UNIVERSITY COLLEGE LONDON
Department of Pharmacology
PHAR2002/2005 General and Systematic Pharmacology Dr T. D. Carter
SMOOTH MUSCLE CONTRACTION & RELAXATION
Learning objectives
1. To understand different ways in which vascular, bronchial and uterine smooth
muscle can be contracted or relaxed.
2. To give examples (where possible) of drugs acting through the mechanisms detailed in
(1) above.
3. To understand the rationale behind the therapeutic application of drugs affecting
smooth muscle tone.
Learning task
1. Supplement the lecture by reading Rang, Dale & Ritter (3rd Ed.) pps. 203-213, 301-313,
358-363 and 469-473 or the more diffuse treatment of the material covered in these
lecture notes in Katzung (5th Ed.)
Vasoconstriction (and vasodilatation) evoked by catecholamines is dealt with in other Lectures
(Adrenoceptors) and (Antihypertensive drugs).
Smooth muscle contraction
The contractile characteristics and the mechanisms that cause contraction of vascular smooth
muscle (VSM) are very different from cardiac muscle. VSM undergoes slow, sustained, tonic
contractions, whereas cardiac muscle contractions are rapid and of relatively short duration (a
few hundred milliseconds). While VSM contains actin and myosin, it does not have the
regulatory protein troponin as is found in the heart. Furthermore, the arrangement of actin
and myosin in VSM is not organized into distinct bands as it is in cardiac muscle. This is not
to imply that the contractile proteins of VSM are disorganized and not well-developed. They
are actually highly organized and well-suited for their role in maintaining tonic contractions
and reducing lumen diameter.
Mechanism
An increase in free intracellular calcium is the trigger for contraction. The free calcium binds
to a special calcium binding protein called calmodulin (see Fig.below). Calcium-calmodulin
activates myosin light chain kinase (MLCK), an enzyme that is capable of phosphorylating
myosin light chains (MLC) in the presence of ATP. Myosin light chains are 20-kD regulatory
subunits found on the myosin heads. MLC phosphorylation leads to cross-bridge formation
between the myosin heads and the actin filaments, and hence, smooth muscle contraction.
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The intracellular concentration of
calcium depends upon the balance
between the calcium that enters the cell
from the external environment, the
calcium that is released by intracellular
storage sites (e.g., SR), and the removal
of calcium either back into storage sites
or out of the cell. Calcium is re-
sequestered by the SR by a ATP-
dependent calcium pump. Calcium is
removed from the cell to the external
environment by either a ATP-dependent
calcium pump or by the sodium-calcium exchanger.
Intracellular calcium concentration is very important in regulating smooth
muscle contraction.
Vascular smooth muscle (VSM) contraction
Blood Vessels;
Arteries are large diameter, thick-walled vessels that carry blood away from the heart.
Arterioles are small, thick-walled vessels that represent the major part of vascular resistance.
These resistance vessels serve as "circulatory stopcocks"and control the distribution of blood
to various organs.
Capillaries are extremely small, extremely thin-walled vessels (one cell thick) that allow
exchange of gases, nutrients, and other small molecules between the blood stream and
tissues. Increases in capillary hydrostatic pressure or capillary permeability can lead to
edema.
Venules are small thin-walled vessels that serve to bring blood back to the heart. These
vessels are highly distensible and (along with veins) contain a large fraction of the blood
volume.
Veins are large diameter thin-walled vessels that bring blood back to heart. They are
distensible and (in addition to venules) contain a large fraction of the blood volume.
The important vessels controlling blood pressure
Resistance vessels. Arterioles are the primary resistance vessels and control mean arterial
blood pressure and blood flow to specific tissues. Vascular smooth muscle tone in these
vessels is controlled by the sympathetic nervous system and local factors (metabolic need)
Capacitance vessels. Systemic venules and veins serve as a volume reservoir for the
circulatory system (approx. 50% of total blood volume is contained in these vessels).
Sympathetic and humoral regulation of these vessels can significantly alter venous return
(preload) and fluid exchange in the associated capillary beds.
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Contraction in VSM can be initiated by mechanical, electrical, and chemical stimuli. Passive
stretching of VSM can cause contraction that originates from the smooth muscle itself and is
therefore termed a myogenic response. Electrical depolarization of the VSM cell membrane
will also elicit contraction, most likely by opening voltage dependent calcium channels (L-
type calcium channels) and causing an increase in the intracellular concentration of calcium.
