca2+ moves in) and release of Ca2+ from intracellular stores
Downstroke
- Opening of voltage-gated K+ channels (efflux of K+)
What are HCN channels?
Hyperpolarisation-activated, cyclic nucleotide-gated channels
- Allow influx of Na+
What is the role of the sinoatrial node?
It is the fastest to depolarise, so it sets the rhythm and acts as the pacemaker
What is the structure of a cardiac myocyte?
- Single central nucleus
- Cells are mechanically joined at intervertebral disks by desmosomes
- There are gap junctions, which permit movement of ions and electrically couple cells
How is cardiac myocyte contraction regulated?
In the same way as skeletal muscle:
- Ca2+ binds to troponin C
- Conformational change shifts tropomyosin to reveal myosin binding site on actin filament
- Sliding filament theory
How are cardiac monocytes relaxed?
Intracellular [Ca2+] must return to resting levels
- Most is pumped back into the sarcoplasmic reticulum be SERCA
- The raised [Ca2+] stimulates the pumps
- Some exits across the cell membrane via the Na+/Ca2+ exchanger or sarcolemmal Ca2+ ATPase
How is the tone of blood vessels controlled?
By contraction and relaxation of vascular smooth muscle cells
- Located in the tunica media
- Present in arteries, arterioles and veins
How is contraction of vascular smooth muscle regulated?
Ca2+ binds to calmodulin
- This activates myosin light chain kinase
- This phosphorylates the myosin light chain to permit interaction with actin
Relaxation as Ca2+ levels decline
- Myosin light chain phosphorylase deactivates the myosin light chain
Phosphorylation by protein kinase A inhibits myosin light chain kinase, hence inhibiting contraction
What initiates contraction of vascular smooth muscle cells?
Depolarisation/activation of alpha-adrenoceptors
What does the autonomic nervous system exert control over?
- Smooth muscle (vascular and visceral)
- Exocrine secretion
- Rate and for of contraction of the heart
What are the divisions of the autonomic nervous system?
- Parasympathetic
- Sympathetic
- Some include a 3rd division, enteric (a network of neurones surrounding the GI tract)
What is the autonomic nervous system important for?
Regulating many physiological functions:
- Heart rate, blood pressure, body temperature, etc.
- Coordinates the body’s response to exercise and stress
Describe the origin and synapse of sympathetic nerves
- Thoracolumbar origin
- Preganglionic neurones arise from segments T1 to L2
- Most synapse with postganglionic neurones in the paravertebral chain of ganglia
- Some synapse in a number of prevertebral ganglia
Describe the origin and synapse of parasympathetic nerves
- Craniosacral origin
- Preganglionic fibres travel in cranial nerves or sacral outflow from S2-S4
- Synapse with neurones in ganglia close to the target tissue
- Short postganglionic neurones
What chemical transmitters and receptors are used in sympathetic neurones?
- Between pre- and post-ganglionic: acetylcholine, with nicotinic ACh receptors
- Between post-ganglionic and target tissue: noradrenaline, with adrenergic receptors
- But sympathetic input to sweat glands in mainly cholinergic (post-ganglionic neurones release ACh which acts on muscarinic ACh receptors)
What chemical transmitters and receptors are used in parasympathetic neurones?
- Between pre- and post-ganglionic: acetylcholine, with nicotinic ACh receptors
- Between post-ganglionic and target tissue: acetylcholine, with muscarinic ACh receptors
Describe muscarinic ACh receptors
- G-protein coupled receptors (M1, M2, M3)
- No integral ion channel
Describe adrenoreceptors
- G-protein-coupled receptors, which have no integral ion channel
- Types and subtypes: alpha (a1 and a2) and beta (b1 and b2)
- Different tissues can have different subtypes (allows of diversity of action and selectivity of drug action)
How do the sympathetic and parasympathetic nervous systems work together?
