Autonomic Pharmacology II

Transmission in the sympathetic system

Cholinergic transmission at the presynaptic neurone

1. Uptake of choline via transporter (CHT – rate limiting)

2. Synthesis of ACh and AcCOA

3. ACh stored within a vesicle

4. Depolarization of terminal by action potential

5. Ca2+ influx through voltage activated Ca2+ channels

6. Ca2+ induces exocytosis of ACh

7. Activation of ACh receptors (nicotinic or muscarinic) cellular response

8. Degradation of ACh to choline and acetate by AChE – terminates transmission

9. Reuptake and use of choline

• Ligand-gated ion channel activated by ACh and other drugs such as nicotine

• Made of 5 glycoprotein subunits (wide range) that form a channel

• Dozens of distinct subtypes

• GDPRs activated by ACh

• 5 subtypes, M1-M3 are the most important in the ANS

Noradrenergic transmission at the postsynaptic neurone

1. NA synthesis and storage

2. Depolarization by action potential

3. Ca2+ influx through voltage activated Ca2+ channels

4. Ca2+ induces release of NA

5. Activation of adrenoreceptor subtypes causing cellular response (tissue dependent)

6. Reuptake and metabolism of NA

• GDPRs activated by adrenaline/noradrenaline

• Classified on the basis of potency of agonists
• ⍺-adrenoceptor: noradrenaline > adrenaline > isoprenaline
• β-adrenoceptor: isoprenaline > adrenaline > noradrenaline

• Subclasses have been identified (⍺1, ⍺2, β1, β2) – targeted by therapeutic agents

• β1: coupled with Gs → stimulation of adenylyl cyclase → increase heart rate and force of contraction

• β2: coupled with Gs → stimulation of adenylyl cyclase → relaxation of bronchial and vascular smooth muscle

• ⍺1: coupled with Gq → stimulation of phospholipase C → contraction of vascular smooth muscle

• ⍺2: coupled with Gi → inhibition of adenylyl cyclase → inhibition of NA release

Transmission in the parasympathetic system

Cholinergic transmission at the presynaptic neurone

• As for in the sympathetic system (see above)

Cholinergic transmission at the postsynaptic neurone

• Same as cholinergic transmission at the presynaptic neurone but with muscarinic ACh receptor subtypes (M1-M3) being activated at step 7 rather than ACh receptors

• M1: coupled with Gq → stimulation of phospholipase C → increases stomach acid secretion

• M2: coupled with Gi → inhibition of adenyl cyclase; opening of K+ channels → decreases heart rate

• M3: coupled with Gq → stimulation of phospholipase C → increases secretion of saliva and contraction of visceral smooth muscle in the bronchioles
• Vascular smooth muscle indirectly relaxed via NO

Blocking cholinergic transmission

• Blockade may be achieved by
• Depolarization block - high concentration of agonists
• Competitive antagonism
• Non-competitive antagonism

• Once used to control hypertension - too many side effects

Examples of drug action in the ANS

Cocaine

• Blocks U1, increasing the concentration of NA in the synaptic cleft, resulting in increased adrenoreceptor stimulation

• Peripheral actions cause vasoconstriction (⍺1 stimulation) and cardiac arrhythmias (β1 stimulation)

Amphetamine

• Substrate for U1, enters NA terminal where it inhibits MAO, enters the synaptic vesicle and displaces NA into the cytoplasm

• NA exits the terminal on U1 and accumulates in the synaptic cleft causing increased adrenoceptor stimulation

Prazosin

• Selective, competitive antagonist of ⍺1

• Vasodilator, anti-hypertensive

Atenolol

• Selective, competitive antagonist of β1

• Anti-anginal, anti-hypertensive

Salbutamol

• Selective antagonist at β2 (does not block ⍺1, ⍺2 or β1)

• Bronchodilator in asthma

Atropine

• Competitive antagonist of muscarinic ACh receptors

• Block all muscarinic receptors with equal affinity

• Widespread effects - blockade of parasympathetic division

• Used to reverse bradycardia following MI and in anticholinesterase poisoning