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RELATIVE INFLUENCE OF ANAESTHETICS ON DEPRESSOR EFFECTS OF INTRAVENOUS PROSTAGLANDINS E2 AND A2
RELATIVE
INFLUENCE
EFFECTS
OF
OF
ANAESTHETICS
INTRAVENOUS
ON
DEPRESSOR
PROSTAGLANDINS
E2 AND
A2
Seigo FUJIMOTO Department o/ Pharmacology, Nagoya City University Medical School, Kawasnmi, Mi_uho-kit, Nagoya 467, Japan Accepted January 24, 1977 It is generally
accepted
that
vasodepressor
effect of prostaglandins
least in part, to their direct action on peripheral of i.v. PGs has been ranked rats (1).
In a preliminary
that of PGA, in ethanol
PGE'.-PGA,
the influence of certain anaesthetics Male Wistar rats, 240-260 urethane
(500 mg/kg),
(t-chloralose tinuous
rats.
After a polythene
of 3
tracheal
on the depressor
sodium
ethanol
recorder
for recording
a small amount
of absolute
concentration
was injected
i.v.
jugular
pressure
(B.P.).
and a-chloralose
ethanol
anaesthetized
rats of the pentobarbital bromide
The fall of the B.P. was expressed
at the dose used reduced
112
2.9 mmHg.
10 -, moles/kg
B.P. from
The depressor
was not varied
a polythene
and a polygraph
cannula
was used for
rats.
Heparin
anaesthetized
In some
(i.c.v.) at a volume The PGs kindly before use in
concentrations: sodium
group,
(8 mg, kg) were additionally
procedures
4
were inserted,
to a transducer
The venous
by a con
the anaesthesis.
and diluted by saline to give appropriate
were given to ensure that experimental
to 90
to maintain
cannulae
of
(220 mg,/kg) and
followed
were dissolved immediately
I.v. and i.c.v. injections of 0.1 ml of 0.3;,,, ethanol
groups,
hydrate
intracerebroventricularly
Co., Ltd., Osaka,
sulfate (8 mg/kg) and hexamethonium the venous cannula.
to determine
with i.p. injections
ethanol
of 10--, mole/ 10 ; 1 of the PGs was 3 °
In some
anaesthetized
0.1 ml plus a 0.1 ml wash) and their vehicles.
pentobarbital
by Ono Pharmaceutical
of 12.5
was connected
PGE, and PGA_ were administered
of 10 , l in urethane,
ethanol
mean arterial
of the PGs (PGs solution,
experiments,
provided
(40 mg/kg), chloral
and right external
inserted into the left carotid artery
effect
effect of i.v. PGE,., and PGA2.
at a rate of 0.1 ml/min
cannula
injections
in pentobarbital
The present work was an attempt
(60 mg/kg) and by oral administration
i.v. infusion
is due, at
activity of PGE„ was found to be greater than
g in body weight, were anaesthetized
pentobarbital
(PGs)
beds (1-3), and the depressor
-=-PGA,-,~PGE2
study, the depressor anaesthetized
vascular
both
(100 U) atropine
injected through
as mmHg. and 10 ;d of 3 °° ethanol,
had no effect on the B.P.
2.4 (S.E.) mmHg,
respectively,
Chloral hydrate
a mean value of all of other
effect of i.v. PGE•, at doses ranging 4 / 10-10 to
by anaesthetics
used (Fig. 1. left panel).
Although
the
Erc.. 1.
Effects of i.v. PGE2 (left panel) and PGA2 (middle
PGA (
(right panel)
in B. P, in urethane
), (t-chloralose
(
V
) and
(
panel)
) ethanol
pentobarbital
(
(
pentobarbital anaesthetized-atropine and hexamethonium Ordinate: changes in blood pressure (mmHg), abscissa: PGs ( log scale). and chloral hydrate difference
from
Significantly greater than (b, P 0.05) anaesthetized
the actisit~
of PGE...
depressor effect of i.s. PGA_,at doses less than 4
and i.c.v. PGE, •
), chloral
and
hydrate
) anaesthetized
and
pretreated ( A doses (moles,lkg)
) rats. of the
those in the urethane (a, R-0.05) groups. (c, P "0.05), significant
13,rs represent
S.E. in 20 animals.
