Autonomic nervous system II Comparison of Sympathetic and

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)

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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 (5 L/min 25 -40 L/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 _________________________________

post pre Parasympathetic Cranial Spinal cord T 1 pre post Sympathetic pre Adrenal medulla Splanchnic nerve L 3 pre Parasympathetic Sacral post S 2 S 3 S 4 Schematic ANS

ANS TRANSMITTERS Ach Spinal cord T 1 Ach Adrenal Splanchnic nerve L 3 S 2 S 3 S 4 All preganglionic neurons release Ach

ANS TRANSMITTERS Ach Spinal cord T 1 Ach Adrenal Splanchnic nerve L 3 S 2 S 3 S 4 Ach All preganglionic neurons release Ach; All postganglionic parasympathetic neurons release Ach

ANS TRANSMITTERS Ach Spinal cord T 1 Sympathetic postganglionics to sweat glands Ach Ach Adrenal L 3 S 2 S 3 S 4 Ach • 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 Spinal cord T 1 Ach NE NE EPI – 80% Adrenal L 3 S 2 S 3 S 4 Ach 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) 2 ndary amine Norepinephrine = Noradrenaline Epinephrine = Adrenaline Adrenergic transmission

Comparison of skeletal muscle NMJ & autonomic NEJ • Skeletal NMJ • Autonomic NEJ • 200 -300 quanta • 2 -3 quanta • 1: 1 Relay: always muscle twitch • Modulates ongoing target organ activity – low concentration of transmitter very effective • EPP amplitude always exceeds threshold for muscle AP twitch (large safety margin)

Adrenal medullary chromaffin cell Preganglionic nerve terminal LARGE DENSE CORED VESICLES (chromaffin granules) store high concentrations of epinephrine (or NE) & ATP; opiate peptides (enkephalins); acidic proteins (chromogranins) & dopamine-b-hydroxylase T 1/2 circulating EPI = 10 secs In 40 sec >90% EPI has disappeared Circulation

O 2 + BH 4

Metabolism of circulating catecholamines COMT HO CH(OH)CH 2 NHCH 3 HO HO MAO CH 3 O EPINEPHRINE CH(OH)CH 2 NHCH 3 METANEPHRINE (10%) Aldehyde dehydrogenase CH(OH)CHO HO CH 3 O HO 3 -methoxy-4 -hydroxy CH 3 O phenylglycoaldehyde CH(OH)COOH 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 Spinal cord T 1 Sympathetic postganglionic Neurons release Ach onto generalized sweat glands. Ach NE NE EPI – 80% Adrenal L 3 S 2 S 3 S 4 Ach Peptides are stored in LDCV in autonomic nerve terminals & released in response to high frequency stimulation.

ANS RECEPTORS - nicotinic Ach nicotinic Spinal cord T 1 Ach nicotinic NE Ach NE EPI – 80% nicotinic L 3 Ach S 2 S 3 S 4 Ach 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 nicotinic Spinal cord T 1 Ach nicotinic NE Ach nicotinic L 3 S 2 S 3 S 4 Differences between ganglionic & skeletal NMJ nicotinic receptors: • Subunit composition • Sensitivity to antagonists Ach nicotinic Somatic motor nerve All postganglionic neurons, cells of the adrenal medulla & skeletal NMJ have nicotinic cholinergic receptors Skeletal NMJ

ANS RECEPTORS - muscarinic Ach Spinal cord Ach muscarinic T 1 Ach Sympathetic postganglionics to generalized sweat glands release Ach muscarinic L 3 Ach S 2 S 3 S 4 Ach Cholinergic receptors of the muscarinic type are on effector tissues innervated by parasympathetic postganglionic neurons and on generalized sweat glands

ANS RECEPTORS Ach (+) (-) Spinal cord muscarinic T 1 Ach Sweat gl. (+) Sympathetic postganglionics to generalized sweat glands release Ach muscarinic L 3 Ach S 2 S 3 S 4 Ach (+) 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 nicotinic Spinal cord muscarinic T 1 Ach nicotinic NE Ach NE EPI – 80% nicotinic muscarinic L 3 Ach S 2 S 3 S 4 Ach nicotinic Somatic motor nerve Skeletal NMJ

ANS RECEPTORS -Adrenergic post pre Parasympathetic Cranial Spinal cord T 1 pre NE post Sympathetic pre Adrenal Splanchnic nerve L 3 pre Alpha Beta EPI NE Parasympathetic Sacral post S 2 S 3 S 4 Schematic ANS

Catecholamines CH(OH)CH 2 NHCH 3 HO HO EPINEPHRINE CH(OH)CH 2 NH 2 NOREPINEPHRINE CH(OH)CH 2 NHCH(CH 3)2 HO HO ISOPROTERENOL CATECHOL ALPHA & BETA receptors EPI > or = NE >>> ISOPRO (a) ISOPRO > EPI >>>>>> or = NE (b)

Receptors for NE and EPI (Adrenergic Receptors) • Alpha-1 • Beta-1 • Alpha-2 • 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 IP 3 production

Receptors for NE Alpha-2 receptors • Inhibitory receptors • Located on nerve terminals. Autoreceptors on sympathetic postganglionic terminals; heteroreceptors on terminals of parasympathetic nerves of the GI tract. • Activated by NE released from sympathetic nerves • NE inhibits transmitter release by reducing Ca 2+ 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 c. AMP 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 c. AMP

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 Dilates pupil (mydriasis) (radial m contracts) a 1 Narrows pupil (excites sphincter muscle) Ciliary muscle Relaxes (far vision) – b 2 Contracts (near vision) Tear glands ---------- Secretion Eye Pupil

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

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

Autonomic actions on target tissues Organ Sympathetic Stimulation + Receptor type Parasympathetic Stimulation Dilates pupil (mydriasis) (radial m contracts) a 1 Narrows pupil (excites sphincter muscle) Ciliary muscle Relaxes (far vision) – b 2 Contracts (near vision) Tear glands ---------- Secretion Eye Pupil

Autonomic actions on target tissues Organ Sympathetic Stimulation + Receptor type Parasympathetic Stimulation Heart Increased rate of beating – b 1 Increased force of contraction – b 1 Slowed rate Decreased force of atrial contraction Lung - Airways - Glands Relaxation – b 2 Contraction Increased secretion Constriction - a 1 Dilation - b 2 Constriction - a 1 None Systemic blood vessels Abdominal viscera Skeletal muscle Skin & mucosa

Blood vessels of skeletal muscle

Autonomic actions on target tissues Organ Gastrointestinal tract Motility & tone Sympathetic Stimulation Parasympathetic + Receptor type Stimulation Decreased - a 2 (indirect) - b 2 Contracted - a 1 Inhibited - a 2 (indirect) Increased peristalsis & tone Relaxed Stimulated Gallbladder & bile ducts Relaxation – b 2 Contraction Urinary bladder contraction Inhibited Excited Skin Piloerector muscles Sweat glands – palms - generalized Contraction - a 1 Secretion - muscarinic None Sphincters Secretions None

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

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