Autonomic Nervous System and the Adrenal Medulla

Chapter 60

Sunday, December 02, 2012

4:11 PM

Autonomic Nervous System and the Adrenal Medulla

·  ANS - controls most visceral functions of the body; changes can occur w/rapidity and intensity

·  Activated mainly by centers located in SC, brain stem, and hypothalmus

·  Portions of cerebral cortex (esp limbic cortex) can transmit signals to lower centers and influence autonomic control

·  Often operates thru visceral reflexes

o  Subconscious sensory signals from a visceral organ enters autonomic ganglia/brain stem/hypothalmus and returns subconscious reflex responses directly back to the visceral organ to control its activities

o  Efferent autonomic signals transmitted to organs via SNS and PSNS

·  SNS

o  Peripheral Portions

·  Two paravertebral sympathetic chains of ganglias interconnected w/spinal nerves on side of vertebral column

·  Two prevertebral ganglia (celiac and hypogastric)

·  Nerves extending from ganglia to different organs

o  Sym nerve fibers originate in SC w/spinal nerves b/w T1 -L2 and pass into sympathetic chain then to tissues and organs

o  Preganglionic Neurons

·  Cell body in intermediolateral horn of SC -> anterior root -> spinal nerve -> white ramus -> ganglia of sympathetic chain then:

1.  Synapse w/postganglionic sym neurons in ganglion

2.  Pass up/down in chain and synapse in other ganglia in chain

3.  Pass for variable distances thru chain, thru sym nerve -> synapsing in a peripheral sym ganglion

o  Postganglionic Neurons

·  Originates in one of the sym chain ganglia or in one of peripheral sym ganglia

·  Some pass back from sym chain into spinal nerves thru gray rami (all very small type C fibers); extend to all parts of the body by way of skeletal nerves

§  Control blood vessels, sweat glands, and piloerector muscle

§  ~8% of fibers in avg skeletal nerves are sym fibers

o  Sym fibers termination - determined partly by locus in embryo

·  T1 - terminate in head

·  T2 - neck

·  T3-T6 - thorax

·  T7-T11 - abdomen

·  T12, L1-L2 - legs

o  Adrenal Medullae

·  Preganglionic sym nerve fibers pass W/O SYNAPSING, from intermediolateral horn cells of SC -> sym chains -> splanchnic nerves -> into adrenal medullae

·  End directly on modified neuronal cells that secrete epinephrine and norepinephrine into the blood

§  Modified neuronal cells - derived from nervous tissue and are postganglionic neurons

·  PSNS

o  Parasym fibers leave CNS thru cranial nerves III, VII, IX and X and 2nd and 3rd sacral spinal nerves (occasionally thru 1st and 4th sacral spinal nerves)

o  75% of all parasym fibers are in vagus nerves (entire thoracic and abd regions)

·  CN III: pupillary sphincter and ciliary muscle of eye

·  CN VII: lacrimal, nasal, and submandibular glands

·  CN IX: parotid gland

·  CN X: heart, lungs, esophagus, stomach, SI, CO-prox, liver, GB, pancreas, kidneys, upper ureters

·  Sacral parasym fiber are in pelvic nerves (sacral plexus S2-S3)

§  COD, rectum, urinary bladder, lower ureters, external genitalia - erection

o  Preganglionic fibers pass uninterrupted all the way to the target organ; postganglionic neurons are located in the wall of the organ

·  Extremely short postganglionic fibers leave neurons to innervate the organ tissues

·  Few exceptions

·  Sym/Parasym Function

o  Two synaptic transmitter substances

·  Acetylcholine

§  Secreting fibers - cholinergic

·  All preganglionic neuron in both SNS/PSNS

·  All (or almost all) postganglionic neurons of PSNS

·  Postganglionic sym nerve fibers to sweat glands, piloerector muscles, very few blood vessel

§  "Parasympathetic Transmitter" but will excite both sym/parasym postganglionic neurons

§  Synthesized in terminal endings/varicosities of cholinergic nerve fibers - stored in vesicles (highly concentrated form)

§  Persists in tissues for a few secs, then is split (see biochem pathway)

·  Norepinephrine

§  Secreting fibers - adrenergic

·  Most of postganglionic sym neurons (few secrete acetylcholine)

§  "Sympathetic Transmitter"

§  Synthesis begins in axoplasm of terminal nerve endings of adrenergic nerve fibers; completed inside the secretory vesicles

§  Removed from secretory site by:

·  Reuptake into adrenergic nerve endings by active transport (50-80% of removal)

·  Diffusion away from nerve endings into surrounding body fluids then into blood

·  Destruction of small amounts by tissue enzymes

§  Secreted directly: remains active for only a few secs (reuptake/diffusion away is rapid

§  Secreted into blood: remain active until diffuses into tissue (mainly liver), remains active for 10-30 secs, activity declines to extinction over 1-several minutes

o  Secretion

·  Many PSNS fibers/almost all SNS fibers merely touch effector cells of target organs

