Cholinergic transmission(Part-II) - PowerPoint Presentation

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Cholinergic transmission(Part-II)

Dr. Rashmi Rekha KumariAsstt. Prof, Deptt. Of Pharmacology & Toxicology,BVC,Patna-14

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Muscarinic and Nicotinic Action of Ach

Dale distinguished two type of effect during a study of pharmacological action of Acetylcholine in cat.These were Muscarinic and NicotinicThe muscarinic action of Acetylcholine are those that can be reproduced by the injection of

muscarine, the active principle of a poisonous mushroom Amanita muscaria

Muscarinic effect can be blocked by

small dose Atropine

( the poisonous constituent of deadly nightshade)

On the whole muscarinic action corresponds to parasympathetic stimulation

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After a muscarinic effect is blocked by atropine, larger dose of Ach produced another set of effect, closely similar to those of nicotine

.They include: Stimulation of All autonomic gangliaStimulation of voluntary muscleSecretion of adrenaline from the adrenal medul

la.Experiment of Dale formed the basis of classification of Ach receptor

There are two type of Ach receptor in body muscarinic(M) and Nicotinic(N)

Capacities of

tubocurarine

and atropine to block nicotinic and muscarinic effect of Ach, respectively, provided further support for the proposal of two distinct type of cholinergic receptor.

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Based on two type of action

( Nicotinic and Muscarinic) of Ach in body, two type of Receptor of Acetylcholine were found

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Nicotinic Receptor

The nicotinic receptors fall in three main classes, the muscle, ganglionic and CNS type Nicotinic receptor are typical of ligand gated ion channel( fast action), and their activation always causes a rapid( millisecond) increase in cellular permeability to Na+ and Ca2+, depolarisation and excitation. By contrast, muscarinic receptors belong to the class of G protein-coupled receptor. Response to muscarinic agonist ae slower, They may be either excitatory or inhibitory

. And they are not necessarily linked to change in ion permeability.

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Nicotinic Muscle Ach receptor(NM): They are confined to the skeletal neuromuscular junction and selectively stimulated by Phenyl Trimethyl Ammonium (PTMA). It is selectively blocked by tubocurarine. They mediate skeletal muscle contraction.

Nicotinic neuronal Ach receptor(NN): These are present on ganglionic cell, adrenal medullary cells and in spinal chord and in certain area of brain

Ganglionic

receptors are responsible for transmission at sympathetic and parasympathetic ganglia

CNS receptor are widespread in

brain(Basal

ganglia,cortex

, spinal cord and other site)

They are

selectively stimulated by Dimethyl Phenyl

Piperazinium

(DMPP

) and

Hexamethonium

.

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Nicotinic Receptors

 

N

M

N

N

1.Location

and function

subserved

2. Nature

3.Transducer mechanism/membrane response

Neuromuscular junction

: Depolarization of muscle end plate



contraction of skeletal muscle.

Has intrinsic ion channel,

pentamer

of

α

2

βε

or

Ϋ

and

δ

 

subunits, each unit has 4TM

Opening of cation(Na+) channel-

Excitatory

Autonomic ganglia

:

Depolarization



post-ganglionic impulse.

Adrenal medulla

:

Catecholamine release.

CNS

:

Site specific excitation or inhibition

.

Has intrinsic ion channel,

pentamer

of only

αβ

subunit, each subunit has 4 TM

Opening of cation(Na+ , K+, ca2+)

channel-Excitatory

Agonists

PTMA(Selective),

Nicotine

DMPP(Selective),

Nicotine

Antagonists

Tubocurarine

, a-

Bungarotoxin

Hexamethonium

,

Trimethaphan

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Muscarinic receptor

There are five subtypes of muscarinic receptor: M1, M2, M3, M4 and M5Th First three are major subtype that are present on effector cells as well as on prejunctional nerve endings and are expressed in both peripheral organ as well as in the CNS

The M4 and M5 receptor are present mainly in certain area of brain regulate the release of other neurotransmitter

Functionally, M1, M3 and M5 fall in one class while M2 and M4 fall in another class

Muscarinic agonist have shown little subtype selectivity, but antagonist have (

Pirenzepine

for M1,

tripitramine

for M2 and

darifenacin

for M3)

Most organs have more than one subtype- but usually one subtype predominates in a given tissue

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Muscarinic Receptors

 

M

1

M

2

M

3

Location and function

subserved

Autonomic ganglia

: Depolarization

Gastric glands

: Histamine release and acid

secretion, relaxation of lower

oesophageal

sphincter (LES)

CNS

:

Learning,

Memory, Motor Function

etc

SA node

:

Hyperpolarization, lowered rate of impulse generation

AV node

:

Lowered velocity of conduction

Atrium

:

Shortening of action potential duration, decreased contractility.

