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Chapter 4: Autonomic (ANS) Pharmacology: Introduction
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Transmitter Synthesis and Degradation
Acetylcholine is synthesized from the immediate precursors acetyl coenzyme A and choline in a reaction catalyzed by choline acetyltransferase (choline acetylase).
Rapid inactivation of acetylcholine is mediated by acetylcholinesterase.
Acetylcholinesterase is present at ganglia, visceral neuroeffector junctions, and neuromuscular junctional endplates.
Another type of cholinesterase, called pseudo-cholinesterase or butyrylcholinesterase has limited presence in neurons, but is present in glia. Most pseudocholinesterase activity is found in plasma and liver.
Pharmacological effects of anti-cholinesterase drugs are due to inhibition of acetylcholinesterase.
Small random release of acetylcholine-quanta, producing miniature end-plate potentials (mepps) , are released by presynaptic terminals.
These small currents were linked to ACh release since anticholinesterases (neostigmine) increased their effects, while cholinergic receptor antagonist (tubocurarine, a nicotinic receptor blocker) blocked.
Anatomical counterpart to the electrophysiological quanta is the synaptic vesicle.
The model is based on the nicotinic, skeletal neuromusclar junction.
Synchronous exocytotic release of many more quanta, dependent on Ca2+ occur when an action potential reaches the terminal.
Exocytotic release of acetylcholine and other neurotransmitters is inhibited by toxins elaborated by Clostridium botulinum.
Botulism
Botulism is caused by the most potent neurotoxins known. The neurotoxins are produced and liberated by Clostridium botulinum.
C. botulinum, ubiquitously found in soil and marine environments, is a group of gram positive anerobes that form spores.
Eight distinct toxins have been characterized, all but one being neurotoxic.
Botulinum neurotoxin affects cholinergic nerve terminals:
postganglionic parasympathetic endings
neuromuscular junctions
peripheral ganglia
CNS is not involved.
Botulinum neurotoxin prevents acetylcholine release:
binds presynaptically
internalized in vesicular form
released into the cytoplasm
the toxin(s), (zinc endopeptidases) causes proteolysis of components of the neuroexocytosis system.
Cholinergic Transmission: Site Differences
Neurotransmitter: Acetylcholine
Receptor Type: Nicotinic
Sectioning and degeneration of motor and post-ganglionic nerve fibers results in:
an enhanced post-synaptic responsiveness, denervation hypersensitivity.
Denervation hypersensivity in skeletal muscle is due to
increased expression of nicotinic cholinergic receptors
and their spread to regions aways from the endplate.
Neurotransmitter: Acetylcholine
Receptor type: Muscarinic
effector coupled to receptor by a G protein
In smooth muscle and in the cardiac conduction system, intrinsic electrical activity and mechanism activity is present, modifiable by autonomic tone.
Activities include propagated slow waves of depolarization: Examples: intestinal motility and spontaneous depolarizations of cardiac SA nodal pacemakers.
Acetylcholine decreases heart rate by decreases SA nodal pacemaker phase 4 depolarization.
The cardiac action potential associated with HIS-purkinje fibers or ventricular muscle consists of five phases
Phase 0 corresponds to Na+ channel activation.
The maximum upstroke slope of phase 0 is proportional to the sodium current.
Phase 0 slope is related to the conduction velocity in that the more rapid the rate of depolarization the greater the rate of impulse propagation.
Phase 1 corresponds to an early repolarizing K+ current. This current like the Phase 0 sodium current is rapidly inactivated.
Phase 2 is the combination of an inward, depolarizing Ca2+ current balanced by an outward, repolarizing K+ current (delayed rectifier).
Phase 3 is also the combination of Ca2+ and K+ currents.
Phase 3 is repolarizing because the outward (repolarizing) K+ current increases while the inward (depolarizing) Ca2+ current is decreasing.
Phase 4 in normal His-Purkinje and ventricular muscle cells is characterized by a balance between outward Na+ current and inward K+ current. As a result, the membrane potential would normally be flat.
In disease states or for other cell types (SA nodal cells) the membrane potential drifts towards threshold. This phenomenon of spontaneous depolarization is termed automaticity and has an important role in arrthymogenesis.
Rate of phase 4 depolarization is decreased by an increase in K+ conductance--which leads to membrane hyperpolarization (takes longer to reach threshold)
Neurotransmitter: Acetylcholine
Receptor type: Nicotinic
Generally similar to skeletal muscle site: initial depolarization is due to receptor activation. The receptor is a ligand-gated channel.
Choline ester administration results in blood vessel dilatation as a result of effects on prejunctional inhibitory synapses of sympathetic fibers and inhibitory cholinergic (non-innervated receptors).
In isolated blood vessel preparations, acetycholine's vasodilator effects are mediated by activation of muscarinic receptors which cause release of nitric oxide, which produces relaxation.
Nicotinic Receptors
Ligand-gated ion channels
Agonist effects blocked by tubocurarine
Receptor activation results in:
rapid increases of Na+ and Ca2+ conductance
deplorization
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
Lefkowitz, R.J, Hoffman, B.B and Taylor, P. Neurotransmission: The Autonomic and Somatic Motor Nervous Systems, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.112-137
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