Br.
J.
Pharmacol.
(1989),
96,
688-692
Prostanoid-induced
contraction
of
human
bronchial
smooth
muscle
is
mediated
by
TP-receptors
1R.A.
Coleman
&
R.L.G.
Sheldrick
Peripheral
Pharmacology
Department,
Glaxo
Group
Research
Ltd,
Ware,
Herts
SG12
ODJ
1
A
range
of
naturally-occurring
prostaglandins
sulprostone,
16,16-dimethyl
prostaglandin
E2
(DME2)
and
the
thromboxane
A2
(TXA2)-mimetic,
lla,9a-epoxymethano
prostaglandin
H2
(U-
46619)
have
been
tested
for
contractile
agonist
activity
on
human
isolated
bronchial
smooth
muscle.
2
Prostaglandin
D2
(PGD2),
PGF2.,
9a,1
lf-PGF2
(1
1#-PGF2)
and
U-46619
all
caused
concentration-related
contractions.
U46619
was
at
least
300
fold
more
potent
than
the
other
prosta-
noids
with
a
mean
EC50
of
12
nm.
Sulprostone
caused
contraction
only
at
the
highest
concentration
tested
(30
pM).
PGE2
and
PGI2
caused
relaxations
at
low
concentrations,
and
only
caused
contrac-
tile
responses
at
high
concentrations
(
>
1OpM).
In
contrast,
DME2
caused
small
contractions
at
low
concentrations
but
relaxation
at
the
highest
concentration
tested
(30
pM).
3
The
rank
order
of
contractile
agonist
potency
was:
U-46619
>
llf-PGF2-
PGF2a
>
PGD2>
PGE2
>
PGI2
sulprostone
=
DME2.
4
The
TP-receptor
blocking
drug,
AH23848
(1
pM)
antagonized
the
contractile
effects
of
U-46619,
PGD2,
PGF2.
and
1l,B-PGF2,
but
had
no
effect
against
contractions
to
carbachol.
In
a
single
experiment,
a
pA2
of
8.3
(slope
=
1.2)
was
obtained
for
AH23848
against
U-46619.
5
In
most
preparations,
administration
of
AH23848
(1
pM)
to
human
bronchus
resulted
in
small,
transient
contractile
responses.
6
The
results
obtained
with
both
the
agonists
and
the
antagonist,
AH23848
are
therefore
consis-
tent
with
prostanoid-induced
contractions
of
human
bronchial
smooth
muscle
being
mediated
by
TP-receptors.
Introduction
Since
Mathe
and
his
colleagues
(Mathe'
et
al.,
1973)
demonstrated
that
asthmatics
may
be
up
to
8,000
times
more
sensitive
than
non-asthmatics
to
the
bronchoconstrictor
effects
of
prostaglandin
F2,
(PGF2a),
there
has
been
an
interest
in
the
possible
role
of
prostanoids
as
causative
factors
in
bronchial
asthma.
It
is
now
well
known
that
human
isolated
bronchial
smooth
muscle
can
contract
in
response
to
prostanoids
(Strandberg
&
Hedqvist,
1977;
Karim
et
al.,
1980;
Black
et
al.,
1986;
Seibert
et
al.,
1987),
and
that
not
only
PGF2g,
but
also
PGD2
and
the
prin-
ciple
metabolite
of
PGD2,
9x,1
lfi-PGF2(1
(l1-
PGF2),
all
cause
bronchoconstriction
in
man
(Robinson
et
al.,
1987).
A
preliminary
investigation
into
the
nature
of
the
receptors
mediating
this
effect
has
recently
been
reported
by
McKenniff
et
al.
(1988),
who
speculated
that
contraction
of
human
Author
for
correspondence.
isolated
bronchus
may
be
mediated
by
a
novel
pros-
tanoid
receptor.
In
the
present
study,
therefore,
we
have
evaluated
the
constrictor
effects
of
a
range
of
prostanoids
on
human
isolated
bronchial
smooth
muscle.
We
have
also
investigated
the
interaction
of
some
of
these
agonists
with
the
TP-receptor
blocking
drug,
AH23848
(Brittain
et
al.,
1985).
From
the
results
of
these
studies,
some
conclusions
have
been
drawn
as
to
the
nature
of
the
receptors
mediating
prostanoid-
induced
bronchoconstriction
in
man.
Methods
Tissue
preparation
Samples
of
human
bronchus
were
obtained
from
patients
undergoing
surgical
resection
of
the
lung.