10-" moles/kg was not affected significantly
by the anaesthetics other than pentobarbital, the activity of 4
10--, moles/ kg of PGA, in
the pentobarbital and u-chloralose anaesthetized rat vvas greater than that in the urethane (a, P __0.05)and chloral hydrate anaesthetized groups (b, P<';0.05) (middle panel). In the ethanol anaesthetized group. the effect of PGA., was greater than that in the chloral hydrate group but identical to that in urethane anaesthetized rats. According to Weeks ci al. (1) who compared the effect of i.v. PGE, and PGA.) at doses of 1.8 and 5.6 og%kgusing pentobarbital anaesthetized, pentoliniufn pretreated, vagotomized rats, PGA., was a more potent depressor than PGE=. The present work, however, showed that at the dose of 4
l0 _Rmoles/kg, PGA_ was less a depressor than PGE7 in chloral hy
drate, urethane, ethanol, c-chloralose and pentobarbital anaesthetized-atropine thonium pretreated groups.
In addition, at the dose of 4 , 10
and hexame
moles/kg, PGA,, was less
potent than PGE, in the chloral hydrate, urethane and ethanol anaesthetized rats and the depressor activity of this dose of PGA= was statistically identical to that of PGE9 in the other three groups.
Thus, the relative potency of i.v. PGE9 to i.v. PGA, as the vasode
pressor agent was altered either by the anaesthetics or their doses used. The combined pretreatment with cholinergic and ganglionic blocking agents did not vary the depressor potencies of i.v. PGE., and PGA ,indicating that these PGs might act 1) directly on the peripheral vasculature or 2) through reduction of an adrenergic activity to reduce I3.P., since it has been demonstrated that PGE can act to depress neurogenic release
of noradrenaline (4-6).
In the former case, the anaesthetics might act directly on the
vascular bed to change the response to PGA2.
In addition, unlike PGA which is invulnerable
to destruction by the lungs, PGE was rapidly removed on passage across the lung (7, 8). The data suggest the possibility that these anaesthetics
may influence rates
of the
removal of PGA2 from the lung, however, the metabolism of PGE_ is assumed to be too rapid to be influenced by the anaesthetics. PGE2, when injected i.c.v. at doses ranging from 4 ;1 l0-s to 4 >_10-' moles/kg, increased B.P. (right panel).
The effect was central in origin, since PGE2 injected i.v. at the same
doses as injected i.c.v., did not produce the same response.
On the other hand, the existence
of PGA2-sensitive depressor mechanisms in the brain could be also proposed, although the possibility should not be excluded that some of the i.c.v. administered PGA2 was transferred to the systemic circulation to decrease B.P., since the i.v. injection of PGA2 at the same doses as injected i.c.v. responded to the same or greater extent than did i.c.v. PGA.,. It is of interest that the effects of i.c.v. PGE, and PGA., on B.P. were not altered by central depressants such as these anaesthetics. Further experiments are underway to elucidate the mechanisms for the effects of the anaesthetics on the depressor action of i.v. PGA..,. REFERENCES 1) WEEKS, J.W., CHANDRASEKHAR, N. AND DUCHARIIF, D.W.: J. Pharm. Pharmacol. 21, 103 (1969); 2) HORTON, E.W. AND JONES,R.L.: Brit. J. Pharmacol. 37, 705 (1969): 3) BINDRA, J.S. ANDBINDRA, R.: Prog. Drug Res., Edited by JUCKER,E., Vol. 17, p. 410, Birkhauser Verlag, Basel and Stuttgart (1973); 4) HFDQVIST,P.: Acta physiol. scand. 75, 511 (1969); 5) HEDQVIST, P. ANDBRUNDIN,J.: Life Sci. 8 Part 1, 389 (1969); 6) HEDQvIST,P.: Brain Res. 62, 483 (1973); 7) FERREIRA,S.H. AND VANE, J.R.: Nature 216, 868 (1967); 8) MCGIFF, J.C., TERRAGNO, NA., STRAND,J.C., LEE, J.B., LONIGRO,A.J. AND Nc, K.K.F.: Nature 223, 742 (1969)
INFLUENCE
EFFECTS
OF
OF
ANAESTHETICS
INTRAVENOUS
ON
DEPRESSOR
PROSTAGLANDINS
E2 AND
A2
Seigo FUJIMOTO Department o/ Pharmacology, Nagoya City University Medical School, Kawasnmi, Mi_uho-kit, Nagoya 467, Japan Accepted January 24, 1977 It is generally
accepted
that
vasodepressor
effect of prostaglandins
least in part, to their direct action on peripheral of i.v. PGs has been ranked rats (1).
