Smooth muscle pharmacology Flashcards
Where do we find smooth muscle ?
- Vascular system
- Airways
- GI-tract
- Genito-urinary tract
Which proteins does smooth muscle contain ?
Which important protein found in sk muscle does it lack ?
How does this affect its contraction ?
Smooth muscle contains the two major proteins of the contractile apparatus, actin and myosin, but does not have the regulatory protein troponin found in skeletal and cardiac muscle.
Smooth muscle uses a different mechanism to regulate contraction –> actin and myosin are arranged in a more random fashion
Smooth muscle is designed to undergo slow, sustained, tonic contractions
Which elements regulate smooth muscle ?
- Autonomic/enteric NS
- Hormones
- Autacoids
- Pacemaker cells
- The vascular endothelium
- Stretch (myogenic contraction)
What are the 2 smooth muscle types ?
What are their characteristics ?
Single unit :
• Only some cells innervated.
• Depolarization spread through gap junctions.
• Pacemaker cells.
Multiunit :
• Each cell is individually innervated
• Little or no communication between cells
What stimulates smooth muscle contraction ?
A rise in intracellular [Ca2+].
What are the different steps in smooth muscle contraction ?
- Ca2+ enter the cell via Ca2+ channels or is released from the SR
- Ca2+ binds Calmodulin (CaM) to form a Ca-CaM complex
- Ca-CaM activates Myosin Light Chain Kinase (MLCK) which phosphorylates MLC to MLC-P, thus increasing myosin ATPase activity
- active myosin cross-bridges slide along actin and create muscle tension = contraction
- MLC-P in dephosphorylated back to MLC by MLC-phosphotase
What is the main source of Ca2+ for smooth muscle contraction ?
Are there secondary sources ?
Voltage-gated Ca2+ channels are the main source of Ca2+ for smooth muscle contraction, but there are also :
- P2X purinoreceptors (permeable to Na+ and Ca2+)
- Gq linked GPCRs
- non-selective cation-channels (permeable to Na+ and Ca2+)
How does depolarization in smooth muscle spread from one cell to another ?
Depolarization spreads through gap junctions and triggers the excitation of adjacent cells via their v-gated Ca2+ channels.
Which Gq-GPCRs mediate smooth muscle contraction ?
Indicate the ligands for each receptor.
- NA/AD –> α1-AR
- ACh –> M3
- Histamine –> H1
- 5H-T –> 5-HT2
- Prostaglandins –> DP, EP, FP
- Angiotensin II –> AT1
- Vasopressin –> V1
- Endothelin –> ET1
- Substance P/Neurokinin A –> NK1, NK2
What is the signalling pathway for Gq mediated smooth muscle contraction ?
- ligand e.g. NA binds GPCR
- Gq activates PLC
- PIP2 split into DAG and IP3
- IP3 triggers Ca2+ from SR
- DAG activated PKC, which inactivates K+ channels (less K+ leves the cell, increasing the driving force attracting Ca2+ and Na+ inside the cell)
- the Ca2+ in the cell activates v-gated Ca2+ channels, Ca2+ activated chloride channels (Cl- EXITS smooth muscle cells) and store operated Non-Specific Cation Channels (NSCC)
- the Na+ entering, the K+ remaining in the cell and the Cl- leaving the cell all contribute to depolarizing the cell, further stimulating the v-gated Ca2+ channels
How can Ca2+ sensitization occur in smooth muscle cells ?
- as Gq agonist, as well as stimulating Gq, can also stimulate Gq12/13
- G12/13 stimulates Rho-GEF, which stimulates Rho-A, which stimulates Rho-K inhibits MLCP
- in addition, PKC stimulates CPI-17, which inhibits MLCP as well
- less MLCP means more MLC-P –> sustained contraction –> desensitization
What are the Gi-linked GPCRs responsible for smooth muscle contraction ?
- alpha2-AR w/ alpha1-AR in arterioles
- M2 receptors w/ M3 in GIT and bladder
- Gi-alpha –> reduced cAMP ?
- Gi-beta/gamma –> other mechanisms ?
Which kinds of drugs stimulates smooth muscle contraction ?
α1-AR agonists : - AD, used for anaphylactic shock - NA, used for septic shock - phenylephrine, nasal decongestant Muscarinic agonists : - pilocarpine, used for glaucoma - bethanechol, used for urinary retention Oxytocin, used to induce labour
What are the 2 types of smooth muscle relaxations ?
Passive - always occurs following contraction
Active - stimulated by a rise in cyclic nucleotides
What is the mechanism of smooth muscle relaxation ?
Calcium can :
- activate de sarcolemma Ca2+ -ATPase to pump Ca2+ back into the SR
- activate the NCX (3 Na3+ for 2 Ca2+ out)
- activate the plasmalemma Ca2+ -ATPase to pump Ca2+ out of the cell
- activate Bk channels to trigger K+ leak from the cell
- the re-polarization of the cell activates Kv channels, causing further re-polarization
- overall, the re-polarization shuts down v-gated Ca2+ channels
Which cyclic nucleotides trigger smooth muscle relaxation ?
Gs-Linked GPCRs –> cAMP
Nitric Oxide –> cGMP
How does a rise in cAMP trigger smooth muscle relaxation ?
Describe all the steps of the pathway, starting w/ ligand binding.
- ligand e.g. AD or prostacyclin bind Gs linked receptor
- AC converts ATP to cAMP
- cAMP activates PKA
- PKA activates K(ATP) and BK(Ca) channels, trigger K+ to flow out the the cell
- the re-polarization inactivates v-gated Ca2+ channels
How is NO synthesized ?
L-arginine is converted to L-citrulline and NO by NO synthase (NOS), w/ NADP and other factors
What are the 3 isoforms of NOS ?
eNOS :
- Expressed in endothelial cells
- Activated by Ca-CaM (i.e. Ca-dependent)
nNOS :
- Expressed in neurons
- Activated by Ca-CaM (i.e. Ca-dependent)
- Responsible for NO release from Non Adrenergic Non Cholinergic nerves (NANC)
iNOS :
- Inducible (cytokines, bacterial endotoxin) form found in
may cell types.
- NOT Ca-dependent
What is the Endothelium Derived Relaxing Factor (EDRF) ?
EDRF = NO
A number of endothelium derived vasodilators exit.
Name those that you know and the receptor they act on.
- Acetylcholine –> M3
- Histamine –> H1
- ADP/ATP –> P2Y
- Bradykinin –> BK2
- Substance P –> NK1
- CGRP –> CGRP1
What causes the release of NO from the endothelium ?
Blood flow causes shear stress on endothelial cells also stimulates NO release from them.
What is the mechanism by which NO acts to cause vasodilation ?
- NO enters the cell and activates sGC
- sGC converts GTP to cGMP
- cGMP activates PKG
- PKG :
- -> inhibits PLC
- -> inhibits v-gated Ca2+ channels
- -> stimulates MLCP
- -> stimulates K+ leak channels
- -> stimulates plasmalemma Ca2+ -ATPase (which pump Ca2+ out of the cell)
- -> stimulates the sarcolemma Ca2+ -ATPase (pump Ca2+ back in SR)
What are natriuretic peptides ?
Where do they act ?
Natriuretic peptides are potent vasodilators.
They stimulate NPR-A and NPR-B receptors, which are particulate guanylate cyclase receptors
