1. Autonomic nervous system II
Comparison of Sympathetic and Parasympathetic
Molecular Mechanisms
January 15, 2009

2. SYMPATHETIC
Mobilizes body to expend energy
Targets widely distributed organ systems
PARASYMPATHETIC
Restorative role; conserves energy
Discrete targeted control

4. Targets of Sympathetic: Diffusely distributed tissues
Sweat glands
Smooth muscle of blood vessels
Smooth muscle of hair follicles
1. Receive no parasympathetic innervation
2. All are excited by the sympathetic

5. Activation of sympathetic
Stimulates sweat production
Contracts smooth muscle of blood vessels  vasoconstriction
Contracts smooth muscle of hair follicles  goosepimpling

6. Functions of the sympathetic
Regulates
Blood Pressure
Distribution of blood flow to & within different organs/tissues
Body temperature (blood flow to skin, activity of sweat glands & brown fat cells)

7. FEAR

8. Sympathetic & adrenal medulla: Fight or flight response
mobilizes the body to expend energy for extreme sustained physical exertion .
Cardiovascular System
Increase in heart rate & force of contraction  increased cardiac output (5L/min  25-40L/min)
Increase in BP
Redistribution of blood flow
Respiratory System
Airways are dilated
Digestive System
GI function (motility and secretions) inhibited
Metabolism
Glucose is mobilized
Lipolysis is stimulated
Metabolic rate increases
HOW DO YOU REMEMBER ALL THESE RESPONSES?

9. Functions of the Parasympathetic
Conservation or replenishment of energy supplies
Role in maintenance/restoration of the individual
Discrete, targeted control of end organ activity

10. Functions of the Parasympathetic Effects on Target Organs
Excitatory effect on GI tract – coordination of activity
Stimulation of glandular secretion (except sweat glands)
Keeps passages & surfaces clean & moist (e.g. eyes, airways, oral cavity)
Slowing of the heart
Voiding of urinary bladder
Pupillary light reflex – regulates amount of light falling on retina
Accommodation of lens for near vision

11. COMPARISON OF SYMPATHO-ADRENAL AND PARASYMPATHETIC ACTIVITY
HEART
Sympatho-adrenal is excitatory, increasing the rate of beating and the force of contraction; Parasympathetic is inhibitory, slowing the rate of beating
SMOOTH MUSCLE
Sympatho-adrenal either excites or relaxes smooth muscle, depending on the muscle (e.g. adrenal medulla relaxes bronchial smooth muscle; sympathetic constricts vascular smooth muscle).
Parasympathetic excites most of the smooth muscle it innervates (e.g. G.I tract, urinary bladder)
GLANDS
Parasympathetic stimulates glandular secretions.
(Sympathetic stimulates sweat glands)
METABOLIC EFFECTS
Mediated by the sympatho-adrenal system
__________________________________________________________________

12. Schematic ANS post pre Parasympathetic Cranial Spinal cord pre T1 post
Adrenal medulla
Splanchnic nerve L3
Parasympathetic
post
pre
Sacral S2 S3 S4
Schematic ANS

13. All preganglionic neurons release Ach
ANS TRANSMITTERS
Ach
Spinal cord
Ach T1
Ach
Adrenal
Splanchnic nerve L3
Ach S2 S3 S4
All preganglionic neurons release Ach

14. All preganglionic neurons release Ach;
ANS TRANSMITTERS
Ach
Ach
Spinal cord
Ach T1
Ach
Adrenal
Splanchnic nerve L3
Ach
Ach S2 S3 S4
All preganglionic neurons release Ach;
All postganglionic parasympathetic neurons release Ach

15. ANS TRANSMITTERS Ach Ach Ach Ach Ach Ach Ach
Spinal cord
Sympathetic postganglionics
to sweat glands
Ach
Ach T1
Ach
Adrenal L3
Ach
Ach S2 S3 S4
All preganglionic neurons release Ach
All postganglionic parasympathetic neurons
release Ach
Sympathetic postganglionics  general sweat glands (except sweat gland on palms, soles of feet, & underarms) release Ach

16. ANS TRANSMITTERS Ach Ach Ach NE Ach NE EPI – 80% Ach Ach
Spinal cord
Ach T1 NE
Ach NE
EPI – 80%
Adrenal L3
Ach
Ach S2 S3 S4
Sympathetic postganglionic neurons release NE (except to generalized sweat glands; Adrenal medulla releases NE and EPI (80%)
Peptides also occur along with Ach & NE