They work together to maintain a balance
- Sympathetic activity is increased under stress
- Parasympathetic activty is more dominant under basal conditions
- But sympathetic drive to different tissues is independently regulated
- Most organs are innervated by the sympathetic nervous system, some have both (which generally oppose each other)
Describe the sympathetic and parasympathetic effect + transmitter/receptor on the airway of the lungs
- Sympathetic: adrenaline, beta-2, relaxation
- Parasympathetic: ACh, M3, contraction
Describe the sympathetic and parasympathetic effect + transmitter/receptor on sweat glands
Sympathetic:
- Localised secretion: alpha-1, adrenaline
- Generalised secretion: M3, ACh
No parasympathetic effect
Describe the sympathetic and parasympathetic effect + transmitter/receptor on the SA node of the heart
- Sympathetic: beta-1, noradrenaline, increases heart rate
- Parasympathetic: M2, ACh, decreases heart rate
Describe the sympathetic and parasympathetic effect + transmitter/receptor on the atrial muscle in the heart
- Sympathetic: beta-1, noradrenaline, increases force
- Parasympathetic: M2, ACh, decreases force
Describe the sympathetic and parasympathetic effect + transmitter/receptor on the ventricular muscle in the heart
- Sympathetic: beta-1, noradrenaline, increases force
- Parasympathetic: no effect
Describe the sympathetic and parasympathetic effect + transmitter/receptor on the blood vessels in most tissues
- Sympathetic: alpha-1, noradrenaline, vasoconstriction
- Parasympathetic: no effect
Describe the sympathetic and parasympathetic effect + transmitter/receptor on the blood vessels in skeletal muscle
- Sympathetic: alpha-1 and alpha-2, noradrenaline, vasodilatation
- Parasympathetic: no effect
Describe the sympathetic and parasympathetic effect + transmitter/receptor on the blood vessels in erectile muscle
- Sympathetic: alpha-1, noradrenaline, vasoconstriction
- Parasympathetic: M3, ACh, dilation
Describe the sympathetic and parasympathetic effect + transmitter/receptor on gut secretion
- Sympathetic: inhibits secretion of digestive juices
- Parasympathetic: M3, ACh, stimulates secretion of digestive juices
Describe the sympathetic and parasympathetic effect + transmitter/receptor on gut motility
- Sympathetic: alpha-1, alpha-2 and beta-2, noradrenaline, inhibits peristalsis
- Parasympathetic: M3, ACh, stimulates peristalsis
Describe the sympathetic and parasympathetic effect + transmitter/receptor on gut sphincters
- Sympathetic: alpha-1 and alpha-2, noradrenaline, contracts internal anal sphincter
- Parasympathetic: M3, ACh, dilatation
Describe the sympathetic and parasympathetic effect + transmitter/receptor on adipose tissue
- Sympathetic: alpha-1, beta-2 and beta-3, noradrenaline, fat breakdown and release of fatty acids
- Parasympathetic: no effect
Describe the sympathetic and parasympathetic effect + transmitter/receptor on the liver
- Sympathetic: alpha and beta-2, noradrenaline, promotes breakdown of glycogen to glucose
- Parasympathetic: no effect
Describe the sympathetic and parasympathetic effect + transmitter/receptor on the kidney
- Sympathetic: beta-2, noradrenaline, stimulate Na+ reabsorption and increases renin secretion
- Parasympathetic: no effect
Describe the sympathetic and parasympathetic effect + transmitter/receptor on the male sex organs
- Sympathetic: alpha, noradrenaline, ejaculation
- Parasympathetic: M3, ACh, erection
What does the autonomic nervous system control in the CVS?
- Heart rate
- Force of contraction of the heart
- Peripheral resistance of blood vessels
What does the parasympathetic nervous system do in the CVS?
- Pre-ganglionic fibres synapse with post-ganglionic cells on epicardial surface or within walls of heart at SA and AV node
- Post-ganglionic cells release ACh which acts on M2 receptors, decreasing heart rate and AV node conduction velocity
- – Increases K+ conductance
- – Decreases cAMP
- – Slows down pacemaker potential
What does the sympathetic nervous system control in the CVS?