In a preliminary
that of PGA, in ethanol
PGE'.-PGA,
the influence of certain anaesthetics Male Wistar rats, 240-260 urethane
(500 mg/kg),
(t-chloralose tinuous
rats.
After a polythene
of 3
tracheal
on the depressor
sodium
ethanol
recorder
for recording
a small amount
of absolute
concentration
was injected
i.v.
jugular
pressure
(B.P.).
and a-chloralose
ethanol
anaesthetized
rats of the pentobarbital bromide
The fall of the B.P. was expressed
at the dose used reduced
112
2.9 mmHg.
10 -, moles/kg
B.P. from
The depressor
was not varied
a polythene
and a polygraph
cannula
was used for
rats.
Heparin
anaesthetized
In some
(i.c.v.) at a volume The PGs kindly before use in
concentrations: sodium
group,
(8 mg, kg) were additionally
procedures
4
were inserted,
to a transducer
The venous
by a con
the anaesthesis.
and diluted by saline to give appropriate
were given to ensure that experimental
to 90
to maintain
cannulae
of
(220 mg,/kg) and
followed
were dissolved immediately
I.v. and i.c.v. injections of 0.1 ml of 0.3;,,, ethanol
groups,
hydrate
intracerebroventricularly
Co., Ltd., Osaka,
sulfate (8 mg/kg) and hexamethonium the venous cannula.
to determine
with i.p. injections
ethanol
of 10--, mole/ 10 ; 1 of the PGs was 3 °
In some
anaesthetized
0.1 ml plus a 0.1 ml wash) and their vehicles.
pentobarbital
by Ono Pharmaceutical
of 12.5
was connected
PGE, and PGA_ were administered
of 10 , l in urethane,
ethanol
mean arterial
of the PGs (PGs solution,
experiments,
provided
(40 mg/kg), chloral
and right external
inserted into the left carotid artery
effect
effect of i.v. PGE,., and PGA2.
at a rate of 0.1 ml/min
cannula
injections
in pentobarbital
The present work was an attempt
(60 mg/kg) and by oral administration
i.v. infusion
is due, at
activity of PGE„ was found to be greater than
g in body weight, were anaesthetized
pentobarbital
(PGs)
beds (1-3), and the depressor
-=-PGA,-,~PGE2
study, the depressor anaesthetized
vascular
both
(100 U) atropine
injected through
as mmHg. and 10 ;d of 3 °° ethanol,
had no effect on the B.P.
2.4 (S.E.) mmHg,
respectively,
Chloral hydrate
a mean value of all of other
effect of i.v. PGE•, at doses ranging 4 / 10-10 to
by anaesthetics
used (Fig. 1. left panel).
Although
the
Erc.. 1.
Effects of i.v. PGE2 (left panel) and PGA2 (middle
PGA (
(right panel)
in B. P, in urethane
), (t-chloralose
(
V
) and
(
panel)
) ethanol
pentobarbital
(
(
pentobarbital anaesthetized-atropine and hexamethonium Ordinate: changes in blood pressure (mmHg), abscissa: PGs ( log scale). and chloral hydrate difference
from
Significantly greater than (b, P 0.05) anaesthetized
the actisit~
of PGE...
depressor effect of i.s. PGA_,at doses less than 4
and i.c.v. PGE, •
), chloral
and
hydrate
) anaesthetized
and
pretreated ( A doses (moles,lkg)
) rats. of the
those in the urethane (a, R-0.05) groups. (c, P "0.05), significant
13,rs represent
S.E. in 20 animals.
