Week 4 - Cellular and Molecular Events in the CVS Flashcards

1
Q

How is the resting membrane potential generated?

A

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

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2
Q

How do cardiac muscles cell cause contraction?

A

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
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3
Q

Explain the changes in membrane potential of ventricular cells over the cardiac cycle

A
  • 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
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4
Q

Explain the changes in membrane potential of pacemaker cells over the cardiac cycle

A

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+)

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5
Q

What are HCN channels?

A

Hyperpolarisation-activated, cyclic nucleotide-gated channels
- Allow influx of Na+

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6
Q

What is the role of the sinoatrial node?

A

It is the fastest to depolarise, so it sets the rhythm and acts as the pacemaker

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7
Q

What is the structure of a cardiac myocyte?

A
  • 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
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8
Q

How is cardiac myocyte contraction regulated?

A

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
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9
Q

How are cardiac monocytes relaxed?

A

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
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10
Q

How is the tone of blood vessels controlled?

A

By contraction and relaxation of vascular smooth muscle cells

  • Located in the tunica media
  • Present in arteries, arterioles and veins
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11
Q

How is contraction of vascular smooth muscle regulated?

A

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

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12
Q

What initiates contraction of vascular smooth muscle cells?

A

Depolarisation/activation of alpha-adrenoceptors

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13
Q

What does the autonomic nervous system exert control over?

A
  • Smooth muscle (vascular and visceral)
  • Exocrine secretion
  • Rate and for of contraction of the heart
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14
Q

What are the divisions of the autonomic nervous system?

A
  • Parasympathetic
  • Sympathetic
  • Some include a 3rd division, enteric (a network of neurones surrounding the GI tract)
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15
Q

What is the autonomic nervous system important for?

A

Regulating many physiological functions:

  • Heart rate, blood pressure, body temperature, etc.
  • Coordinates the body’s response to exercise and stress
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16
Q

Describe the origin and synapse of sympathetic nerves

A
  • 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
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17
Q

Describe the origin and synapse of parasympathetic nerves

A
  • 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
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18
Q

What chemical transmitters and receptors are used in sympathetic neurones?

A
  • 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)
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19
Q

What chemical transmitters and receptors are used in parasympathetic neurones?

A
  • Between pre- and post-ganglionic: acetylcholine, with nicotinic ACh receptors
  • Between post-ganglionic and target tissue: acetylcholine, with muscarinic ACh receptors
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20
Q

Describe muscarinic ACh receptors

A
  • G-protein coupled receptors (M1, M2, M3)

- No integral ion channel

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21
Q

Describe adrenoreceptors

A
  • 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)
22
Q

How do the sympathetic and parasympathetic nervous systems work together?

A

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)
23
Q

Describe the sympathetic and parasympathetic effect + transmitter/receptor on the airway of the lungs

A
  • Sympathetic: adrenaline, beta-2, relaxation

- Parasympathetic: ACh, M3, contraction

24
Q

Describe the sympathetic and parasympathetic effect + transmitter/receptor on sweat glands

A

Sympathetic:
- Localised secretion: alpha-1, adrenaline
- Generalised secretion: M3, ACh
No parasympathetic effect

25
Q

Describe the sympathetic and parasympathetic effect + transmitter/receptor on the SA node of the heart

A
  • Sympathetic: beta-1, noradrenaline, increases heart rate

- Parasympathetic: M2, ACh, decreases heart rate

26
Q

Describe the sympathetic and parasympathetic effect + transmitter/receptor on the atrial muscle in the heart

A
  • Sympathetic: beta-1, noradrenaline, increases force

- Parasympathetic: M2, ACh, decreases force

27
Q

Describe the sympathetic and parasympathetic effect + transmitter/receptor on the ventricular muscle in the heart

A
  • Sympathetic: beta-1, noradrenaline, increases force

- Parasympathetic: no effect

28
Q

Describe the sympathetic and parasympathetic effect + transmitter/receptor on the blood vessels in most tissues

