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

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

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

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)

FEAR

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?

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

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

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 __________________________________________________________________

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

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

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

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

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

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

Comparison of skeletal muscle NMJ & autonomic NEJ 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

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

O2 + BH4

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

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.

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

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.

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.

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

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

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

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

FIG 1

SLUDE SYNDROME S L U D E

SLUDE SYNDROME Salivation, sweating, Lacrimation Urination Defecation Emesis

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

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)

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

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

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

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

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

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

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

Conserve transmitter under conditions of high utilization

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

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

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

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

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.

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

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

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

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

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

Blood vessels of skeletal muscle

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

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 _______________

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