- Email: [email protected]
PAF increases vascular permeability in selected tissues: Effect of BN52021 and L-655,240
PROSTAGLANDINS
ACTIVITY
OF
INDUCED
THE
NEW
AND
SPECIFIC
BRONCHOCONSTRICTION
PAF-ANTAGONISTS
AND
WEB
INTRATHORACIC
2170
AND
ACCUMULATION
STY
OF
2108
ON
PAF--
IN THE
PLATELETS
GUINEA-PIG. Heuer
H.,
Ingelheim
The be
Casasls-Stenzel KG,
WEB
selective
and
acether).
the
effect
of
these
and
intrathoracic
by
of
and
increase
STY
2108
a
in
and
in
was
induced
In
conclusion
by
x
iv.
an
iv.
both
pigs bolus
or
platelet-aggregation
of in
Boehringer
WEB study
the
2170 was
in
and
to paf-
STY
2108
undertaken
to
pig. Guinea pigs
mean
platelets
shown (paf,
bronchoconstric-
guinea
and
been
factor
paf-induced
in
arterial
the
blood
thoracic
2
bronchoconstriction,
thorax.
mg/kg at
the
with at
WEB
similar paf
at
paf-induced
PO.)
iv.
region
2170
of
or
STY
as
above,
or
were
2108
2170
STY
or
effects 2108
were
increase
of
disaggregated.
prevented
when
WEB these
paf-induced
platelets
2170
hypotension with
prevented
WEB
maximum
doses 100
WEB
Pretreatment
mg/kg
accumulated
hetrarepines
antagonists
recently
flow
induced the
0.005-0.5
When
of
has
present
platelets
min)
approach
pretreatment guinea
K.H.;
activating
on
labelled
in
intrathoracic iv.
constriction
ng/(kg
curative
Weber
counter.
manner. a
W.,
hetrazepines The
respiratory
Ill-Iridium
mg/kg
dose-dependent
gamma-radiation,
potent
30
the
hetrazepines of
of
gamma-radiation
(0.001-0.100
administered Perorsl
of
at
of
to
accumulation
gamma-radiation
paf
Stransky
platelet
effects.
new
recording
Accumulation
followed
a
for
of
led
sedative
prepared
in
variation of
tion
Infusion
antagonist
devoid
were
G.,
(FRG)
also
investigate
pressure.
Muacevic
2086 (JPET 241, 974-981, 1987) potent
structure are
J.,
Ingelheim/Rh.
hetrazepine a
which
was
D-6507
the
broncho-
bronchoconstriction
ng/kg. 2170
and
STY
2108
bronchoconstriction,
(orally
and
iv.)
hypotension
are and
vivo.
PAF IUCREASES VASCIJL~N PSSMEASILIl'I IA SSLSCTSD TISSUES: EVVSCT OF BN52021 AND L-655,240. Siroisl, P., Siroisl, M., Jancar*, S., Braquet3, P., Plantel, G.E. lDept. of Pharmacol., Fat. Med., Univ. Sherbrooke, QC, Canada. 2Univ. Sao Paulo, Brazil; 31nst. Henri Beaufour, Le Plessis Robinson, France. The effects of the potent inflammatory mediators, PAF, was studied on selected rat tissues (Wistar) using the extravasation of Evans blue dye (EB) as a marker. EB (20 mg/kg) was injected in the caudal vein together with increasing doses of PAF. The animals were killed and the dye was extracted in selected organs using formamide (4 ml/g wet tissue). Extravasation of EB varied markedly from one tissue to another and increased as a function of time (from 0 to 60 min). PAF (0.1, 1.0 and 5 ug/kg) caused increases in the vascular permeability of the pancreas and duodenum (respectively 12 and 4 folds respectively at the dose of 5 ug/kg). PAF did not affect significantly the vascular permeability of the heart, liver, spleen, kidneys and lungs (in toto). However, when the total lungs were dissected into trachea, upper bronchi, lower bronchi and parenchyma, it was found that PAF (5 ug/kg) increased the vascular permeability of the trachea (3 folds), upper bronchi (7 folds) and lower bronchi (5 folds) but decreased by 1.5 folds the vascular permeability of the parenchyma. The PAF antagonist BN 52021 (2 and 10 mg/kg) produced a dose-dependent inhibition of the PAF effects on the pancreas, duodenum and lung tissues. Maximum inhibition was achieved (95%) at the dose of 10 mg/kg. Interestingly, this antagonist given in the absence of PAF reduced the plasma extravasation below control levels. A thromboxane antagonist (L-655240) also inhibited PAF-induced increases in vascular permeability in heart, lung and duodenum. These results further confirm the role of PAF in inflammatory reactions and underline its complex mechanism of action. (Supported by the MRC)
798
MAY 1988 VOL. 35 NO. 5
ACTIVITY
OF
INDUCED
THE
NEW
AND
SPECIFIC
BRONCHOCONSTRICTION
PAF-ANTAGONISTS
AND
WEB
INTRATHORACIC
2170
AND
ACCUMULATION
STY
OF
2108
ON
PAF--
IN THE
PLATELETS
GUINEA-PIG. Heuer
H.,
Ingelheim
The be
Casasls-Stenzel KG,
WEB
selective
and
acether).
