Dr Rashmi Rekha Kumari Asstt Prof Deptt Of Pharmacology amp ToxicologyBVCPatna14 Muscarinic and Nicotinic Action of Ach Dale distinguished two type of effect during a study of pharmacological action of Acetylcholine in cat ID: 907974
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Slide1
Cholinergic transmission(Part-II)
Dr. Rashmi Rekha KumariAsstt. Prof, Deptt. Of Pharmacology & Toxicology,BVC,Patna-14
Slide2Muscarinic 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
Slide3Slide4After 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.
Slide5Based on two type of action
( Nicotinic and Muscarinic) of Ach in body, two type of Receptor of Acetylcholine were found
Slide6Slide7Slide8Slide9Slide10Nicotinic 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.
Slide11Nicotinic 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
.
Slide12Nicotinic 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
Slide13Muscarinic 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
Slide14Muscarinic 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
Slide15Muscarinic 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
Slide16Slide17Slide18Action 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
Slide19[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.
Slide20[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…)
:
Slide21Action 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
Slide22Autonomic innervation of eye and effect of sympathetic and parasympathetic stimulation
Effect of Ach on pupil Size: Miosis
Slide23