• ANS Anatomy
  • Autonomic and Somatic Innervation
  • Autonomic Reflex Arc
  • Autonomic Reflex Arc: First Link
  • Sensory Fiber Neurotransmitter(s)
  • Autonomic Nervous System Neurotransmitters: Summary
  • CNS and the Autonomic Nervous System
    • Spinal Cord Reflexes
    • Hypothalamus and Nucleus tractus solitarii
    • Higher Centers
  • Peripheral ANS Divisions
• Comparison between Sympathetic & Parasympathetic Systems
• Sympathetic Nervous System Anatomy
  • Diagram Sympathetic System
  • Anatomical Outline
    • Paravertebral Ganglia
    • Prevertebral Ganglia
    • Terminal Ganglia
    • Adrenal Medulla
• Parasympathetic System Anatomy
• ANS Neurotransmitter Effector Organs

• Interactions between Sympathetic & Parasympathetic Systems
• "Fight or Flight": Characteristics of the ANS

• ANS Neurotransmission
  • Neurotransmitter Criteria
  • Neurotransmission Steps:
    • Axonal Conduction
    • Storage and Release of Neurotransmitter
    • Combination of Neurotransmitter and Post-Junctional Receptors
    • Termination of Neurotransmitter Action
    • Other Non-electrogenic Functions
  • Cholinergic Neurotransmission
    • Transmitter Synthesis and Degradation
    • Acetylcholinesterase
    • Acetylcholine: Storage and Release
    • Site Differences:
      • Skeletal Muscle
      • Autonomic Effectors
      • Autonomic Ganglia
      • Blood vessels
    • Signal Transduction: Receptors
• Adrenergic Transmitters: Biosynthetic Pathways
• Adrenergic Neurotransmission: Introduction to the Neurotransmitters
• Catecholamine Synthesis, Storage, Release and Reuptake
  • Enzymes
  • Catecholamine storage
  • Regulation of adrenal medullary catecholamine levels
  • Reuptake
  • Metabolic Transformation
  • Indirect-acting sympathomimetics
  • Release
• Adrenergic Receptor Subtypes
  • ß-adrenergic receptors
  • Alpha-adrenergic receptors
  • Catecholamine Refractoriness
• Other Autonomic Neurotransmitters
  • Co-transmission
    • ATP
    • VIP
    • Neuropeptide Y family
  • Purines
  • Nitric Oxide (Modulator)
• Predominant Sympathetic/Parasympathetic Tone
• Baroreceptor Reflexes
• Pharmacological Modification of Autonomic Function
• Autonomic Dysfunction

Nicotinic Receptors

• Ligand-gated ion channels
• Agonist effects blocked by tubocurarine
• Receptor activation results in:
  • rapid increases of Na⁺ and Ca²⁺ conductance
  • depolarization
  • excitation
• Subtypes based on differing subunit composition: Muscle and Neuronal Classification

Muscarinic Receptors

• G-protein coupled receptor system
• Slower responses
• Agonist effects blocked by atropine
• At least five receptor subtypes have been described by molecular cloning. Variants have distinct anatomical locations and differing molecular specificities

• Norepinephrine: transmitter released at most postganglionic sympathetic terminals
• Dopamine: major CNS neurotransmitter of mammalian extrapyramidal system and some mesocortical and mesolimbic neuronal pathways.
• Epinephrine: most important hormone of the adrenal medulla

Aromatic L-amino acid decarboxylase (DOPA decarboxylase)

1. dopa leads to dopamine
2. methyldopa leads to a-methyldopamine (converted by dopamine ß hydroxylase to the "false transmitter" alpha-norepinephrine)
3. 5-hydroxy-L-tryptophanleads to5-hydroxytryptamine (5-HT)

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Tyrosine Hydroxylase

1. tyrosine leads to DOPA
2. rate limiting step in pathway
3. tyrosine hydroxylase is a substrate for cAMP-dependent and Ca²⁺ - calmodulin-sensitive protein kinase and protein kinase C
4. Increased hydroxylase activity is associated with the phosphorylated enzyme

• In adrenergically innervated tissue: norepinephrine is localized in post-ganglionic nerve terminals

  • large dense core vesicles (corresponding to chromaffin granules)

  • small dense core vesicles (containing norepinephrine, ATP, and membrane-bound dopamine ß-hydroxylase

• In the adrenal medulla, catecholamines are localized in chromaffin granules.

• The most abundant catecholamine in the adrenal medulla is epinephrine.

• The adrenal medulla has two cells types containing catecholamines:

  •  one type contains mainly norepinephrine

  •  the second type contains mainly epinephrine.

• Epinephrine-containing cells express cytoplasmic phenylethanolamine-N-methyl transferase, allowing conversion of norepinephrine to epinephrine.

  •  Norepinephrine:

    1. synthesized in granules

    2. diffuses out, is methylated in the cytoplasm to epinephrine

    3. then reenters the chromaffin granules.

•  About half of dopamine is formed in sympathetic neuronal cytoplasm is actively translocated into dopamine ß-hydroxylase-containing vesicles, where the final step, conversion to norepinephrine occurs.

  • The remaining dopamine is converted to homovanillic acid.

• An important factor controlling the rate of epinephrine synthesis and adrenal medullary epinephrine concentration is glucocorticoid concentration.