Finally, a number of chemical stimuli such can elicit contraction;
noradrenaline (α1-adrenoceptor)
angiotensin II
endothelin (ETA, ETB2)
vasopressin (V1 receptor)
ergot alkaloids e.g. ergotamine
5-hydroxytryptamine (5-HT1D-like receptor)
Each of these substances bind to specific receptors on the VSM cell (or to receptors on the
endothelium adjacent to the VSM) and can cause contraction of the VSM. The mechanism of
contraction can involve different signal transduction pathways (see below) all of which
converge to increase intracellular calcium (see below).
Endothelium
Noradrenaline ATP
Endothelin Na
Angiotensin II
G-protein-coupled L-type Ca Ca
Non-selective cation
receptor channel channel
Gq +
GDP Depolorisation
PLC GTP
InsP3 [Ca2+]i
PL
+ CaM Ca-CaM
+
Calcium MLCK
Store (SR)
Contraction
Smooth muscle cell
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Noradrenaline (NA)
From sympathetic nerves acting via alpha1-adrenoceptors coupled via Gq to PLC and InsP3
production. Co-transmitters may include; ATP that can cause contraction acting via
activation of a non-selective cation channel (P2x.receptors- very fast) or Gq coupled
receptors to PLC (e.g. P2y receptors—slow), Neuropeptide Y, mechanism of action not clear
but can potentiate action of NA.
alpha1-adrenoceptor antagonists acts as vasodilators, e.g. Prazosin, Indoramine. Cause
vasodilation and a fall in blood pressure.
Indirect acting vasoconstrictors that cause NA release from nerve terminals include
amphetamine, tyramine (e.g ‘the cheese reaction’) and ephedrine. Cocaine blocks uptake of
NA into nerve terminals and has a similar sympathomimetic effect.
Angiotensin II (AII).
A potent vasoconstrictor formed from the inactive angiotensin I by the angiotensin converting
enzyme (ACE; expressed onvascular endothelial cells). This enzyme is inhibited by captopril
which is an anti-hypertensive drug. AII, acts via ATI receptors coupled via Gq to PLC and
InsP3 production.
Endothelin (ETA, ETB2)
21 aa peptide, 3 isoforms ET1, ET2 and ET3. ET1 made by endothelium. ET1 acts via ETA and
ETB2 receptors that are coupled by Gq to PLC and InsP3 production. Antagonists include BQ-
123 (a cylic pentapeptide) and BMS 182874 (a sulphonamide derivative).
Vasopressin (VP).
VP is a posterior pituitary peptide hormone with major actions on the kidney (see Chp 20 Rang,
Dale & Ritter) It vascular actions are via V1 receptors to elicit VSM contraction (via Gq, PLC
and InsP3 production). Will also constrict gastrointestinal and uterine SM). The vasopressin
analog, felypressin (selective for V1 receptors) is used as a vasoconstrictor with local
anaesthetics.
Ergot alkaloids, 5-hydroxytryptamine and Migraine
Migraine is a common condition characterized by a headache and contraction and/or dilatation of
cerebral blood vessels. The symptoms have been treated with ergotamine which causes marked
vasoconstriction (must be avoided in patients with peripheral vascular disease). Very recently
the 5-HT1D-like receptor agonist sumatriptan, which also constricts intracranial vascular smooth
muscle, has been introduced. It has been suggested that migraine is a neurogenic inflammatory
condition mediated by nerves from the trigeminal nucleus. Sumatriptan may act prejunctionally
on these nerves which innervate cerebral blood vessels. The complex role of 5-HT in migraine is
shown by the prophylactic use of methysergide, which has some selectivity as an antagonist for
5-HT2 receptors.
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VSM relaxation:
The G-protein coupled pathway can either stimulate (via Gs protein) or inhibit (via Gi
protein) adenylyl cyclase (AC) that catalyzes the formation of cAMP. In VSM, unlike the
heart, an increase in cAMP (e.g., a beta-agonist such as epinephrine or isoproterenol) causes
relaxation. The mechanism for this is cAMP inhibition of MLCK. This decreases MLC
phosphorylation, thereby decreasing the interactions between actin and myosin. Therefore,
drugs which increase cAMP (e.g., β2-adrenoceptor agonists, phosphodiesterase inhibitors)
cause vasodilation.
A third mechanism that is
very important in
regulating VSM tone is the
nitric oxide (NO)-cGMP
system. Briefly, increases
in NO activate guanylyl
cyclase causing increased
formation of cGMP and
vasodilation. The precise
mechanisms by which
cGMP relaxes VSM is
unclear; however, cGMP
can activate a cGMP-
dependent protein kinase,
inhibit calcium entry into the VSM, activate K+ channels, and decrease IP3.