Bronchial
tissue
was
dissected
clear
of
lung
par-
I
The
Macmillan
Press
Ltd
1989
TP-RECEPTORS
IN
HUMAN
BRONCHIAL
SMOOTH
MUSCLE
689
enchyma
and
vascular
tissue,
and
stored
overnight
in
modified
Krebs
solution
at
20°C.
The
composition
of
the
Krebs
solution
was
as
described
by
Apperley
et
al.
(1976).
Bronchus
of
lumen
diameter
3-4mm
was
cut
into
rings
of
3-4mm
width,
which
were
then
opened
to
form
strips.
These
strips
were
mounted
in
organ
baths
and
bathed
in
Krebs
solution
at
37°C,
containing
indomethacin
(2.8
pM)
and
bubbled
with
5%
CO2
in
02.
A
resting
tension
of
1
g
was
applied
to
each
preparation.
Experimental
design
and
evaluation
of
agonist
and
antagonist
potency
was
dissolved
in
0.9%
w/v
NaCl
solution
(saline),
indomethacin,
PGD2,
PGE2,
1
f-PGF2,
DME2
and
U-46619
were
all
dissolved
in
1.0%
NaHCO3
in
saline,
sulprostone
was
dissolved
in
3%
EtOH/
0.01%
Tween
80
in
saline,
AH23848
was
dissolved
in
6%
EtOH/0.01%
Tween
80
in
saline.
All
dilutions
were
made
in
saline.
PGI2
was
dissolved
in
Tris/HCl
buffer
pH
9.0
on
the
day
of
the
experiment,
and
dilu-
tions
made
in
Tris/HCI
buffer
pH
8.0
immediately
before
use.
Results
In
all
agonist
studies,
control
cumulative
concentration-effect
curves
to
the
standard,
the
thromboxane
A2
mimetic
U-46619
(Coleman
et
al.,
1981),
were
repeated
at
approximately
90min
inter-
vals
until
constant
responses
were
obtained,
after
which
a
similar
curve
was
constructed
to
another
agonist.
Agonist
potency
is
expressed
as
equipotent
molar
concentration
(EPC,
U-46619
=
1),
defined
as:
EC50
test
agonist
EC50
U-46619
In
antagonist
studies,
agonist
cumulative
concentration-effect
curves
were
repeated
at
approx-
imately
90
min
intervals
until
constant
responses
were
obtained,
and
then
a
single
concentration
of
AH23848
(1
pM)
was
added
to
the
bathing
solution
before
a
further
agonist
concentration-effect
curve
was
constructed.
An
antagonist
contact
time
of
between
30
and
45
min
was
used.
Antagonist
potency
is
expressed
as
concentration-ratio
(CR),
defined
as:
agonist
EC50
in
presence
of
antagonist
agonist
EC5o
iin
absence
of
antagonist
In
a
single
experiment,
a
pA2
value
for
AH23848
against
U-46619
was
determined
by
the
method
of
Arunlakshana
&
Schild
(1959).
Drugs
used
The
following
drugs
were
used:
[14Z),2fi,5a]-(±)-7-
[5
-
[[(1,1'
-
biphenyl)
-
4
-
yl]methoxy]
-
2
{4
-
morphol-
inyl)-3-oxocyclopentyl]4-heptenoic
acid,
calcium
salt
(AH23848,
Glaxo
Group
Research);
car-
bamylcholine
chloride
(carbachol,
BDH);
indo-
methacin
(Sigma);
PGD2
(Glaxo
Group
Research);
PGE2
(Upjohn);
PGF2.
tromethamine
(Upjohn);
PGI2
Na
salt
(Glaxo
Group
Research);
11fi-PGF2
(Glaxo
Group
Research);
1
1a,9a-epoxymethano
PGH2
(U46619,
Glaxo
Group
Research);
sulpros-
tone
(Glaxo
Group
Research)
and
16,16-dimethyl
PGE2
(DME2,
Glaxo
Group
Research).
Carbachol
Agonist
studies
PGD2
(0.1-30.uM),
PGF2.
(0.1-30pM),
lfl-PGF2
(0.1-30pM)
and
U-46619
(0.001-0.3pM)
all
caused
concentration-related
contractions
of
human
bron-
chial
strips,
while
sulprostone
caused
a
contraction
at
the
highest
concentration
tested
(30gM)
only.
In
contrast,
low
concentrations of
PGE2
(0.01-1.OgM)
and
PGI2
(0.1-10gM)
caused
concentration-related
relaxation,
higher
concentrations
(PGE2,
10-301iM
and
PGI2,
30pM)
causing
contractions.