• Glucocorticoids:
  1.  are secreted by the adrenal cortex
  2.  are carried by an intra-adrenal portal vascular system to the adrenal medullary chromaffin cells
  3.  induce synthesis of phenylethanolamine-N-methytransferase.
  4.  also increase levels of tyrosine hydroxylase and dopamine ß-hydroxylase.

  Stress leads to increased corticotropin leads to increased cortisol, increased epinephrine

• Following release from adrenergic nerve endings, termination of norepinephrine effect is mainly due to reuptake into presynaptic terminals.
• In tissues with wide synaptic gaps and in blood vessels, the effect of released norepinephrine is ended by:
  1. enzymatic breakdown
  2. diffusion away from receptors
  3. extraneuronal uptake.

• Neuronal norepinephrine reuptake requires two systems:
  •  a transport system that translocates norepinephrine from extraneuronal spaces into cytoplasm.
  •  a transport system that translocates norepinephrine from the cytoplasm into vesicles.

• Translocation of norepinephrine from extraneuronal spaces (uptake I) into the cytoplasm is blocked by:
  1.  cocaine
  2.  tricyclic antidepressants (e.g. imipramine (Tofranil))

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• Uptake II is an extraneuronal (glia, heart, liver, etc )amine translocator that exhibits low affinity for norepinephrine and higher affinities for epinephrine and isoproterenol. This system is of limited physiological significance, unless Uptake I is blocked.

• Besides reuptake and diffusion away from receptor sites, catecholamine action can end due to metabolic transformation.

• Inhibitors of MAO, such as pargyline, phenelzine (Nardil), and tranylcypromine (Parnate) increase norepinephrine, dopamine, and serotonin (5-HT) brain concentrations. 
  • These concentration increases may be responsible for antidepressant action of MAO inhibitors.

Shannon, M.T., Wilson, B.A., Stang, C. L. In, Govoni and Hayes 8th Edition: Drugs and Nursing Implications Appleton & Lange, 1995, pp. 904-905

Release steps: Chromaffin Granule Adrenal medulla

preganglion fiber releases Ach nicotinic receptor activationdepolarizationCa2+ entry exocytosis of granular content

• Ca²⁺ influx is important in excitation (depolarization)--release coupling

• ß-receptors are divided into two major categories: ß₁ and ß₂.
  • ß₁ receptors myocardium.
  • ß₂ receptors smooth muscle and most other sites.
• The subdivision of beta receptors followed from the observation that in the heart norepinephrine and epinephrine were equipotent, whereas epinephrine was many fold (10 - 50) more potent at smooth muscle.
• A ß₃ receptor has been found that is strongly activated by norepinephrine compared to epinephrine and may explain "atypical" pharmacological properties of adipose tissue. The ß₃ -receptor is not blocked by propranolol, classified as a non selective beta-receptor blocker.
• Activation of ß₁, ß₂ and ß₃ receptors increases adenylyl cyclase activity (G_s mediated) resulting in a rise of intracellular cAMP.
  • Cardiac inotropic effects result from increases in Ca²⁺ concentration, due to:
    • phosphorylation of L-type Ca²⁺ channels
    • phosphorylation of sarcolemmal Ca²⁺ pumps
    • direct action G_s action on the L-type channel
  • Effects on the liver lead to activation of glycogen phosphorylation

• ß₂ receptor activation mediates relaxation of vascular smooth muscle
•  ß₂ receptor activation mediates relaxation of G.I. smooth muscle. alpha₂ adrenergic receptor activation acts presynaptically to reduce Ach release and promote G.I. smooth muscle relaxation. The alpha₂ receptor effect is the more important.

• Multiple alpha receptor subtypes have been identified.
• Multiple forms were suggested when, after administration of an alpha-receptor antagonist, repetitive nerve stimulation resulted in increasing amount of norepinephrine release. This findings suggested a presynaptic alpha-receptor binding site.
• Post-synaptic receptors alpha₁ .
• Pre-synaptic receptors alpha₂ .
• Alpha₂ receptors are also present post-synaptically. This site is involved in the action of some centrally-acting antihypertensive agents, e.g. clonidine.
• Some drugs, such as clonidine are more active at alpha₂ receptors.

  Clonidine (Catapres)

  Clonidine acts in the brain at post-synaptic alpha2 receptors, inhibiting adrenergic outflow from the brainstem. Inhibition of sympathetic outflow results in a decrease in blood pressure. Clonidine reduces cardiac output (by reducing both stroke volume and heart rate) and peripheral resistance. Reduction in stoke volume occurs due to increased venous pooling (decreased preload). Clonidine does not interfere with cardiovascular responses to exercise. Renal blood flow and function is maintained during clonidine treatment. Clonidine has minimal or no effect on plasma lipids.

   

   Adverse Effects

  Dry Mouth (xerostomia) bradycardia (in patients with SA nodal abnormality)

  Withdrawal syndrome upon abrupt discontinuation (increased blood pressure, headache, tachycardia, apprehension, tremors)

• Some drugs such as methoxamine (Vasoxyl) or phenylephrine (Neo-Synephrine) are more active at alpha₁ receptors.
• Multiple forms of both alpha₁ and alpha₂ receptors have been identified.