10-" moles/kg was not affected significantly
by the anaesthetics other than pentobarbital, the activity of 4
10--, moles/ kg of PGA, in
the pentobarbital and u-chloralose anaesthetized rat vvas greater than that in the urethane (a, P __0.05)and chloral hydrate anaesthetized groups (b, P<';0.05) (middle panel). In the ethanol anaesthetized group. the effect of PGA., was greater than that in the chloral hydrate group but identical to that in urethane anaesthetized rats. According to Weeks ci al. (1) who compared the effect of i.v. PGE, and PGA.) at doses of 1.8 and 5.6 og%kgusing pentobarbital anaesthetized, pentoliniufn pretreated, vagotomized rats, PGA., was a more potent depressor than PGE=. The present work, however, showed that at the dose of 4
l0 _Rmoles/kg, PGA_ was less a depressor than PGE7 in chloral hy
drate, urethane, ethanol, c-chloralose and pentobarbital anaesthetized-atropine thonium pretreated groups.
In addition, at the dose of 4 , 10
and hexame
moles/kg, PGA,, was less
potent than PGE, in the chloral hydrate, urethane and ethanol anaesthetized rats and the depressor activity of this dose of PGA= was statistically identical to that of PGE9 in the other three groups.
Thus, the relative potency of i.v. PGE9 to i.v. PGA, as the vasode
pressor agent was altered either by the anaesthetics or their doses used. The combined pretreatment with cholinergic and ganglionic blocking agents did not vary the depressor potencies of i.v. PGE., and PGA ,indicating that these PGs might act 1) directly on the peripheral vasculature or 2) through reduction of an adrenergic activity to reduce I3.P., since it has been demonstrated that PGE can act to depress neurogenic release
of noradrenaline (4-6).
In the former case, the anaesthetics might act directly on the
vascular bed to change the response to PGA2.
In addition, unlike PGA which is invulnerable
to destruction by the lungs, PGE was rapidly removed on passage across the lung (7, 8). The data suggest the possibility that these anaesthetics
may influence rates
of the
removal of PGA2 from the lung, however, the metabolism of PGE_ is assumed to be too rapid to be influenced by the anaesthetics. PGE2, when injected i.c.v. at doses ranging from 4 ;1 l0-s to 4 >_10-' moles/kg, increased B.P. (right panel).
The effect was central in origin, since PGE2 injected i.v. at the same
doses as injected i.c.v., did not produce the same response.
On the other hand, the existence
of PGA2-sensitive depressor mechanisms in the brain could be also proposed, although the possibility should not be excluded that some of the i.c.v. administered PGA2 was transferred to the systemic circulation to decrease B.P., since the i.v. injection of PGA2 at the same doses as injected i.c.v. responded to the same or greater extent than did i.c.v. PGA.,. It is of interest that the effects of i.c.v. PGE, and PGA., on B.P. were not altered by central depressants such as these anaesthetics. Further experiments are underway to elucidate the mechanisms for the effects of the anaesthetics on the depressor action of i.v. PGA..,. REFERENCES 1) WEEKS, J.W., CHANDRASEKHAR, N. AND DUCHARIIF, D.W.: J. Pharm. Pharmacol. 21, 103 (1969); 2) HORTON, E.W. AND JONES,R.L.: Brit. J. Pharmacol. 37, 705 (1969): 3) BINDRA, J.S. ANDBINDRA, R.: Prog. Drug Res., Edited by JUCKER,E., Vol. 17, p. 410, Birkhauser Verlag, Basel and Stuttgart (1973); 4) HFDQVIST,P.: Acta physiol. scand. 75, 511 (1969); 5) HEDQVIST, P. ANDBRUNDIN,J.: Life Sci. 8 Part 1, 389 (1969); 6) HEDQvIST,P.: Brain Res. 62, 483 (1973); 7) FERREIRA,S.H. AND VANE, J.R.: Nature 216, 868 (1967); 8) MCGIFF, J.C., TERRAGNO, NA., STRAND,J.C., LEE, J.B., LONIGRO,A.J. AND Nc, K.K.F.: Nature 223, 742 (1969)