·  Some terminate in connective tissue located adjacent to target cells

§  Have bulbous enlargements called varicosities

·  acetylcholine or norepinephrine are synthesized and stored

·  Has large #'s of mitochondria supply ATP

·  AP spreads over terminal fibers -> depolarization process inc permeability of fiber membrane to Ca+ -> ions diffuse into nerve terminals or nerve varicosities -> ions cause them to empty contents to exterior - transmitter substance is secreted

o  Receptors on Effector Organs

·  Must bind w/specific receptors on effector cells

·  Receptor - bound as a prosthetic group to a protein molecule - goes thru membrane all the way

·  Binding causes conformational change

·  Altered protein molecule excites/inhibits the cell

§  Causing change in cell membrane permeability to one or more ions

·  Often opens/closes an ion channel

·  i.e. Na+ and/or Ca+ ion channels freq are opened -> allow rapid influx of ions into cell

·  Usually depolarizing cell membrane and exciting the cell

·  i.e. K+ channels are opened allowing K+ to diffuse out of cell -> inhibits cell b/c loss of electropositive K+ ions creates hypernegativity inside the cell

§  Activating/inactivating an enzyme attached to the other end of the receptor protein

·  Enzyme often attached to receptor protein where receptor protrudes interiorly

·  i.e. binding of norepinephrine w/receptor inc the activity of enzyme adenylyl cyclase inside the cell -> causes formation of cAMP -> initiates action

·  Acetylcholine Receptors

§  Muscarinic - Muscarine (toadstool poison) only activates muscarinic receptors

·  Found on all effector cells stim by postganglionic cholinergic neurons of SNS/PSNS

§  Nicotinic - Nicotine only activates nicotinic receptors

·  Found in autonomic ganglia at synapses b/w pre/postganglionic neurons of SNS/PSNS

·  Adrenergic Receptors

§  Alpha (both excitatory/inhibitory)

·  Alpha1, alpha2

·  Norepinephrine - excites mainly

·  Epinephrine - excites

·  Isopropyl norepinephrine - no action

§  Beta (both excitatory/inhibitory)

·  Beta1, beta2, beta3

·  Norepinephrine - excites to a lesser extent

·  Epinephrine - excites

·  Isopropyl norepinephrine - strong action

o  Function of Adrenal Medullae

·  Stimulation of sym nerves -> large quantities of epinephrine/norepinephrine to be released in blood

§  80% epinephrine, 20% norepinephrine

§  Effects last 5-10X longer than direct sym stim, b/c hormone are removed slowly (2-4 min)

§  Circulating norepinephrine -> constriction of most vessels, inc heart activity, inhibition of GI tract, dilation of pupils, inc total peripheral resistance and elevates arterial pressure

§  Circulating Epinephrine -> same effects, plus: greater heart stim b/c better effect in stim beta receptors, weaker constriction of blood vessels, raises arterial pressure to lesser extent, inc cardiac output more, 5-10X metabolic effect (can inc metabolic rate of body as much as 100% above normal - inc activity/excitability of body)

·  Stim of Target Organs

§  Organs stim directly by SNS and indirectly by adrenal medullary hormones simultaneously

·  Two systems support and can substitute each other (provides a safety net for stimulation)

·  Normal resting rate of secretion ~ 0.2 ug/kg/min of epinephrine; 0.05 ug/kg/min of norepinephrine

§  Quantities are enough to maintain the BP almost to normal even if all direct sym pathways to cardiovascular system are removed

o  Stimulus Rate

·  ANS - lower freq of stim required for full activation (compared to skeletal NS)

·  Only one nerve imulse/few secs to maintain normal SNS/PSNS effect

·  Full activation occurs when fibers discharge 10-20 times/sec

§  Skeletal NS at 50-500+ impulses/sec

o  Sym/Parasym Tone

·  Value of tone = allows a single NS both to inc and dec the activity of a stimulated organ

·  i.e. Sym tone: systemic arterioles constricted to ~ 1/2 their max diameter

§  This way the SNS can both cause vasoconstriction and vasodilation

·  i.e. Surgical removal of parasym supply to GI by cutting vagus nerves -> serious/prolonged GI atony -> blockage of normal GI propulsion -> serious constipation :(

o  Denervation

·  Sym/Parasym nerve cut -> innervated organ loses its sym/parasym tone

·  Intrinsic tone - occurs over min/hours/days/weeks

§  After denervation intrinsic tone inc

·  i.e. blood vessels - inc tone caused by inc smooth muscle contractile force that is NOT resultant of sym stim but of chemical adaptations in smooth muscle fibers -> eventually restores almost normal vasoconstriction

§  Intrinsic compensation - return function of the organ almost to its normal basal level

·  In PSNS may take many months

·  i.e. loss of parasym tone to the heart after cardiac vagotomy inc HR to 160 beats/min -> still partially elevated 6 months later

·  Denervation Supersensitivity - post-denervation, organ is more sensitive to injected norepinephrine or acetylcholine