In
a
single
experiment,
DME2
caused
small
contractions
at
1.0-
1OgM
and
relaxation
at
30gM.
U-46619
was
the
most
potent
agonist,
with
a
mean
EC_o
of
12
nm
(95%
confidence
limits
=
7-17,
n
=
7),
determined
from
those
experiments
in
which
a
maximum
response
was
clearly
established.
Mean
concentration-effect
curves
to
the
agonists
tested
are
shown
in
Figure
1
and
the
contractile
agonist
potencies
of
the
prosta-
noids,
relative
to
U-46619,
are
summarised
in
Table
1.
Due
to
their
relatively
low
potency,
full
contractile
concentration-effect
curves
were
only
obtained
in
a
proportion
of
experiments
with
11fl-PGF2
(n
=
3/4),
PGF2.
(n
=
2/4)
and
PGD2
(n
=
2/4),
in
the
concentration-range
tested.
Thus
the
maximum
Table
1
Mean
equipotent
molar
concentration
(EPC)
values
(U-46619
=
1)
for
prostanoids
in
contracting
human
isolated
bronchial
smooth
muscle
Agonist
U-46619
Ilf#-PGF2
PGF2.
PGD2
PGE2
PGI2
Sulprostone
DME2
EPC
1
319
383
628
1260
>2000
940015O0
>
1000
(95%
CL)
n
(47-2176)
(177-830)
(58-6804)
(540-2930)
21
4
4
4
4
2
2
1
I
Range
of
EPC
values.
690
R.A.
COLEMAN
&
R.L.G.
SHELDRICK
a
2.0
0-L
0m01
O.01
Ot
',
a
0
01)
C
a)
4-
Co
co
a)
C.)
C
12E
[U-466191
FtM
b
c;,r
1001
C
0
Co
4-1
Co
cB
E
_O
75k
50F
251
0
-251
-50
-75L
0.001
0.01
0.1
1.0
10
30
[Prostanoid]
gM
Figure
1
(a)
Typical
concentration-effect
curve
to
U-46619
on
human
bronchus.
(b)
Mean
concentration-
effect
curves
to
U-46619
(0),
1lfi-PGF2
(A),
PGD2
(A),
PGF2.
(0),
PGE2
(A),
PGI2
(O),
sulprostone
(V)
and
DME2
(V)
on
human
bronchus.
All
responses
were
calculated
as
a
percentage
of
the
response
obtained
to
U-46619
(0.1guM)
in
the
final
control
curve.
Each
point
is
the
mean
of
4
experiments
except
for
U-46619
(n
=
21),
PG12
and
sulprostone
(n
=
2)
and
DME2
(n
=
1).
Vertical
bars
represent
s.e.mean
except
for
PGI2
and
sulprostone,
where
they
represent
range.
obtainable
responses
to
PGF2.
and
PGD2
were
con-
sistently
(7-25%)
less
than
the
corresponding
maximum
responses
obtained
to
U-46619.
In
two
of
those
experiments
in
which
llfi-PGF2
produced
full
concentration-effect
curves,
response
maxima
were
identical
to
those
to
U-46619,
whereas
in
the
other
experiment,
the
maximum
was
only
58%
of
the
U-46619
maximum.
Antagonist
studies
AH23848
(1
pM)
was
tested
for
its
ability
to
inhibit
contractile
responses
to
U-46619,
PGD2,
PGF2a,
1f-PGF2
and
carbachol.
In
some
experiments
(15/20),
addition
of
AH23848
(1
pM)
caused
modest,
transient
contractile
responses.
The
mean
amplitude
of
these
contractions
was
53
(±
13)mg
as
compared
with 791
(±
181)
mg
obtained
with
U-46619
(0.1
pM).
In
all
cases,
the
AH23848-induced
contraction
had
disappeared
within
3-8
min,
despite
the
continued
presence
of
the
drug.
AH23848
caused
parallel
right-
ward
shifts
of
curves
to
U-46619,
with
a
mean
concentration-ratio
(CR)
(95%
confidence
limits)
of
313
(109-897,
n
=
8),
consistent
with
a
pA2
value
of
8.5
as
determined
by
the
Gaddum
equation
(Gaddum,
1957).
In
a
single
experiment,
AH23848
at
concentrations
of
0.03,
0.3
and
3.0yM
caused
paral-
lel,
rightward
shifts
of
concentration-effect
curves
to
U-46619
resulting
in
CRs
of
11,
150
and
2600
respec-
tively.