Ventricle

:

Lowered contractility (slight) - due to sparse cholinergic receptors

Cholinergic nerve endings

: Decreased

ACh

release

CNS; Tremor, Analgesia

Visceral smooth muscle: Contraction

Visceral smooth muscles

: Contraction

Exocrine glands

:

Secretion

Vascular endothelium

: Release of nitric

oxide

(NO)



vasodilatation

Iris:

constriction of pupil

Ciliary muscle: contraction

Nature

G-protein

coupled, 7-TM

G-protein

coupled, 7-TM

G-protein

coupled, 7-TM

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Muscarinic Receptors

 

M

1

M

2

M

3

3. Transducer mechanism

IP3/DAG-increased cytosolic ca2+ ion,

PLA2 stimulation-PG synthesis

K channel opening, decrease

in

cAMP

level

IP3/DAG-increased cytosolic ca2+ ion,

PLA2 stimulation-PG synthesis

Agonist

Oxotremorine

Methacholine

Bethanechol

Antagonist

Pirenzepine, Telenzepine

Methoctramine

Hexahydrosiladifenidol

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Action of Acetylcholine

Muscarinic ActionUpon stimulation of muscarinic Ach receptor, stimulation or inhibition of autonomic effector cell occur.In contrast to skeletal muscle and neuron, smooth muscle and cardiac conduction system normally exhibit intrinsic activity, both electrical and mechanical that is modulated but not initiated by nerve impulse

.In basal condition unitary smooth muscle exhibit the waves of depolarisation and spikes that are propagated from cell to cell at rate that are considerably slower than the action potential of axons or skeletal muscle.

In intestinal smooth muscle, the site of pacemaker activity continually shifts

But in heart spontaneous depolarisation normally arises from the SA node

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[I

]. Muscarinic actions:

Actions of Acetylcholine

1

.

Heart:

SA

node

: Hyperpolarization

, Rate of impulse generation reduced and bradycardia.

AV

node & His-Purkinje

fibres

:

Conduction slowed.

Atria : The

force of atrial contraction is markedly reduced.

Ventricles : Contractility

also reduced but not

marked.

2.

Blood

vessels:

Vasodilatation



Fall

in B.P.

Vasodilatation

is primarily mediated through

EDRF (NO).

3.

Smooth

muscles:

Smooth

muscles

contracted

. Tone and peristalsis in the

GI tract

is increased and sphincters relax



abdominal cramps and evacuation of

bowel.

Peristalsis

in

ureter

is increased. The detrusor muscle contracts while the bladder trigone and sphincters relax



voiding of

urine.

Bronchial

muscles

constrict, asthmatics are highly sensitive



dyspnoea

, precipitation of an attack of bronchial

asthma.

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[II]. Nicotinic actions

: Actions of Acetylcholine continued…..

1.

Autonomic ganglia:

Both sympathetic and parasympathetic ganglia are stimulated. The effect is manifested at higher doses. High dose of

ACh

given after atropine causes tachycardia and rise in B.P.

2.

Skeletal

muscles:

Contraction

of

fibre

,

fasciculations

etc

.

4.

Glands

:

Secretion from all

parasympathetically

innervated glands is

increased



sweating, salivation,

lachrimation

, tracheobronchial and gastric secretion. The effect on pancreatic and intestinal glands is not marked.

Secretion of milk and bile is not

affected.

5.

Eyes

:

Contraction

of circular muscles of iris



miosis

. Contraction

of ciliary muscles of iris  spasm of accommodation, increased outflow facility, reduction in intraocular tension.

[I].

Muscarinic actions

(continued…)

:

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Action of Ach on

Blood VesselsAll blood vessels are dialated, though only

few vessels (skin of face, neck, salivary gland) receive cholinergic innervation.

Fall in BP occurs

Ach binds with

M3 receptor on vascular endothelial cell-------

Release of NO from endothelial cell--

--

Act on smooth muscle

cell ----Activation of

Guanyl

cyclase enzyme-----Relaxation of BV---

hypotention

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Autonomic innervation of eye and effect of sympathetic and parasympathetic stimulation

Effect of Ach on pupil Size: Miosis

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