- Post-ganglionic fibres from the sympathetic trunk innervate the SA node, AV node and myocardium
- They release noradrenaline, which:
- – Acts on β-1 adrenoreceptors
- – Increases heart rate
- – Increases force of contraction
- Increases cAMP release
- Speeds up pacemaker potential
What is noradrenaline’s effect on the force of contraction?
- Acts on β-1 receptors in myocardium, causing an increase in cAMP which activates protein kinase
- Phosphorylates Ca2+ channels, increasing Ca2+ entry during action potentials
- Increases uptake of Ca2+ in sarcoplasmic reticulum
- Increases sensitivity of contractile machinery to Ca2+
- Increases force of contraction
What type of receptors do most arteries and veins have?
Alpha-1 adrenoreceptors
- Coronary and skeletal muscle aalso have β-2 receptors
What is the effect of β-2 adrenoreceptors on vascular smooth muscle?
Activating β-2 adrenoreceptors causes vasodilation
- Increases cAMP
- This activates protein kinase A
- This opens K+ channels and inhibits myosin light chain kinase
- This leads to the relaxation of smooth muscle
What is the effect of alpha-1 adrenoreceptors on vascular smooth muscle?
Causes vasoconstriction
- Stimulates IP3 (inositol triphosphate) production
- Increase in intracellular Ca2+ from stores and via influx of extracellular Ca2+
- This leads to contraction of smooth muscle
What is the role of local metabolites in contraction of vascular smooth muscle?
- Active tissue produces more metabolites
- Local increases in metabolites has a strong vasodilator effect
- It is more important for ensuring adequate perfusion of skeletal and coronary muscle than activation of β-2 receptors is
How is the vasomotor tone of vascular smooth muscle controlled?
Sympathetic output:
- Normal: vasomotortone
- Decreased: acts on alpha-1 to cause vasodilation
- Increased: acts on alpha-1 to cause vasoconstriction
Overall, how is the CVS controlled?
Changes in the state of the system are communicated to the brain via afferent nerves
- Baroreceptors (high pressure side of system)
- Atrial receptors (low pressure side of system)
Alters activity of efferent nerves
What are baroreceptors?
Nerve endings in the carotid sinus and aortic arch that are sensitive to stretch
- Increased arterial pressure stretches them
What drugs can act on the autonomic nervous system?
Sympathomimetics - Alpha-adrenoceptor agonists - Beta-adrenoceptor agonists Alpha-adrenoreceptor antagonists - Alpha-1 antagonists (e.g. prazosin) - Anti-hypertensive agent (inhibits NA action on vascular smooth muscle alpha-1 receptors, causing vasodilatation) Beta-adrenoreceptor antagonists - Propranolol - Atenolol Cholinergics - Muscarinic agonists (e.g. pilocarpine) - Muscarinic antagonists (e.g. atropine or tropicamide)
What are the uses of sympathomimetics?
CVS uses:
- Administration of adrenaline to restore function in cardiac arrest
- Adrenaline administered fo anaphylactic shock
- Beta-1 agonist, dobutamine, may be given in cardiogenic shock
Other uses:
- Beta-2 agonist, salbutamol, for asthma treatment
What do the beta-adrenoreceptor antagonist drugs do?
Propranolol
- Non-selective beta-1/2 antagonist
- Slows heart rate and reduces force of contraction
- Acts on bronchial smooth muscle, causing bronchoconstriction, which is bad
Atenolol
- Selective beta-1
- Less risk of bronchoconstriction than propranolol
When can cholinergic drugs be used?
Muscarinic agonist: - In treatment of glaucoma - Activates constrictor pupillae muscle Muscarinic antagonist: - Increases heart rate - Causes bronchial dilation - Used to dilate pupils for examination of the eye