17. Norepinephrine and epinephrine are catecholamines
3,4-dihydroxyphenylethanolamine
(primary amine)
2ndary amine
Norepinephrine = Noradrenaline
Epinephrine = Adrenaline
Adrenergic transmission

21. Comparison of skeletal muscle NMJ & autonomic NEJ
Skeletal NMJ
quanta
1:1 Relay: always  muscle twitch
EPP amplitude always exceeds threshold for muscle AP  twitch (large safety margin)
Autonomic NEJ
2-3 quanta
Modulates ongoing target organ activity – low concentration of transmitter very effective

26. Adrenal medullary chromaffin cell
LARGE DENSE CORED VESICLES (chromaffin
granules) store high concentrations of
epinephrine (or NE) & ATP; opiate
peptides (enkephalins); acidic proteins
(chromogranins) & dopamine-b-hydroxylase
Preganglionic nerve
terminal
T1/2 circulating EPI = 10 secs
In 40 sec >90% EPI has disappeared
Circulation

27. O2 + BH4

28. Metabolism of circulating catecholamines
COMT
MAO
CH(OH)CH2NHCH3 HO
CH(OH)CH2NHCH3 HO HO
CH3O
EPINEPHRINE
METANEPHRINE (10%)
Aldehyde
dehydrogenase HO
CH(OH)CHO HO
CH(OH)COOH
CH3O
CH3O
3-methoxy-4-hydroxy
phenylglycoaldehyde
VMA (90%)
3-methoxy-4-hydroxy
mandelic acid)
VMA derived from NE & EPI comprises 90% or urinary metabolites
COMT = catechol-O-methyltransferase
MAO = monoamine oxidase

29. 24 h urinary excretion of catecholamines and their metabolites
Unchanged amines: NE: ug (mostly from sympathetic nerves)
EPI: 0-20 ug
O-methylated amines: normetanephrine: ug
metanephrine ug
Acid: VMA: ug
Most metabolites originate from sympathetic nerves.
Abnormally high levels of metabolites are diagnostic for pheochromocytoma.

30. END

31. AUTONOMIC NERVOUS SYSTEM III
Molecular Mechanisms: Receptors
January 16, 2009

32. ANS TRANSMITTERS Ach Ach Ach NE Ach NE EPI – 80% Ach Ach
Spinal cord
Sympathetic postganglionic
Neurons release Ach onto
generalized sweat glands.
Ach T1 NE
Ach NE
EPI – 80%
Adrenal L3
Ach
Ach S2 S3 S4
Peptides are stored in LDCV in autonomic nerve terminals & released in response to high frequency stimulation.

33. ANS RECEPTORS - nicotinic
Ach
Ach
nicotinic
Spinal cord
nicotinic
Ach T1 NE
Ach NE
EPI – 80%
nicotinic L3
Ach
Ach S2 S3 S4
nicotinic
Somatic motor nerve
Skeletal NMJ
All postganglionic neurons & cells of the adrenal medulla have nicotinic cholinergic receptors; Receptors at the skeletal NMJ are also nicotinic.

34. Ligand-gated ion channel
ACh
Outside
Ach receptor
Lipid Bilayer
Inside
Net inward movement
of +ve charge
IONOTROPIC SIGNALING

35. ANS RECEPTORS - nicotinic
Ach
Ach
nicotinic
Spinal cord
nicotinic
Ach T1 NE
Ach
Differences between ganglionic
& skeletal NMJ nicotinic receptors:
Subunit composition
Sensitivity to antagonists
nicotinic L3
Ach
Ach S2 S3 S4
nicotinic
Somatic motor nerve
Skeletal NMJ
All postganglionic neurons,cells of the adrenal medulla & skeletal NMJ have nicotinic cholinergic receptors

36. ANS RECEPTORS - muscarinic
Ach
Ach
Spinal cord
muscarinic
Sympathetic postganglionics to generalized sweat glands release Ach
Ach T1
Ach
muscarinic L3
Ach
Ach S2 S3 S4
Cholinergic receptors of the muscarinic type are on effector tissues innervated by parasympathetic postganglionic neurons and on generalized sweat glands