From
these
data
a
pA2
value
of
8.3
(slope
=
1.2)
was
calculated.
In
all
experiments
in
the
presence
of
AH23848,
contractions
to
PGF2g
(n
=
2),
PGD2
(n
=
3)
and
1lfI-PGF2
(n
=
3)
were
small
or
absent
even
at
the
highest
concentration
tested,
such
that
accurate
CR
values
could
not
be
determined.
In
the
presence
of
AH23848,
PGF23
at
concentrations
of
10-100pm
actually
caused
small
relaxations.
In
contrast,
curves
to
carbachol
were
unaffected
by
AH23848
(1
gM),
giving
a
mean
CR
of
1.5
(0.4-6.3,
n
=
4).
Mean
concentration-effect
curves
to
U-46619,
PGF2.,
1
If-PGF2
and
carbachol
in
the
absence
and
presence
of
AH23848
(1
pM)
are
illustrated
in
Figure
2.
Discussion
In
the
present
study,
we
have
confirmed
the
findings
of
Seibert
et
al.
(1987)
who
showed
that
lIfJ-PGF2
contracts
human
isolated
bronchial
smooth
muscle,
and
that
its
potency
is
similar
to
that
observed
with
PGF2.
and
PGD2.
We
have
also
demonstrated
that
the
rank
order
of
prostanoid
contractile
agonist
potency
on
human
bronchial
smooth
muscle
is
similar
to
that
previously
reported
in
preparations
containing
TP-receptors,
such
as
guinea-pig
lung
and
rat
aorta
(Kennedy
et
al.,
1982),
with
U-46619
being
at
least
two
orders
of
magnitude
more
potent
than
PGD2,
PGE2,
PGF2.
and
PGI2.
In
support
of
this,
we
have
shown
that
AH23848
specifically
inhi-
bits
the
contractile
agonist
actions
of
U-46619,
PGD2,
PGF2a
and
1l1B-PGF2,
suggesting
not
only
that
human
bronchial
smooth
muscle
contains
TP-
receptors,
but
that
all
of
these
prostanoids
exert
their
contractile
activities
through
this
receptor.
Further-
more,
the
similarity
in
the
pA2
value
determined
for
AH23848
against
U-46619
on
human
bronchus
with
those
previously
obtained
on
blood
platelets
and
vascular
smooth
muscle
from
a
range
of
species
(Brittain
et
al.,
1985),
suggests
that
the
TP-receptors
in
all
of
these
tissues
are
of
the
same
type.
The
weak
contractile
actions
of
PGE2,
DME2,
sulprostone
0
TP-RECEPTORS
IN
HUMAN
BRONCHIAL
SMOOTH
MUSCLE
691
c
0
4._
C.)
x
C-
0
0
CU
E
E
a
100
80
60
T
40/
20
0
0--
0.001
0.
01
0.1
1.0
1o
30
[U-466191
FM
C
C
100
-
0
,
80
'
60
°
40
E
20
-
E
*x
0
*-
E-20
'
`11
-.-
-
40
a'
I
0.1
1.0
1030100
[PGF2p]
FM
b
100
-
80
-
60
-
40-
20-
0.1
1.0
1030
[llp-PGF2]
FM
d
120
-
100
-
80
-
5
60
-
40
-
20-
0v
0.01
0.1
1.0
10
30
[Carbacholl
jiM
Figure
2
Mean
concentration-effect
curve
to
(a)
U-
46619,
(b)
1lfi-PGF2,
(c)
PGF2.,
and
(d)
carbachol
in
the
absence
(0)
and
presence
(0)
of
AH23848
(1
pM)
on
human
bronchus.
The
ordinate
scale
shows
%
contrac-
tion,
100%
being
defined
as
the
response
in
the
absence
of
AH23848
to
(a)
U-46619
(0.1
pM),
(b)
1I#-PGF2
(30
pM),
(c)
PGF2.
(30
pM)
and
(d)
carbachol
(10pM).
All
responses
are
expressed
as
a
percentage
of
this
100%
response.
Each
point
is
the
mean
of
6-7
(a),
3
(b),
2
(c),
4
(d)
experiments.
Vertical
bars
represent
s.e.mean
(U-
46619
and
carbachol)
or
range
(1
lf-PGF2
and
PGF2J)
and
PGI2
are
presumably
also
mediated
by
TP-
receptors,
but
to
date
AH23848
has
not
been
tested
against
any
of
these
prostanoids.