A
  • Sympathetic: alpha-1, noradrenaline, vasoconstriction

- Parasympathetic: no effect

29
Q

Describe the sympathetic and parasympathetic effect + transmitter/receptor on the blood vessels in skeletal muscle

A
  • Sympathetic: alpha-1 and alpha-2, noradrenaline, vasodilatation
  • Parasympathetic: no effect
30
Q

Describe the sympathetic and parasympathetic effect + transmitter/receptor on the blood vessels in erectile muscle

A
  • Sympathetic: alpha-1, noradrenaline, vasoconstriction

- Parasympathetic: M3, ACh, dilation

31
Q

Describe the sympathetic and parasympathetic effect + transmitter/receptor on gut secretion

A
  • Sympathetic: inhibits secretion of digestive juices

- Parasympathetic: M3, ACh, stimulates secretion of digestive juices

32
Q

Describe the sympathetic and parasympathetic effect + transmitter/receptor on gut motility

A
  • Sympathetic: alpha-1, alpha-2 and beta-2, noradrenaline, inhibits peristalsis
  • Parasympathetic: M3, ACh, stimulates peristalsis
33
Q

Describe the sympathetic and parasympathetic effect + transmitter/receptor on gut sphincters

A
  • Sympathetic: alpha-1 and alpha-2, noradrenaline, contracts internal anal sphincter
  • Parasympathetic: M3, ACh, dilatation
34
Q

Describe the sympathetic and parasympathetic effect + transmitter/receptor on adipose tissue

A
  • Sympathetic: alpha-1, beta-2 and beta-3, noradrenaline, fat breakdown and release of fatty acids
  • Parasympathetic: no effect
35
Q

Describe the sympathetic and parasympathetic effect + transmitter/receptor on the liver

A
  • Sympathetic: alpha and beta-2, noradrenaline, promotes breakdown of glycogen to glucose
  • Parasympathetic: no effect
36
Q

Describe the sympathetic and parasympathetic effect + transmitter/receptor on the kidney

A
  • Sympathetic: beta-2, noradrenaline, stimulate Na+ reabsorption and increases renin secretion
  • Parasympathetic: no effect
37
Q

Describe the sympathetic and parasympathetic effect + transmitter/receptor on the male sex organs

A
  • Sympathetic: alpha, noradrenaline, ejaculation

- Parasympathetic: M3, ACh, erection

38
Q

What does the autonomic nervous system control in the CVS?

A
  • Heart rate
  • Force of contraction of the heart
  • Peripheral resistance of blood vessels
39
Q

What does the parasympathetic nervous system do in the CVS?

A
  • 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
40
Q

What does the sympathetic nervous system control in the CVS?

A
  • 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
41
Q

What is noradrenaline’s effect on the force of contraction?

A
  • 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
42
Q

What type of receptors do most arteries and veins have?

A

Alpha-1 adrenoreceptors

- Coronary and skeletal muscle aalso have β-2 receptors

43
Q

What is the effect of β-2 adrenoreceptors on vascular smooth muscle?

A

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
44
Q

What is the effect of alpha-1 adrenoreceptors on vascular smooth muscle?

A

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
45
Q

What is the role of local metabolites in contraction of vascular smooth muscle?

A
  • 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
46
Q

How is the vasomotor tone of vascular smooth muscle controlled?

A

Sympathetic output:

  • Normal: vasomotortone
  • Decreased: acts on alpha-1 to cause vasodilation
  • Increased: acts on alpha-1 to cause vasoconstriction
47
Q

Overall, how is the CVS controlled?

A

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

48
Q

What are baroreceptors?

A

Nerve endings in the carotid sinus and aortic arch that are sensitive to stretch
- Increased arterial pressure stretches them

49
Q

What drugs can act on the autonomic nervous system?

A
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)
50
Q

What are the uses of sympathomimetics?

A

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

51
Q

What do the beta-adrenoreceptor antagonist drugs do?

A

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

52
Q

When can cholinergic drugs be used?

A
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