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Autonomic nervous system II

Autonomic nervous system II. Comparison of Sympathetic and Parasympathetic Molecular Mechanisms January 15, 2009. SYMPATHETIC Mobilizes body to expend energy Targets widely distributed organ systems PARASYMPATHETIC Restorative role; conserves energy Discrete targeted control.

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Autonomic nervous system II

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  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

  3. 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

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

  5. 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)

  6. FEAR

  7. 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?

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

  9. 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

  10. 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 __________________________________________________________________

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

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

  13. 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

  14. ANS TRANSMITTERS 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

  15. ANS TRANSMITTERS 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

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

  17. Skeletal NMJ 200-300 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 Comparison of skeletal muscle NMJ & autonomic NEJ

  18. 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

  19. O2 + BH4

  20. Metabolism of circulating catecholamines COMT MAO HO CH(OH)CH2NHCH3 CH(OH)CH2NHCH3 HO HO CH3O EPINEPHRINE METANEPHRINE (10%) Aldehyde dehydrogenase CH(OH)CHO HO CH(OH)COOH HO 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

  21. 24 h urinary excretion of catecholamines and their metabolites Unchanged amines: NE: 10-70 ug (mostly from sympathetic nerves) EPI: 0-20 ug O-methylated amines: normetanephrine: 1000 ug metanephrine 40-300 ug Acid: VMA: 1800- 9000 ug Most metabolites originate from sympathetic nerves. Abnormally high levels of metabolites are diagnostic for pheochromocytoma.

  22. END

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

  24. ANS TRANSMITTERS 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.

  25. 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.

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

  27. 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

  28. ANS RECEPTORS - muscarinic Ach Ach Spinal cord muscarinic Sympathetic postganglionics to generalized sweat glandsrelease 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

  29. ANS RECEPTORS (+) Ach Ach (-) Spinal cord muscarinic Sweat gl. (+) Sympathetic postganglionics to generalized sweat glandsrelease 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

  30. FIG 1

  31. SLUDE SYNDROME • S • L • U • D • E

  32. SLUDE SYNDROME • Salivation, sweating, • Lacrimation • Urination • Defecation • Emesis

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

  34. 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)

  35. 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

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

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

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

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

  40. 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

  41. 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

  42. Conserve transmitter under conditions of high utilization

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