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PHAR2005 > Smooth muscle pharmacology > Flashcards

Smooth muscle pharmacology Flashcards

1
Q

Where do we find smooth muscle ?

A
  • Vascular system
  • Airways
  • GI-tract
  • Genito-urinary tract
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2
Q

Which proteins does smooth muscle contain ?
Which important protein found in sk muscle does it lack ?
How does this affect its contraction ?

A

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

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3
Q

Which elements regulate smooth muscle ?

A
  • Autonomic/enteric NS
  • Hormones
  • Autacoids
  • Pacemaker cells
  • The vascular endothelium
  • Stretch (myogenic contraction)
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4
Q

What are the 2 smooth muscle types ?

What are their characteristics ?

A

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

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5
Q

What stimulates smooth muscle contraction ?

A

A rise in intracellular [Ca2+].

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6
Q

What are the different steps in smooth muscle contraction ?

A
  • 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
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7
Q

What is the main source of Ca2+ for smooth muscle contraction ?
Are there secondary sources ?

A

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+)
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8
Q

How does depolarization in smooth muscle spread from one cell to another ?

A

Depolarization spreads through gap junctions and triggers the excitation of adjacent cells via their v-gated Ca2+ channels.

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9
Q

Which Gq-GPCRs mediate smooth muscle contraction ?

Indicate the ligands for each receptor.

A
  • 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
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10
Q

What is the signalling pathway for Gq mediated smooth muscle contraction ?

A
  • 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
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11
Q

How can Ca2+ sensitization occur in smooth muscle cells ?

A
  • 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
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12
Q

What are the Gi-linked GPCRs responsible for smooth muscle contraction ?

A
  • alpha2-AR w/ alpha1-AR in arterioles
  • M2 receptors w/ M3 in GIT and bladder
  • Gi-alpha –> reduced cAMP ?
  • Gi-beta/gamma –> other mechanisms ?
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13
Q

Which kinds of drugs stimulates smooth muscle contraction ?

A 
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
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14
Q

What are the 2 types of smooth muscle relaxations ?

A

Passive - always occurs following contraction

Active - stimulated by a rise in cyclic nucleotides

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15
Q

What is the mechanism of smooth muscle relaxation ?

A

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
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16
Q

Which cyclic nucleotides trigger smooth muscle relaxation ?

A

Gs-Linked GPCRs –> cAMP

Nitric Oxide –> cGMP

17
Q

How does a rise in cAMP trigger smooth muscle relaxation ?

Describe all the steps of the pathway, starting w/ ligand binding.

A
  • 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
18
Q

How is NO synthesized ?

A

L-arginine is converted to L-citrulline and NO by NO synthase (NOS), w/ NADP and other factors

19
Q

What are the 3 isoforms of NOS ?

A

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

20
Q

What is the Endothelium Derived Relaxing Factor (EDRF) ?

A

EDRF = NO

21
Q

A number of endothelium derived vasodilators exit.

Name those that you know and the receptor they act on.

A
  • Acetylcholine –> M3
  • Histamine –> H1
  • ADP/ATP –> P2Y
  • Bradykinin –> BK2
  • Substance P –> NK1
  • CGRP –> CGRP1
22
Q

What causes the release of NO from the endothelium ?

A

Blood flow causes shear stress on endothelial cells also stimulates NO release from them.

23
Q

What is the mechanism by which NO acts to cause vasodilation ?

A
  • 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)
24
Q

What are natriuretic peptides ?

Where do they act ?

A

Natriuretic peptides are potent vasodilators.

They stimulate NPR-A and NPR-B receptors, which are particulate guanylate cyclase receptors

25
Q

Name 7 smooth muscle relaxing drugs you know.

A
  • β2-adrenoceptor agonists
  • Prostacyclin analogues
  • Receptor Antagonists
  • Calcium channel blockers
  • Potassium channel openers
  • Nitrovasodilators
  • Phosphodiesteraseinhibitors
26
Q

What kind of Gs-linked GPCR smooth muscle agonists do you know ?

A

β2-Adrenoceptor Agonists
- e.g.salbutamol, salmeterol –> uses => asthma, premature labour
Prostacyclin Analogues
- e.g.iloprost –> uses => pulmonary arterial hypertension

27
Q

What kind of smooth muscle receptor antagonists do you know ?

A

α1-Adrenoceptor Antagonists :
- e.g. prazosin, doxazosin –> uses => hypertension, benign prostatic hyperplasia
Muscarinic Antagonists :
- e.g. atropine, ipratropium, darifenacin, tropicamide –> uses => asthma, urinary incontinence, mydriasis
Angiotensin AT1 Antagonists :
- e.g. losartan use => hypertension

28
Q

Inhibition of Ca2+ influx through v-gated Ca2+ channels is an efficient way of relaxing smooth muscle.
With which drugs can this be done, and on which receptor do they act ?

A

L-Type Voltage-Gated Ca2+Channel Blockers :
- dihydropyridines e.g. nifedipine, nimodipine
uses => hypertension
K(ATP) Channel Openers
- e.g. minoxidil, cromakalim, pinacidil, diazoxide
uses => severe hypertension

29
Q

What are nitrovasodilators ?
Provide examples.
Do any other similar drugs exist ?

A

Nitrovasodilators = agents that causesvasodilation by donation of nitric oxide, and are mostly used for the treatment and prevention of angina pectoris
e.g. glyceryl nitrate, isosorbide mononitrate
Other NO donors = sodium nitroprusside, amyl nitrite

30
Q

How does glyceryl trinitrate work ?

A

Glyceryl trinitrate (GTN) enters the cell, it is then converted to NO2-, then NO, which binds sGC etc…

31
Q

What is hydralazine ?

How does it work ?

A 
Hyddralazine = stimulates vasorelaxation, was used for hypertension
Mechanism of action still unknown :
- blocks intracellular Ca2+ release ?
- K+ channel opener ?
- increases cGMP ?
32
Q

Phosphodiesterase inhibitors cause relaxation.

Which kinds of phosphodiesterase inhibitors do you know ?

A

Methylxanthines :
- theophylline, used for asthma
Papaverine :
- from the opium poppy, smooth muscle relaxant

33
Q

How does sildenafil (VIAGRA) work ?

A

It is a PDE-5 inhibitor.

PHAR2005 (24 decks)

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