the
effect
of
these
and
intrathoracic
by
of
and
increase
STY
2108
a
in
and
in
was
induced
In
conclusion
by
x
iv.
an
iv.
both
pigs bolus
or
platelet-aggregation
of in
Boehringer
WEB study
the
2170 was
in
and
to paf-
STY
2108
undertaken
to
pig. Guinea pigs
mean
platelets
shown (paf,
bronchoconstric-
guinea
and
been
factor
paf-induced
in
arterial
the
blood
thoracic
2
bronchoconstriction,
thorax.
mg/kg at
the
with at
WEB
similar paf
at
paf-induced
PO.)
iv.
region
2170
of
or
STY
as
above,
or
were
2108
2170
STY
or
effects 2108
were
increase
of
disaggregated.
prevented
when
WEB these
paf-induced
platelets
2170
hypotension with
prevented
WEB
maximum
doses 100
WEB
Pretreatment
mg/kg
accumulated
hetrarepines
antagonists
recently
flow
induced the
0.005-0.5
When
of
has
present
platelets
min)
approach
pretreatment guinea
K.H.;
activating
on
labelled
in
intrathoracic iv.
constriction
ng/(kg
curative
Weber
counter.
manner. a
W.,
hetrazepines The
respiratory
Ill-Iridium
mg/kg
dose-dependent
gamma-radiation,
potent
30
the
hetrazepines of
of
gamma-radiation
(0.001-0.100
administered Perorsl
of
at
of
to
accumulation
gamma-radiation
paf
Stransky
platelet
effects.
new
recording
Accumulation
followed
a
for
of
led
sedative
prepared
in
variation of
tion
Infusion
antagonist
devoid
were
G.,
(FRG)
also
investigate
pressure.
Muacevic
2086 (JPET 241, 974-981, 1987) potent
structure are
J.,
Ingelheim/Rh.
hetrazepine a
which
was
D-6507
the
broncho-
bronchoconstriction
ng/kg. 2170
and
STY
2108
bronchoconstriction,
(orally
and
iv.)
hypotension
are and
vivo.
PAF IUCREASES VASCIJL~N PSSMEASILIl'I IA SSLSCTSD TISSUES: EVVSCT OF BN52021 AND L-655,240. Siroisl, P., Siroisl, M., Jancar*, S., Braquet3, P., Plantel, G.E. lDept. of Pharmacol., Fat. Med., Univ. Sherbrooke, QC, Canada. 2Univ. Sao Paulo, Brazil; 31nst. Henri Beaufour, Le Plessis Robinson, France. The effects of the potent inflammatory mediators, PAF, was studied on selected rat tissues (Wistar) using the extravasation of Evans blue dye (EB) as a marker. EB (20 mg/kg) was injected in the caudal vein together with increasing doses of PAF. The animals were killed and the dye was extracted in selected organs using formamide (4 ml/g wet tissue). Extravasation of EB varied markedly from one tissue to another and increased as a function of time (from 0 to 60 min). PAF (0.1, 1.0 and 5 ug/kg) caused increases in the vascular permeability of the pancreas and duodenum (respectively 12 and 4 folds respectively at the dose of 5 ug/kg). PAF did not affect significantly the vascular permeability of the heart, liver, spleen, kidneys and lungs (in toto). However, when the total lungs were dissected into trachea, upper bronchi, lower bronchi and parenchyma, it was found that PAF (5 ug/kg) increased the vascular permeability of the trachea (3 folds), upper bronchi (7 folds) and lower bronchi (5 folds) but decreased by 1.5 folds the vascular permeability of the parenchyma. The PAF antagonist BN 52021 (2 and 10 mg/kg) produced a dose-dependent inhibition of the PAF effects on the pancreas, duodenum and lung tissues. Maximum inhibition was achieved (95%) at the dose of 10 mg/kg. Interestingly, this antagonist given in the absence of PAF reduced the plasma extravasation below control levels. A thromboxane antagonist (L-655240) also inhibited PAF-induced increases in vascular permeability in heart, lung and duodenum. These results further confirm the role of PAF in inflammatory reactions and underline its complex mechanism of action. (Supported by the MRC)
798
MAY 1988 VOL. 35 NO. 5