PHSC 328: Introduction to Autonomic Pharmacology

1. PHSC 328: Introduction to Autonomic Pharmacology Dr. Thomas Abraham Spring 2006

2. Overview of the Peripheral Autonomic Nervous System Nervous System Central Nervous System Peripheral Nervous System Autonomic Nervous System Somatic Nervous System Parasympathetic Nervous System Sympathetic Nervous System • Autonomic Nervous System: • Involuntary • Not necessary for immediate maintenance of life • Function to maintain homeostasis

3. Anatomical distribution of the Autonomic Nervous System

4. The Parasympathetic Nervous System • The parasympathetic nervous system (PNS) is responsible for discreet changes in organ function e.g. increased salivation or lacrimation or urination or sexual arousal, etc. • Associated with “Rest and digest” phenomenon • Preganglionic fibers emerge from brain stem or sacral portion of spinal cord and are generally long. The ganglia with the postganglionic nerves are thus usually found within the innervated tissue. • Cranial nerves III, VII, IX and X supply the muscles of the eyes, salivary glands, heart, lungs, and GI tract. • Sacral nerves supply the descending colon, rectum, urinary bladder and erectile tissue.

5. Neurotransmission in the ganglia is achieved by preganglionic fibers releasing acetylcholine (ACh) into the synaptic space, which activates Nicotinic, cholinergic (N)receptors on postganglionic nerve dendrites. • Nicotine from tobacco is able to bind and activate the ganglionic nicotinic receptor to enhance ganglionic transmission. • -CNS effects • -Neuromuscular junction effects • Depolarization of postganglionic cholinergic nerves results in the release of stored ACh within the innervated tissue, that activates Muscarinic, cholinergic (M) receptors to produce biological effects.

6. The effect of ACh on postsynaptic tissue is terminated by rapid action of Acetylcholinesterase (AChE) that metabolizes ACh to acetate and choline: • Liberated choline is taken into the nerve terminal (blocked by hemicholinium-3) • where it is conjugated to acetate by Choline Acetyltransferase (ChAT) to produce ACh. • Synthesized ACh is transported into synaptic vesicles where is released upon subsequent depolarization of the nerve terminus. Uptake of ACh into vesicles is blocked by vesamicol.

7. Effector Organ Receptor Subtype Response to Cholinergic Stimulation Eye: Sphincter muscle, iris Ciliary muscle Heart: Sinoatrial node Atria Atrioventricular node Arteries, arterioles: Endothelial cells Lungs: Tracheal, bronchial sm. muscle Bronchial glands Contract to decrease pupil size Contract for near vision Decrease rate of depolarization Decrease contractility Decrease rate of depolarization Vasodilation Constriction Increased mucous secretion M M M M M M M M

8. Effector Organ Receptor Subtype Response to Cholinergic Stimulation Gastrointestinal tract: Urinary Bladder: Detrusor muscle Trigone & sphincter m. Salivary glands: Erectile tissue: Increased contractility, motility & secretions Contraction Relaxation Increased watery secretion Vasodilation of cavernosa, increased blood pooling M M M M M

9. Botulinum toxin from Clostridium botulinum degrades synaptobrevin, a vesicle protein • required for binding of the vesicle to the nerve terminal membrane. The toxin decreases ACh • release from cholinergic and motor nerves. • Latrotoxins from Black widow spider venom enhances the release of acetylcholine from motor nerves to cause muscle spasms and respiratory arrest.

10. The Sympathetic Nervous System • Fundamental role of the SNS is to allow the animal to respond to stressful situations i.e. fight or flight response. • The sympathetic chain ganglion • (paravertebral chain ganglion) allows • simultaneous activation of multiple organ systems. • Pre-synaptic sympathetic neurons • originating in the thoracic and lumbar portions of spinal cord innervate the chain ganglia.

11. Preganglionic nerves synapsing in the chain ganglia: • 1.are generally short. • 2.Effector Organ release acetylcholine as the primary neurotransmitter. • Post-ganglionic nerves: • 1.leave the chain ganglia to innervate specific effector organs. •   2.are longer than pre-ganglionic nerves. • 3. release (-) norepinephrine as the primary neurotransmitter.

12. Synthesis and Release of Norepinephrine from Sympathetic nerve endings • The amino acid tyrosine • is converted to dopamine which • is taken into vesicles where it • is converted to norepinephrine. • NE is stored in the vesicle with • ATP and neuropeptide Y. • Depolarization of the • nerve terminal results in • the fusion of the neurotransmitter • vesicles with the synaptic • membrane resulting in release of • the contents into synaptic cleft.

13. Released norepinephrine: • 1.Interacts with specific adrenergic • receptors to produce tissue/organ response. • - postsynaptic response. • 2.is taken back into the nerve terminal by Uptake 1 process. • - blocked by cocaine  • - after uptake NE can be incorporated into vesicles or metabolized by MAO  • 3.metabolized by Monoamine oxidase or Catechol-O- methyltransferase to inactive intermediates and finally to h omovanillic acid (HVA) or methoxyhydroxy mandelic acid (VMA).

14. Effect of the Sympathetic nervous system on selected organ systems Effector Organ Receptor Subtype Response to Adrenergic Stimulation Contracts to cause pupil dilation Relaxes to allow for far vision Increases Heart Rate and Contractility Contraction Relaxation Relaxation Decreased mucous secretion a b b b b a b b a, b Eye: Radial muscle, iris Ciliary muscle Heart: Sinoatrial node Atrioventricular node Atria, ventricles Arteries, arterioles: Smooth muscle cells Lungs: Tracheal, bronchial smooth muscle Bronchial glands

15. Effector Organ Receptor Subtype Response to Adrenergic Stimulation Relaxation Contraction Relaxation Contraction Glycogenolysis Lipolysis Renin release Ejaculation, orgasm Epinephrine release b a b a a, b b b a N Gastrointestinal tract: Smooth muscle wall Sphincters Urinary Bladder: Detrusor muscle Trigone & sphincter m. Metabolic function: Liver Fat cells Kidneys Sexual organs: Adrenal Medulla:

16. Integration of Autonomic Function to Maintain Homeostasis • Generally the parasympathetic system causes discreet changes in organ function and usually associated with “rest & digest”: • -         increased salivary secretion • -         increased GI motility • -         increased urination, defecation • -         increased bronchial constriction, secretions • -         decreased heart rate • -         pupillary constriction, decreased visual accomodation • -         increased sexual arousal • Parasympathetic activity does not usually cause generalized organ system activation unless: • -acetylcholine metabolism is significantly inhibited (nerve gas, insecticides) •   -exposure to muscarinic agonists (muscarine from mushrooms)

17. Sympathetic nervous system is designed to provide more wide-spread activation of organ systems during severe stress; assured by interconnections between ganglia in the chain ganglia that allow almost simultaneous activation of multiple nerve bundles supplying different organs. • Sympathetic activation prepares the organism to flee from or fight a potential threat: • -         pupils dilate, lens flatten for far-vision • -         heart rate, force increased • -         vasoconstriction • -         blood shunted from viscera to skeletal muscle • -         increased respiration rate • -         glucose release by liver • -         kidney blood flow and water loss decreased • -         GI and bladder function decreased • -         Skin blood flow decreased, piloerection • Sympathetic and parasympathetic systems do not oppose each other: • parasympathetic tone is decreased to specific organs with increased sympathetic tone and vice versa.