VSM vasodilators include;
adrenaline (β2-adrenoceptor)
nitrovasodilators e.g. glyceryl trinitrate
nitric oxide
calcium antagonists e.g. nifedipine
potassiun channel openers
histamine (H1 and H2 receptors; Lecture 14)
prostacyclin (Lecture 16)
The nitrovasodilators relax vascular smooth muscle by releasing nitric oxide (NO). The NO
stimulates guanylate cyclase which leads to an increase in cyclic GMP in the smooth muscle.
Nitric oxide is a gas (not to be confused with nitrous oxide, N2O) and has recently been given to
relieve respiratory distress syndrome. Some drugs act via receptors on the endothelium to
stimulate NO synthase and the NO produced diffuses to the smooth muscle to evoke relaxation.
Inhibitors of NO synthase, which increase blood pressure, are being tested in septic shock.
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Pelvic nerve stimulation leads to the release of nitric oxide and subsequent relaxation of the
smooth muscle of the corpus cavernosum.. The nitric oxide is metabolised by a
phosphodiesterase, PDE-5. Sildenafil (Viagra) inhibits this enzyme so prolonging the effect of
nitric oxide stimulated cGMP.
The calcium antagonists block voltage-gated calcium channels and prevent calcium entry. In
smooth muscle the L-type channels are responsible for the inward movement of calcium that
plays a role in contraction. The dihydropyridine derivative nifedipine evokes arteriolar dilatation
and a fall in blood pressure with a transient reflex tachycardia.
Smooth muscle relaxation can also occur by increasing the membrane permeability to potassium
ions, leading to hyperpolarization. Drugs with this type of action are being developed.
Bronchial smooth muscle
A. Contraction:
acetylcholine (M3 muscarinic receptor)
some neuropeptides e.g. neurokinin A
leukotrienes C4 and D4
histamine (H1-receptor)
The bronchi are contracted by acetylcholine released from the postganglionic parasympathetic
nerve terminals. The muscarinic receptor antagonist, ipratropium bromide, is used as an anti-
asthmatic drug and is given by aerosol inhalation. It is a quaternary compound and therefore,
because it has low lipid solubility, it is not well absorbed into the circulation and does not readily
cross the blood-brain barrier.
B. Relaxation:
salbutamol (β2-adrenoceptor)
methyl xanthines e.g. caffeine and theophylline
β2-Adrenoceptor agonists are widely used to dilate bronchial smooth muscle (acting as
"physiological" antagonists) and they also inhibit the release of mediators from mast cells. These
drugs are usually taken by inhalation and have a quicker onset of action than ipratropium.
The methyl xanthines are bronchodilators and are given orally. Theophylline is often used,
sometimes complexed with ethylene diamine and known as aminophylline. Other effects which
also contribute to the use of aminophylline in left ventricular failure with pulmonary oedema are
positive chronotropic and inotropic effects on the heart, vasodilatation and the weak diuretic
activity. The mechanism of action of the methyl xanthines is unclear. Inhibition of
phosphodiesterase and the release of intracellular calcium have been shown but at fairly high
concentrations. A more likely mechanism for therapeutic drug doses is the antagonism of
adenosine at adenosine receptors.
Uterine smooth muscle
A. Contraction:
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noradrenaline (α1-adrenoceptor)
acetylcholine (muscarinic receptor)
oxytocin (pregnant uterus)
ergometrine
prostaglandin E2 and F2α
The posterior pituitary hormone oxytocin increases the force and rate of contractions of the
pregnant uterus, with increased receptor numbers (oestrogen dependent) towards term. Oxytocin
may have a role in the initiation of paturition. At term oxytocin is often given by a slow,
intravenous infusion to induce labour. It causes regular contractions but the uterus relaxes in
between, allowing oxygenated blood flow to the foetus. In higher doses oxytocin can be used to
reduce post-partum haemorrhage (see below).
The ergot alkaloid ergometrine evokes contraction of smooth muscle including the pregnant and
non-pregnant uterus. The sustained contraction is unsuitable to induce labour. It is given,
intramuscularly or intravenously, in the third stage of labour (often combined with oxytocin) to
contract the uterus and to reduce the risk of post-partum haemorrhage.
The prostaglandins E2 and F2α cause marked rhythmical contractions of the pregnant and non-
pregnant uterus. Given by the extra-amniotic route these drugs are used in the second trimester
of pregnancy for therapeutic abortion.
B. Relaxation:
salbutamol (β2-adrenoceptor)
In some cases of premature labour the β2-adrenoceptor agonists are used to relax uterine smooth
muscle.
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