Transient
contrac-
tile
agonist
actions
of
AH23848,
like
those
observed
in
the
present
study,
have
previously
been
reported
in
other
TP-receptor
containing
tissues,
such
as
human
pulmonary
vascular
preparations
and
dog
saphenous
vein
(Brittain
et
al.,
1985).
It
is
believed
that
this
activity
results
from
a
partial
agonist
action
of
AH23848
at
TP-receptors
(Humphrey
et
al.,
1986).
The
results
in
this
study
differ
from
those
obtained
in
a
limited
study
by
McKenniff
and
her
colleagues
(McKenniff
et
al.,
1988).
They
found
DME2
to
be
a
potent
contractile
agonist
which
was
not
antago-
nized
by
either
the
TP-receptor
blocking
drugs,
AH23848
and
EP092,
or
the
EP,-receptor
blocking
drug,
AH6809.
These
results
are
consistent
with
the
presence
of
contractile
EP-receptors
which
are
insen-
sitive
to
AH6809
(i.e.
EP3-receptors,
Coleman
et
al.,
1987a).
However,
we
have found
that
DME2
is
only
a
very
weak
contractile
agonist
on
human
bronchus.
Furthermore,
the
potent
EP1-
and
EP3-receptor
selective
agonist,
sulprostone
(Coleman
et
al.,
1987a),
is
also
a
very
weak
contractile
agonist,
being
approx-
imately
1000
times
less
potent
than
U-46619.
We
have
therefore
been
unable
to
confirm
McKenniffs
observations
with
DME2
and
have found
no
evi-
dence
for
the
presence
of
either
EP1-
or
EP3-receptors
mediating
the
contractile
effects
of
prostanoids
in
this
tissue.
Our
results
with
the
TP-
receptor
blocking
drug
AH23848
are
also
in
dis-
agreement
with
those
obtained
by
McKenniff.
In
our
experiments,
AH23848
is
a
potent
TP-receptor
blocking
drug,
whereas
McKenniff
found
AH23848
to
be
at
least
an
order
of
magnitude
weaker.
A
pos-
sible
explanation
for
the
differences
in
the
results
obtained
with
AH23848
and
DME2
in
the
two
studies
may
be
related
to
the
part of
the
bronchial
tree
from
which
the
tissue
was
taken.
In
our
studies,
we
have
used
bronchus
of
lumen
diameter
3-4mm,
whereas
McKenniff
used
bronchus
of
much
larger
diameter,
between
6-10mm,
presumably
from
higher
up
the
bronchial
tree.
Whether
receptor
differences
exist
in
the
prostanoid
receptor
populations
at
differ-
ent
levels
of
the
bronchial
tree
or
whether
there
is
some
other
reason
for
the
differences
in
the
results
from
the
two
studies
remains
to
be
determined.
In
addition
to
TP-receptors
mediating
contrac-
tion,
human
bronchial
smooth
muscle
also
contains
prostanoid
receptors
mediating
relaxation
since
PGE2,
PGI2
and
DME2
all
caused
relaxant
responses. Indeed,
in
the
presence
of
TP-receptor
blockade
with
AH23848,
even
PGF2.
sometimes
caused
relaxation.
An
action
of
PGD2
and
PGF2.
at
relaxant
receptors
in
human
bronchus,
coupled
with
their
relatively
low
potency
at
TP-receptors
may
explain
the
apparent
inability
of
these
prostanoids
to
elicit
maximal
contractile
responses
equal
to
those
to
U-46619.
The
identity
of
such
relaxant
receptors
cannot
be
determined
from
the
present
study.
However,
other
evidence
is
consistent
with
these
receptors
being
similar
to
those
mediating
relaxation
of
tracheal
smooth
muscle
from
guinea-pig
and
cat
(Gardiner,
1986),
which
we
have
previously
classified
as
EP2-receptors
(Coleman
et
al.,
1987b).
In
conclusion,
the
present
results
suggest
that
if,
as
we
believe,
prostanoids
play
a
role
in
asthmatic
bronchoconstriction,
this
effect
will
be
mediated
by
TP-receptors.
If
so,
such
bronchoconstriction
will
be
inhibited
by
TP-receptor
blocking
drugs
like
AH23848,
irrespective
of
the
particular
type
of
pros-
tanoid
concerned.
AH23848
and
other
such
drugs
should
not
only
serve
as
tools
to
determine
the
extent
to
which
prostanoids
contribute
to
the
patho-
genesis
of
bronchial
asthma,
but
may
also
represent
valuable
drugs
in
the
treatment
of
this
disease.
692
R.A.
COLEMAN
&
R.L.G.
SHELDRICK
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