Sympathetic Nervous System

Question 1

What do beta-adrenoceptors couple to?

Answer 1

B1- adenylate cyclase AGONIST: dobutamine ANTAGONIST: atenolol
B2- adenylate cyclase AGONIST: salbutamol, salmeterol, clenbuterol ANTAGONIST: propranolol
B3- adenylate cyclase AGONIST: mirabegron

Question 2

What is the difference between alpha and beta adrenoceptors

Answer 2

Noradrenaline activates adrenoceptors
Work done on receptors lead to ranking of different physiological responses based
upon what different chemicals did
They came up with separation of alpha and beta
Alpha is where noradrenaline is more potent than adrenaline and adrenaline is more potent than isoprenaline (synthetic compound)
Beta where isoprenaline is more potent than adrenaline which is more potent than noradrenaline
In our bodies there is no isoprenaline only noradrenaline made in sympathetic nerves and adrenaline made in adrenal glands

Beta receptors = positive stimulators of adenylate cyclase meaning cyclic AMP goes up unlike alpha 1 = negative impact meaning decrease in cyclic amp

In our body alpha adrenoceptor more likely to be activated if we have noradrenaline around the beta activated when adrenaline is around
Classification of adrenoceptors

Question 3

List all of the andrenergic effects

Answer 3

• Activating Alpha 1 adrenoceptor - vascular smooth muscle contraction
• Alpha 2 - inhibition of transmitter release on the sympathetic nerve terminals
• Beta 1 - stimulatory effects of the heart
• Beta 2 -smooth muscle relaxation- airway relaxation vascular dilatation

Question 4

The main physiological effects of sympathetic nervous system.

Answer 4

• dilates pupil
• inhibits salvia production
• dilates bronchi
• accelerates heart
• stimulates epinephrine and norepinephrins release
• stimulates glucose release
• inhibits stomach, pancreas and intestines
• inhibits urination
• promotes ejaculation and vagina contractions

Question 5

What are 2 main mechanisms involved in sympathetic nervous system

Answer 5

Short pre ganglionic fibre - the ganglia - then long post ganglionic - terminal
messenger = noradrenaline
- Some sympathetic nerves going to adrenal gland - activation of these nerves cause
release of adrenaline

• Neuronal nicotinic receptor present on post ganglionic fibre where acetylcholine
  binds ( this is the ganglia) - when the receptor is activated there is an influx of
  sodium ions

Question 6

Sympathetic responses effects on the heart

Answer 6

Noradrenaline increases:

• Force of contraction - positive inotropy
• Rate of contraction - positive chronotropy
• Rate of relaxation - positive lusitropy

Graph 1: when cardiac accelerator sympathetic nerves are stimulated there is a
more pronounced depolarization. The action potential is much briefer
- Graph 2 - in red is controlled contraction. When the cardiac accelerator nerve is
stimulated there is a more forceful contraction, there is a difference in amplitude in both graphs and how long the contraction lasts is different. When nerve is stimulated the contraction does not last as long
- It is a larger and briefer lasting contraction

Question 7

Sympathetic responses effects on blood vessels-contraction of arteries

Answer 7

Sympathetic nerves go out to blood vessels - they end up as varicosities (appearance of beads on a necklace)

• We have a network of bulges containing transmitter ( noradrenaline) contained inside vesicles
• The varicosities are interacting with the smooth muscle cells. When the sympathetic is stimulated you get smooth muscle contraction which narrows the artery

Question 8

Effects on some arteries and other smooth muscle

Answer 8

Certain arteries like coronary and skeletal muscle - relax to adrenaline - less contractions and more relaxation

• Non vascular smooth muscle - bladder , uterus and GI smooth muscle relaxes due to sympathetic nerve activation
• Airway smooth muscle - here there aren’t many sympathetic nerves, there adrenergic receptors stimulation of this relaxes the smooth muscle

Question 9

Effects on kidney

Answer 9

Juxtaglomerular apparatus ( JGA) - located between afferent and efferent renal arteries - has rich innervation from sympathetic nerves
- Stimulation of Sympathetic nerves going to the kidney increase renin release
- Renin converts agent Angiotensinogen ( inactive ) found in our blood - angiotensin I
(active)
- Angiotensin I is converted by an enzyme into angiotensin II - a very potent
vasoconstrictor, also increases blood volume as well as effects on cardiac remodelling

Question 10

Effects on her liver and skeletal muscle

Answer 10

Sympathetic nervous system in this case does not affect cells itself instead the energy stores within them

• Increased nerve activation by turning in a phosphorylase in the muscle and in liver you get increased glycogenolysis, lipolysis ( break down of fats by stimulating a lipase leading to increase in energy rich metabolites)
• Overall product = more glucose and TCA cycle intermediates that feed into generation of energy

Question 11

Effect on eyes

Answer 11

• Sympathetic nervous system innervates radial muscle in the eye
• Stimulation of sympathetic nerve leads to contraction of radial muscle resulting in
  dilated ( wide) pupil
• Increases aqueous humour production

Question 12

Effect on sweat and hair

Answer 12

Hairs have piloerector muscles at the base
- Sympathetic nerve causes the muscle to contract they shorten pulling on vase of hair
making it stand on the end this is known as piloerection
- The skin where the hair comes out ( the bump) is a goose bump
- Sympathetic nervous system also Increases sweat production - not mediated by
noradrenaline instead mediated by acetylcholine

