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Smooth muscle Pharmacology (Contraction mechanism (Sources of Calcium for…
Smooth muscle Pharmacology
Anatomy
generally found around hollow viscera (tubes)
Vascular system
A2-adrenoceptors (Gi-linked)
A1-Adrenoceptors (Gi-linked)
Respiratory system
Gastro-intestinal tract
M2/M3 mAChRs (Gi-linked)
Genito-urinary tract
M2/M3 mAChRs (Gi-linked)
Function
designed for slow, sustained, tonic contraction
Regulation
Autonomic/Enteric NS
ACh - M3 mAChRs
Hormones
Oestrogen/Testosterone/Insulin/Adrenaline
Autoacoids
Secreted from basal or mass cells
Pacemaker cells
Spontaneous depolarisation spreading
through the smooth muscle
Vascular endothelium
regulates vascular smooth muscle relaxation
Stretch
myogenic contraction
Types
Single Unit
Only some cells are innervated
depolarisation spreads through gap junctions
Pacemaker cells
Multi Unit
Each cell is innervated individually
little or no communication between cells
(no gap junctions)
Contraction mechanism
Ligand binds to a receptor, which
triggers intracellular cascade
Calcium is released from the intracellular
stores in the Endoplasmic Reticulum
Calcium binds to Calmodulin
Ca-CaM activates the Myosin Light Chain Kinase (MLCK)
Phosphorylated MLCs react with actin
and contract the muscle
Sources of Calcium for contraction
Ligand-gated cation channels --> depolarisation --> voltage-gated
ion channels opening --> Ca2+ influx
GPCRs activating voltage-gated Ca2+ channels
NA/Adrenaline - A1-adrenoceptor
ACh - M3
Histamine - H1
5HT - 5-HT2R
Prostaglandins - DP, EP, FP
Angiotensin II - AT1R
Vasopressin - V1R
Endothelin - ET1R
Substance P/Neurokinin A - NK1R, NK2R
(Stretch channels) Non-selective cation
channels --> depolarisation --> voltage-gated
ion channels opening --> Ca2+ influx
Depolarisation is spread through gap junctions
Calcium sensitisation
regulated by the activity of MLCK and MLCP (phosphorylase)
same [Ca] can produce different
level of contraction in different cells
Contraction stimulants
A1-adrenoceptor agonists
Adrenaline
anaphylactic shock treatment
Noradrenaline
septic shock treatment
Phenylephrine
nasal decongestant
Muscarinic agonists
Pilocarpine
Glaucoma treatment
Bethanechol
urinary retention treatment
Oxytocin
used to induce labour
Relaxation stimulants
Relaxation mechanism
Passive
always follows contraction
slow relaxation
Ca2+ pumped back to reticular stores
or outside the cell by Ca2+-ATPases
Active
stimulated by a rise in cyclic nucleotides
cAMP
Gs-Linked GPCR intracellular cascade resulting in closing
of the voltage-gated ion channels hyperpolarisation
cGMP
NO
Synthesis
L-arginine --> L-citrulline + NO
Enzyme: Nitric Oxide Synthase (NOS)
Co-factors: NADP & others
Isoforms
eNOS
expressed in endothelial cells
Activated by Ca-CaM (Ca-dependent)
nNOS
expressed in neurons
Activated by Ca-CaM (Ca-dependent)
iNOS
expressed in many cell types
Ca-independent
Endothelium Dependent Vasorelaxation
some vasodilators act on endothelial receptors,
which cause the release of NO from endothelium
and stimulate smooth muscle relaxation
ACh - M3
Histamine - H1
ADP/ATP - P2Y
Bradykinin - BK2
Substance P - NK1
CGRP - CGRP1
Mechanism
NO diffuses through the cell membrane
NO triggers a cascade, which activates PKG
PKG causes smooth muscle relaxation
Increase the transport of Ca2+ to the
intracellular stores and outside of the cell
Inhibit the voltage-gated Ca2+ influx
Activate the MLCP
NO-independent relaxation through PKG mechanism
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rapid relaxation
SM-relaxing drugs
B2-adrenoceptor agonists
salbutamol, salmeterol
asthma & premature labour treatment
Prostacyclin analogues
iloprost
pulmonary arterial hypertension
Antagonists
A1-adrenoceptor antagonists
prazosin, doxazosin
hypertension, benign prostatic hyperplasia treatment
Muscarinic antagonists
atropine, ipratropium, derifenacin, tropicamide
asthma, urinary incontinence, mydriasis treatment
Angiotensin AT1 antagonists
losartan
hypertension treatment
Nitrovasodilators
glyceryl trinitrate, isosorbide mononitrate
angina treatment
Phosphodiesterase inhibitors
theophylline
asthma treatment
papaverine
L-type vg Ca2+ channel blockers
nifedipine, nimodipine
hypertension treatment
KATP channel openers
minoxidil, cromakalim, pinacidil, diazoxide
severe hypertension treatment
PDE-5 inhibitors
viagra