Tijmen Lourens Summary Research Skills in Life Sciences
Summary Research Skills in Life Sciences
2 examples concerning the autonomic nervous system:
- Heart – anaesthesiology → first part of lecture
- Vessels – GP / vascular specialist → second part of lecture.
-
o 3 pillars of anaesthetic management:
▪ Pain relief
• Pain killers → morphine
▪ Loss of consciousness (sleep)
• Specific drugs →
▪ Muscle relaxation
• Muscle relaxers
o OR: one compound anaesthesia:
▪ Volatiles
• Ether, chloroform, N2O
• Halothane, desflurane
o Sleep: OK
o Pain: as long as it is present → as long as patient is
sleeping
o Muscle relaxation: just enough
o Need muscle relaxation because:
▪ Operation
• Intubation and ventilation
o In abdomen or thoracic cavity
• Enables surgery
▪ Intoxication
• Tetanus
o Where to act?
▪ Brain
▪ Spinal cord
▪ Peripheral nerves
▪ Neuromuscular junction
▪ Striated muscle
o
Neuromuscular junction
- Nicotinic ACh receptor – specific type (a2bye)
- All or nothing conduction
- Transmitter: ACh
- Nerve ending:
o Transmitter mobilization and release
o Presynaptic ACh-receptor
- Motor endplate:
o Endplate potential → action potential
,Tijmen Lourens Summary Research Skills in Life Sciences
o Postsynaptic ACh-receptor (Nicotinic!)
Structure nAChR = nicotinic ACh receptor
- Structure
o 5 subunits
o Always 2 x alpha (binding ACh)
o Varying: b, y, d, e
o Alpha: 9 different genes
o Beta: 4 different genes
▪ So there are very much different nAChRs
Selectivity fur NMJ (neuromuscular junction) in nature
- Hunt
- Defence
o Flaccid paralysis (only NMJ)
Toxins: snake milking
- 10.000 x price of gold (per g)
Muscle relaxants:
- Competitive antagonist of nAChR
o nAChR only opens when 2 molecules of acetylcholine are bound to it. The
competitive antagonist sits on 1 of these 2 places so that the receptor will not
open.
Subtypes of AChR:
- nicotinic AChR – ionotropic
o muscle-type
o neuronal type
▪ ganglia
▪ brain
- muscarinic AChR – metabotropic
o parasympatic system
o heart, Blatter etc.
,Tijmen Lourens Summary Research Skills in Life Sciences
Overcome muscle relaxant block:
- Increase ACh concentration at Neuro muscular junction
o Inhibition of ACh-Esterase
▪ Prevent breakdown of ACh at higher ACh concentration in synaptic
cleft
▪ So it can compete with amount of competitive antagonist of muscle
relaxants
- What are additional effects?
o Activate parasympathetic nervous system
- Mild dose of ACh → mild side effects
o Bradycardia → low heart rate
o Drooling
o Headache
o Miosis → small pupils
o Stomach cramps
o Ventilation problems
o Local sweating
- Severe inhibition of ACh-esterase
o Incontinence for urine
o Confusion, convulsions
o Pinpoint pupils
o Muscle cramps
o Vomiting
o ‘asthma’, pulm, oedema
o Coma → eventual die
In practice:
Neostigmine: AChE inhibitor
- Increases ACh in NMJ
Atropine: antagonist muscarinic receptor
- Blocks parasympathetic effects on target organ
- Precludes (thus) ACh action on heart (and other organs)
Also AChE inhibitors: initiate all parasympathetic symptoms and may result in death
- Nerve gasses
o Soman
o Sarin
o Tuban
o Vx
- Insecticides
Stimulation of neurotransmission:
When?
- Residual block (anaesthesia)
- Diseases (Myasthenia Gravis, Lambert Eaton)
, Tijmen Lourens Summary Research Skills in Life Sciences
o In Myasthenia Gravis you create antibodies against your nicotinic ACh
receptor. This results in way less ACh receptors so to make an action potential
you need to more less open the receptors all up.
▪ So you need much more concentrations of Acetyl Choline in the
synaptic cleft.
Vascular function:
- Reynaud’s phenomenon: le tricolore (three colours)
o White fingers at the top, and blue and reddish at the bottom.
o = vasoconstriction in the fingers when in touch with something cold
Raynaud syndrome =
- Vasospasm (mostly) in fingers (sometimes toes)
- White-blue-red (ischemia – cyanosis – hyperaemia)
- Primary Raynaud’s disease
o Temporary vasospasm (cold, stress, vibrations, drugs)
o 3-5% of persons
o No underlying disease, no tissue damage
- Cause = unknown
Cause of vasoconstriction =
- Inside ANS
- Outside ANS
o RAAS: angiotensin II
o Endothelin
▪ These 2 are potent vasoconstrictors
o NO (nitric oxide)
o CGRP
▪ These 2 are potent vasodilators
- Vasoconstriction is result of excess of vasoconstrictors or lack of vasodilators
In the skin there are only sympathetic activated a-receptors photo
- Sensitivity to a-agonists
o Skin biopsy, isolate arteries (136 uM diameter)
o Temperature reduction < 2 min, 37 → 31 degrees Celsius
o Measure vessels contraction to alpha agonist
Outcome:
- Increased agonist sensitivity in cold condition → photo
Why is this sensitivity increased in Raynaud patients?