37. ANS RECEPTORS (+) (-) (+) Ach Ach Spinal cord muscarinic Sweat gl. (+)
Sympathetic postganglionics to generalized sweat glands release Ach
(+)
Ach T1
Ach
muscarinic L3
Ach
Ach
(+) S2 S3 S4
Cholinergic receptors of the muscarinic type are on effector tissues innervated by parasympathetic postganglionic neurons and on generalized sweat glands

38. FIG 1

39. SLUDE SYNDROME S L U D E

40. SLUDE SYNDROME
Salivation, sweating,
Lacrimation
Urination
Defecation
Emesis

41. SLUDE SYNDROME Salivation, sweating, Lacrimation Urination Defecation
Emesis
+ Bradycardia, bronchospasm,
pinpoint pupil, blurred vision

42. Atropine Obtained from a plant, the deadly nightshade
–Atropa belladonna
Competitive antagonist at muscarinic receptors
Reverses muscarine poisoning
Also reverses the excessive activation of muscarinic receptors seen with nerve gas poisons (cholinesterase inhibitors)

43. Atropine
Inhibition of glandular secretions: dry mouth, dry eyes, dry skin, dry nasal passages, dry skin
Tachycardia
Loss of pupillary light reflex – pupils dilate
Loss of the ability to focus the lens for near vision (cycloplegia)
Constipation & difficulty urinating

44. SUMMARY - ANS RECEPTORS - cholinergic
Ach
Ach
nicotinic
Spinal cord
muscarinic
nicotinic
Ach T1 NE
Ach NE
EPI – 80%
nicotinic L3
muscarinic
Ach
Ach S2 S3 S4
nicotinic
Somatic motor nerve
Skeletal NMJ

45. Schematic ANS ANS RECEPTORS -Adrenergic NE Alpha Beta EPI NE post pre
Parasympathetic
Cranial
Spinal cord NE
pre T1
post
Sympathetic
Alpha
Beta
pre
EPI NE
Adrenal
Splanchnic nerve L3
Parasympathetic
post
pre
Sacral S2 S3 S4
Schematic ANS

46. Catecholamines ALPHA & BETA receptors
CH(OH)CH2NHCH3 HO
CH(OH)CH2NH2 HO HO HO
NOREPINEPHRINE
EPINEPHRINE HO
CH(OH)CH2NHCH(CH3)2 HO
ISOPROTERENOL
ALPHA & BETA receptors
EPI > or = NE >>> ISOPRO (a)
ISOPRO > EPI >>>>>> or = NE (b) HO
CATECHOL HO

47. Receptors for NE and EPI (Adrenergic Receptors)
Alpha-1
Alpha-2
Beta-1
Beta-2
Epinephrine = adrenaline
Norepinephrine = noradrenaline

48. Receptors for NE Alpha-1 receptors Smooth muscle (& a few glands)
Most important location -- smooth muscle of blood vessels
Excitatory  contraction of smooth muscle
Insensitive - require high concentrations of agonist; NE & EPI ~ equipotent
Under physiological conditions, alpha-1 receptors are activated by NE released from sympathetic nerves.
EPI released from adrenal in response to stress never reaches high enough concentrations in the circulation to activate alpha-1 receptors
Effects mediated by IP3 production

49. Receptors for NE Alpha-2 receptors Inhibitory receptors
Located on nerve terminals. Autoreceptors on sympathetic postganglionic terminals; hetero-receptors on terminals of parasympathetic nerves of the GI tract.
Activated by NE released from sympathetic nerves
NE inhibits transmitter release by reducing Ca2+ entry into presynaptic terminal

50. Conserve transmitter under
conditions of high utilization

51. Alpha-2 hetero-receptors inhibit ACh release from parasympathetic nerves in the GI tract, thereby reducing excitation of the GI tract.
Postganglionic sympathetic nerve
Postganglionic parasympathetic nerve

52. BETA RECEPTORS Beta-1 Beta-2
Much more sensitive than alpha receptors – activated at much lower concentrations of amine

53. BETA-1 RECEPTORS Excitatory response to both NE & EPI Location – heart
Heart beats faster and more strongly
Beta-1 receptor is very sensitive to both NE & EPI – so heart can be stimulated by NE released from sympathetic nerves or EPI released from the adrenal medulla
Beta-1 effects mediated by stimulation of cAMP production

54. BETA-2 RECEPTORS Inhibitory  relaxation of smooth muscle
Very sensitive to EPI, but not NE
Hence only activated in response to stress (when adrenal medulla secretes EPI into the circulation)
Found on smooth muscle of airways, GI tract, & blood vessels supplying skeletal muscle (along with alpha-1 receptors)
Beta-2 agonists used for acute treatment of asthmatic attacks
Stimulate production of cAMP