§  Process:

·  Stellate ganglion removed

·  Blood flow rises b/c lost vascular tone

·  Days/weeks later - blood flow returns toward normal b/c inc in intrinsic tone of vascular musclature

·  Norepinephrine injected, and blood flow dec much more (as compared to before the denervation) b/c vessels have become ~ 2-4X more responsive to norepinephrine

§  Mechanism

·  # of receptors in postsynaptic membranes of effector cell inc when norepinephrine/acetylcholine is no longer released at the synapses

o  Mass Discharge - almost all portions of the SNS discharge simultaneously as a complete unit

·  Freq occurs when hypothalmus is activated by fright, fear, or severe pain

·  Alarm or Stress Response - widespread rxn thruout the body (fight or flight response)

§  Inc arterial pressure

§  Inc blood flow to active muscles, dec flow to organs

§  Inc rates of cellular metabolism thruout body

§  Inc blood glucose concentration

§  Inc glycolysis in liver and in muscle

§  Inc muscle strength

§  Inc mental activity

§  Inc rate of blood coagulation

§  Process: hypothalmus stim -> signals transmitted downward thru the reticular formation of the brain stem and into the SC -> massive sym discharge

o  SNS Localized Responses

·  Process of heat regulation

§  SNS controls sweating and blood flow in skin w/o affected other organs

·  Local reflexes involving sensory afferent fibers

§  i.e. heating a skin area

·  GI control functions by way of nerve pathways that do not enter SC

o  PSNS Localized Responses

·  Cardiovascular reflexes usually only act on the heart - change HR

·  Isolated parts of the GI system (mouth glands, stomach gland etc)

o  Medullary, Pontine, and Mesencephalic Control

·  Transection of brain stem above midpontine level

§  Allows basal control of arterial pressure

§  Prevents arterial pressure modulation by higher nervous centers (i.e. hypothalmus)

·  Transection immediately below medulla

§  Arterial pressure falls to less than 1/2 normal

o  Control of Brain Stem Autonomic Centers

·  Hypothalmus and Cerebrum (higher brain centers)

§  i.e. posterior hypothalmus - can activate medullary cardiovascular control centers (inc arterial pressure to more than 2X normal)

·  Autonomic centers in brain stem act as relay stations for control activities initiated at higher levels of the brain

·  Higher areas of the brain can alter function of the whole ANS or portions of it strongly enough to cause severe autonomic-induced dz (i.e. peptic ulcer of STM or SBDU, constipation, heart palpitation or MI)

·  Pharmocology of ANS

o  Sympathomimetic or Adrenergic Drug

·  i.e. Norepinephrine, Epinephrine, Methoxamine

·  Norepinephrine/epinephrine have actions 1 to 2 minutes

·  Other commonly used sympathomimetic drugs last for 30min to 2 hours

·  Phenylephrine - alpha receptors

·  Isoproterenol - beta receptors

·  Albuterol - only beta2 receptors

o  Indirect Sympathomimetic Action

·  i.e. ephedrine, tyramine, amphetamine

·  Cause release of norepinephrine from its storage vesicles in the sym nerve endings

o  Drugs that block Adrenergic activity

·  Reserpine

§  Synthesis and storage of norepinephrine is sym nerve endings is prevented

·  Guanethidine

§  Release of norepinephrine from sym endings is blocked

·  Phenoxybenzamine and Phentolamine

§  Sym alpha receptors are blocked

·  Propranolol

§  Blocks beta1 and beta2 receptors

·  Metoprolol

§  Blocks beta1 receptors

·  Hexamethonium

§  Blocks transmission of nerve impulses thru autonomic ganglia (sym and parasym)

o  Drugs that act on Cholinergic Effector Organs

·  Cholinergic Drugs (parasym drugs)

§  Are not rapidly destroyed like IV acetylcholine

§  Produce typical widespread parasym effects

§  Commonly used: pilocarpine and methacholin - act directly on muscarinic cholinergic receptors

·  Anticholinesterase Drugs

§  Do not have direct effect on parasym effector organs

§  Potentiate effect so fnaturally secreted acetylcholine at parasym endings

§  Include: neostigmine, pyridostigmine, and ambenonium

·  Inhibit acetylcholinesterase, preventing rapid destruction of the acetylcholine

·  Quantity of acetylcholine inc w/successive stimuli and the degree of action also inc

·  Antimuscarinic Drugs

§  Block the action of acetylcholine on the muscarinic cholinergic effector organs

§  Do not affect the nicotinic action

§  i.e. atropine, homatropine, and scopolamine

o  Drugs that stim Autonomic Postganglionic Neurons

·  Preganglionic neurons (sym/parasym) secrete acetylcholine at endings -> stim the postganglionic neurons

§  Injected acetylcholine can also stim postganglionic neurons of both systems

§  Nicotine -

·  can stim postganglionic neurons b/c nicotinic type of acetylcholine receptor