- Cold induces alpha-2C receptor translocation
o Photo
Summary Research Skills in Life Sciences
2 examples concerning the autonomic nervous system:
- Heart – anaesthesiology → first part of lecture
- Vessels – GP / vascular specialist → second part of lecture.
-
o 3 pillars of anaesthetic management:
▪ Pain relief
• Pain killers → morphine
▪ Loss of consciousness (sleep)
• Specific drugs →
▪ Muscle relaxation
• Muscle relaxers
o OR: one compound anaesthesia:
▪ Volatiles
• Ether, chloroform, N2O
• Halothane, desflurane
o Sleep: OK
o Pain: as long as it is present → as long as patient is
sleeping
o Muscle relaxation: just enough
o Need muscle relaxation because:
▪ Operation
• Intubation and ventilation
o In abdomen or thoracic cavity
• Enables surgery
▪ Intoxication
• Tetanus
o Where to act?
▪ Brain
▪ Spinal cord
▪ Peripheral nerves
▪ Neuromuscular junction
▪ Striated muscle
o
Neuromuscular junction
- Nicotinic ACh receptor – specific type (a2bye)
- All or nothing conduction
- Transmitter: ACh
- Nerve ending:
o Transmitter mobilization and release
o Presynaptic ACh-receptor
- Motor endplate:
o Endplate potential → action potential
,Tijmen Lourens Summary Research Skills in Life Sciences
o Postsynaptic ACh-receptor (Nicotinic!)
Structure nAChR = nicotinic ACh receptor
- Structure
o 5 subunits
o Always 2 x alpha (binding ACh)
o Varying: b, y, d, e
o Alpha: 9 different genes
o Beta: 4 different genes
▪ So there are very much different nAChRs
Selectivity fur NMJ (neuromuscular junction) in nature
- Hunt
- Defence
o Flaccid paralysis (only NMJ)
Toxins: snake milking
- 10.000 x price of gold (per g)
Muscle relaxants:
- Competitive antagonist of nAChR
o nAChR only opens when 2 molecules of acetylcholine are bound to it. The
competitive antagonist sits on 1 of these 2 places so that the receptor will not
open.
Subtypes of AChR:
- nicotinic AChR – ionotropic
o muscle-type
o neuronal type
▪ ganglia
▪ brain
- muscarinic AChR – metabotropic
o parasympatic system
o heart, Blatter etc.
,Tijmen Lourens Summary Research Skills in Life Sciences
Overcome muscle relaxant block:
- Increase ACh concentration at Neuro muscular junction
o Inhibition of ACh-Esterase
▪ Prevent breakdown of ACh at higher ACh concentration in synaptic
cleft
▪ So it can compete with amount of competitive antagonist of muscle
relaxants
- What are additional effects?
o Activate parasympathetic nervous system
- Mild dose of ACh → mild side effects
o Bradycardia → low heart rate
o Drooling
o Headache
o Miosis → small pupils
o Stomach cramps
o Ventilation problems
o Local sweating
- Severe inhibition of ACh-esterase
o Incontinence for urine
o Confusion, convulsions
o Pinpoint pupils
o Muscle cramps
o Vomiting
o ‘asthma’, pulm, oedema
o Coma → eventual die
In practice:
Neostigmine: AChE inhibitor
- Increases ACh in NMJ
Atropine: antagonist muscarinic receptor
- Blocks parasympathetic effects on target organ
- Precludes (thus) ACh action on heart (and other organs)
Also AChE inhibitors: initiate all parasympathetic symptoms and may result in death
- Nerve gasses
o Soman
o Sarin
o Tuban
o Vx
- Insecticides
Stimulation of neurotransmission:
When?
- Residual block (anaesthesia)
- Diseases (Myasthenia Gravis, Lambert Eaton)
, Tijmen Lourens Summary Research Skills in Life Sciences
o In Myasthenia Gravis you create antibodies against your nicotinic ACh
receptor. This results in way less ACh receptors so to make an action potential
you need to more less open the receptors all up.
▪ So you need much more concentrations of Acetyl Choline in the
synaptic cleft.
Vascular function:
- Reynaud’s phenomenon: le tricolore (three colours)
o White fingers at the top, and blue and reddish at the bottom.
o = vasoconstriction in the fingers when in touch with something cold
Raynaud syndrome =
- Vasospasm (mostly) in fingers (sometimes toes)
- White-blue-red (ischemia – cyanosis – hyperaemia)
- Primary Raynaud’s disease
o Temporary vasospasm (cold, stress, vibrations, drugs)
o 3-5% of persons
o No underlying disease, no tissue damage
- Cause = unknown
Cause of vasoconstriction =
- Inside ANS
- Outside ANS
o RAAS: angiotensin II
o Endothelin
▪ These 2 are potent vasoconstrictors
o NO (nitric oxide)
o CGRP
▪ These 2 are potent vasodilators
- Vasoconstriction is result of excess of vasoconstrictors or lack of vasodilators
In the skin there are only sympathetic activated a-receptors photo
- Sensitivity to a-agonists
o Skin biopsy, isolate arteries (136 uM diameter)
o Temperature reduction < 2 min, 37 → 31 degrees Celsius
o Measure vessels contraction to alpha agonist
Outcome:
- Increased agonist sensitivity in cold condition → photo
Why is this sensitivity increased in Raynaud patients?
- Cold induces alpha-2C receptor translocation
o Photo