55. COMPARISON OF SYMPATHO-ADRENAL AND PARASYMPATHETIC EFFECTS
HEART: Sympathetic (NE) or adrenal (EPI) excites the heart, increasing the rate of
beating and the force of contraction via activation of b-1 receptors.
Parasympathetic slows the heart via the action of ACh on MUSCARINIC receptors
SMOOTH MUSCLE:
Sympathetic excites smooth muscle via a-1 receptor activation (blood vessels, piloerector muscles)
Adrenal EPI activates b-2 receptors & produces relaxation of certain smooth muscle (e.g. airways, GI tract, blood vessels supplying skeletal muscle).
Parasympathetic excites most of the smooth muscle it innervates and responses are mediated by MUSCARINIC receptors (GI tract)
GLANDS: Parasympathetic always stimulates glandular secretions, via MUSCARINIC receptors.
Sympathetic stimulates generalized sweat glands via MUSCARINIC ACTION of ACh and via a-1 effects of NE for sweat glands on palms of hands, etc
METABOLIC
EFFECTS: Mediated by the sympathetic nervous system and adrenal medulla via activation of alpha and beta receptors.

56. Autonomic actions on target tissues
Organ
Sympathetic Stimulation + Receptor type
Parasympathetic
Stimulation
Eye
Pupil
Ciliary muscle
Dilates pupil (mydriasis) (radial m contracts) a1
Relaxes (far vision) – b2
Narrows pupil
(excites sphincter muscle)
Contracts (near vision)
Tear glands
Secretion

57. Muscles of Iris Sphincter muscle: Radial muscle: Parasympathetic
innervation:
Excitatory action of Ach on muscarinic receptors constricts pupil
Radial muscle:
Sympathetic
Innervation:
Excitatory action
of norepinephrine
at alpha-1 receptors
dilates pupil
Muscles of Iris
Radial muscle
Sphincter muscle

58. Muscles of Iris Sphincter muscle: Radial muscle: Parasympathetic
innervation:
Excitatory action of
Ach on muscarinic
receptors constricts
pupil
Radial muscle:
Sympathetic
Innervation:
Excitatory action
of norepinephrine
at alpha-1 receptors
dilates pupil
Muscles of Iris
miosis
mydriasis

59. Autonomic actions on target tissues
Organ
Sympathetic Stimulation + Receptor type
Parasympathetic
Stimulation
Eye
Pupil
Ciliary muscle
Dilates pupil (mydriasis) (radial m contracts) a1
Relaxes (far vision) – b2
Narrows pupil
(excites sphincter muscle)
Contracts (near vision)
Tear glands
Secretion

60. Autonomic actions on target tissues
Organ
Sympathetic Stimulation + Receptor type
Parasympathetic
Stimulation
Heart
Increased rate of beating – b1
Increased force of contraction – b1
Slowed rate
Decreased force of atrial contraction
Lung - Airways
- Glands
Relaxation – b2
Contraction
Increased secretion
Systemic blood vessels
Abdominal viscera
Skeletal muscle
Skin & mucosa
Constriction - a1
Constriction - a1
Dilation - b2
None

61. Blood vessels of skeletal muscle

62. Autonomic actions on target tissues
Organ
Sympathetic Stimulation + Receptor type
Parasympathetic
Stimulation
Gastrointestinal tract
Motility & tone
Sphincters
Secretions
Decreased - a2 (indirect)
- b2
Contracted - a1
Inhibited - a2 (indirect)
Increased peristalsis
& tone
Relaxed
Stimulated
Gallbladder & bile ducts
Relaxation – b2
Contraction
Urinary bladder
contraction
Inhibited
Excited
Skin
Piloerector muscles
Sweat glands – palms
- generalized
Contraction - a1
Secretion
Secretion - muscarinic
None

63. Autonomic actions on target tissues
Organ
Sympathetic Stimulation + Receptor type
Parasympathetic
Stimulation
Blood – Coagulation
- Glucose
Increased
None
Basal metabolism
Increased up to 150%
Liver
Glucose released
Adrenal cortex
Increased secretion
Mental activity
Increased alertness
Skeletal muscle
__________________
Fat
Increased glycogenolysis
Increased strength of contraction
____________________
Increased lipolysis
_______________

64. END