Question 13

Adrenergic neurons

Answer 13

Sympathetic nerves that make noradrenaline

-biological response occurs through activation of adrenoceptors

Question 14

Adrenergic receptors

Answer 14

Example of G protein coupled receptor via alpha G proteins

Adrenoceptors

Alpha 1 vs alpha2 vs beta

a1A, a1B, a1D vs a2A, a2B, a2C vs b1, b2, b3

Question 15

Alpha receptors

Answer 15

A1- phospholipase c ,phenlylephrine, oxymetazoline and prazosin, doxazosin, tamsulosin (1a)
A2- adenylate cyclase (Gi), clonidine and yohimbine

Question 16

Alpha 1 adrenoceptor - contracts smooth muscle

Answer 16

Noradrenaline released from nerve terminal or circulation adrenaline, if they interact
with alpha 1 adrenoceptor on the vascular smooth muscle - this leads to vascular
smooth muscle contraction - meaning artery will go from wide lumen to narrow lumen How the alpha1 adrenoceptor does this
- The alpha 1 receptor coupled to alpha gq/11 which is bound to phospholipase c

• Phospholipase c interacts with PIP2 which is cleaved leaving diacylglycerol and IP3
• IP3 bind to its own receptor releasing calcium from internal stores ( if you want
  calcium conc to increase activate a phospholipase c linked receptor)
• Alpha 1 receptors also involved in contraction of iris muscle leading to dilated pupil
• Contraction of pilomotor muscle leading to piloerection
• Contraction of seminal vesicles in the male reproductive tissue
• These are all done through same mechanism mentioned above: alpha 1 increasing
  calcium conc leading to contraction

Question 17

Alpha 2 - Inhibition of sympathetic nerve transmission

Answer 17

• Alpha 2 involved in inhibition of sympathetic neurotransmission as they are negatively linked to adenylate cyclase resulting in decrease in cyclic amp
• Consequence - activation of these calcium channels occurs less often despite the action potential traveling down the nerve the channels are still less responsive meaning no vesicular fusion

Question 18

Beta 1 adrenoceptors - cardiac effects

Answer 18

• Positively linked to cyclic AMP production
• Positive inotropy
• Positive chronotropy
• Positive lusitropy
  How does it do this?
• Beta 1 receptors predominantly expressed in the heart - the alpha subunit is coupled
  to adenylate cyclase which makes cyclic AMP
• Cyclic AMP binds directly to a channel in the pacemaker region of the heart ( SAN or
  AVN)
• The binding maked the channel more active meaning these regions depolarise
  quicker - this explains increase in cardiac rate of contraction
• Cyclic amp also interact via mediators - protein kinase a
• Protein kinase attaches phosphate group to protein altering how the protein operates
• In this case it activates calcium channels - the increased concentration in cyclic AMP
  increases calcium channel activity meaning more calcium coming in and more calcium induced calcium release - leading to more contraction and more forceful contraction
• Protein kinase a also activates potassium channels - explaining more brief nature of cardiac action potential - more action potentials over a given time
• Protein kinase a works on protein release channels and calcium uptake channels which is how cardiac myocytes can relax quicker

Question 19

Beta 1 / 2 adrenoceptors - relaxsion of smooth muscles

Answer 19

• Especially in airways
• Skeletal muscle vasculature
• Also coronary and cerebral blood vessels
• Bladder and uterus and gi tracts
  How does it work?
• Difference between the effects of increased cyclic amp in cardiac and smooth muscle
  is not dependent on the receptor - in both cases the receptors are cyclic amp linked
• The increased cAMP decreases ca release and increases k+ channel activity
• Main difference is how the smooth muscle contracts - in cardiac muscle it is removal tropomyosin allowing the 2 proteins to come together
• In smooth muscle the increase in calcium that leads to contraction leads to activation of a go mechanism
• The go mechanism is known as myosin light chain kinase - this kinase is inhibited by protein kinase a
• This leads to relaxation Beta 1 / 2 adrenoceptors - relaxsion of smooth muscles
• Especially in airways
• Skeletal muscle vasculature
• Also coronary and cerebral blood vessels
• Bladder and uterus and gi tracts
  How does it work?
• Difference between the effects of increased cyclic amp in cardiac and smooth muscle
  is not dependent on the receptor - in both cases the receptors are cyclic amp linked
• The increased cAMP decreases ca release and increases k+ channel activity
• Main difference is how the smooth muscle contracts - in cardiac muscle it is removal tropomyosin allowing the 2 proteins to come together
• In smooth muscle the increase in calcium that leads to contraction leads to activation of a go mechanism
• The go mechanism is known as myosin light chain kinase - this kinase is inhibited by protein kinase a
• This leads to relaxation

Question 20

Effects on liver and skeletal muscle

Answer 20

• Phosphorylase leading to degradation of glycogen and generation of G6P is sensitive to beta 3 activation usually through protein kinase a this occurs in muscle and liver
• The lipase is also sensitive to protein kinase a activation

Question 21

Noradrenaline effects on arterial smooth muscle

Answer 21

• The smooth muscle cells can express both beta receptors and alpha 1 receptors - depending on receptor expressed or whether its noradrenaline you will get 2 different responses
• Noradrenaline will predominantly hit alpha adrenoceptors resulting in vasoconstriction
• Adrenaline more potent on beta adrenoreceptors will initially at high concentration produce the vasoconstriction effect but then at lower concentration will result is a arterial relaxation effect beta mediated
• The response to adrenaline is an
  Beta adrenoceptors also linked to:
• Carbohydrate metabolism ( Beta 1) And lipolysis ( beta 3) through manipulating
  enzymes
• Influence renin release from kidney (beta 3)