• 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

• Following exposure to catecholamines, there is a progressive loss of the ability of the target site to respond to catecholamines. This phenomenon is termed tachyphylaxis, desensitization or refractoriness.
• Regulation of catecholamine responsiveness occurs at several levels:

• Stimulation of ß-adrenergic receptors rapidly causes receptor phosphorylation and decreased responsiveness. The phosphorylated receptor exhibits:
  • decreased coupling to G_s and
  • decreased stimulation of adenylyl cyclase.

Antatomical Site

Predominant Autonomic Tone

Arterioles

Sympathetic-adrenergic

Veins

Sympathetic-adrenergic

Heart

Parasympathetic-cholinergic

Ciliary Muscle

Parasympathetic-cholinergic

Gastrointestinal Tract

Parasympathetic-cholinergic

Salivary Glands

Parasympathetic-cholinergic

Sweat Glands

Sympathetic-cholinergic

• A principal mechanism for arterial blood pressure control is the baroreceptor reflex.

• The reflex is initiated by activation of stretch receptors located in the wall of most large arteries of the chest and neck.

• A high density of baroreceptors is found in the wall of each internal carotid artery (just above the carotid bifurcation i.e. carotid sinus) and in the wall of the aortic arch.

 As pressure rises and especially for rapid increases in pressure:

• baroreceptor input to the tractus solitarius of the medulla results in inhibition of the vasoconstrictor center and excitation of the vagal (cholinergic) centers resulting in:

1. a vasodilatation of the veins and arterioles in the peripheral vascular beds.
2. negative chronotropic and inotropic effects on the heart. (slower heart rate with reduced force of contraction)

• Transmitter Synthesis: Site 1
• Transmitter Release: Site 2
• Receptor Interactions: Site 3
• Termination of Transmitter Effect: Site 4

• Hemicholinium (HC-3) blocks the choline transport system into the nerve ending, thus limiting acetylcholine (ACh) synthesis.

• Alpha-methyltyrosine inhibits tyrosine hydroxylase thus preventing synthesis of norepinephrine.

• Methyldopa inhibits aromatic amino acid decarboxylase and is itself decarboxylated and hydroxylated to form the "false transmitter" alpha-methyl norepinephrine

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• Botulinum toxin can be used clinically to treat ocular muscle spasms, muscle dystonias, and spasms.
• Botulinus toxin binding at a presynaptic site blocks ACh release.
• Vesamicol blocks ACh transport into storage vesicles, thus limiting release.

• Bretylium and guanethidine prevent action-potential mediated norepinephrine release.
• Transient release may occur with these agents because they displace norepinephrine from storage sites.
• Tyramine, amphetamine, and ephedrine can produce a brief liberation of transmitter.
• Reserpine, by inhibiting vesicular uptake, produces a slow, depletion of norepinephrine, ultimately causing adrenergic blockade. Cytoplasmic MAO metabolizes the neurotransmitter.
• Reserpine similarly depletes dopamine and serotonin. Physiological effects of reserpine are due to depletion of many transmitters.

• Tetraethylammonium, trimethaphan and hexamethonium are nicotinic ganglionic antagonists.
• Decamethonium, a depolarizing drug, selectively causes neuromuscular blockade.
• All classes of muscarinic receptors are blocked by atropine.

•  Phenylephrine (Neo-Synephrine):  an alpha₁ receptor agonist.
•  Clonidine (Catapres): an alpha₂ receptor agonist.
•  Prazosin (Minipress): an example of an alpha₁ receptor antagonist.
•  Yohimbine (Yocon): an example of an alpha₂ receptor antagonist.

•  Isoproterenol (Isuprel): ß₁ and ß₂ receptor agonist.
•  Dobutamine (Dobutrex):  a relatively selective myocardial ß₁ receptor agonist.
•  Terbutaline (Brethine):  relatively selective ß₂ receptor agonist.
•  Propranolol (Inderal):  an example of a non-selective beta-adrenergic receptor blocker.
•  Metoprolol (Lopressor):  an example of a relatively selective ß₁ receptor antagonist.

• Acetylcholinesterase inhibitors prevent breakdown and inactivation of acetylcholine.
  • ACh accumulation at the neuromuscular junction causes flacid paralysis.
  • ACh accumulation at postganglionic muscarinic sites results in either excessive stimulation (contraction & secretion) or inhibition (hyperpolarization), depending on the site.
  • ACh accumulation at autonomic ganglia cause increased transmission.

• Interference with neurotransmitter reuptake results in potentiation of catecholamine effects.
• Cocaine and imipramine are examples of drugs that inhibit the reuptake system.
• Monoamine oxidase (MAO) inhibitors potentiate actions of tyramine; whereas catechol-O-methyl transferase (COMT) inhibitors (pyrogallol and tropolone) only slightly increase catecholamine effects.