EFFECTS IN
OF
DOGS
SOME
BILE
-WITH
Yoshikazu
ACIDS
ON
REFERENCE
YAMATAKE,
Shigeru
HEPATIC
BLOOD
BILIARY
EXCRETION
TO ISHIKAWA
FLOW
and Saizo YANAURA
Department of Pharmacology. Hoshi College of Pharmacy, Shinagawa-kn, Tokyo 14?, Japan Accepted January 9, 1976
The relationship
between effects of bile acids on hepatic blood flow and on bile formation
has not been extensively salts on arterial study,
studied (1, 2).
the effects
(UDC)
and chenodesoxycholic
(LTBF)
and on bile formation,
Male mongrel
blood
of dehydrocholic
acid (CDC)
on portal
flow, animals
probe (Nihon
Kohden
Femoral
vein via a cannula were performed
dissolved
using a pressure
every 5 min with a drop counter
via a tracheal
In the
cannula.
electromagnetic
flow
PBF (basal
(Shincorder
transducer.
or into a small branch
(25 mg/kg i.v.) anesthesia. Biliary outflow
(basal secretion:
CTE-201,
with NaOH
In Fig. 1, the results of systemic
aqueous
Drugs were of the portal experiments The common
from the cannula
1.5-2.0 ml/30 min). Animals
saline, 25 ml/30 min, during the experiment.
out at a room temp. of 23 'C and at a humidity
and neutralized
flow
pentobarbital
In the studies on biliary secretion,
and the cystic duct was ligated.
were infused with physiological were carried
artificially
thermocouples
i.v. injections,
injections.
on dogs under sodium pentobarbital
bile duct was cannulated
blood
acid
into the free end of the left medial lobe of liver to measure
vein for systemic
for intraportal
liver-tissue
the portal vein to measure
and a wire element of crossed
blood pressure was also recorded
given into the cephalic
In the present
ursodesoxycholic
with i.v. sodium
A non-cannulating
Co., Ltd.) was placed around
Shin-ei Co., Ltd.) was implanted
and
response.
is discussed.
were anesthetised
was opened by a midline incision.
was measured
(PBF)
and s.c. Urethane (1.2 g/kg) and ventilated
flow: 190-260 inljmin),
(DHC),
out that effects of bile
9-13 kg were fasted for 18 hr before experiments.
The abdomen
LTBF.
acid
and their relationship
dogs weighing
on hepatic
(15 mg/kg)
et al. (1) pointed
flow to the liver were not essential for a choleretic
we investigated
studies
Grodin,
of 65'),,/. ,Bile
All experiments acids used were
solution.
i.v. injections
of the bile acids in doses of 3, 10 and
SHORT
CO tt. 1U.VICATIOAS
Japan.
J. Pharmacol.
26, 274 (1976)
Fir,. I . Effects of systemic i.v. administrations of dehvdrocholic acid, ursodesox\cholic acid and chenodeso.xycholic acid on portal and liver-tissue blood flows, systemic blood pressure, and biliary now in mongrel dogs. C'holeretic activity is expressed as "„ increase in biliary flow. Administration of bile acids 30 mg kg, i.s. (0), 10 mg kg, i.v. ( ), 3 mg'kg, i.s. (A) was carried out at '0' time, respectisely. Each point represents the mean of six dogs in the experiments of hepatic circu lation, and of four dogs in those of hiliair excretion. Vertical bars indicate the S.E. of means at 10 and 30 min after administration. 30 mg/ kg are shown
(N
6 for each agent in the study on hepatic
in the study on biliary secretion). biliary outflow, dose-dependently. On the other
hand,
The three
bile acids used markedly
10 mg/kg of DHC and UDC, despite
different
responses
their strong
in both PBF and LTBF.
Among
CDC significantly
decrease.
produced
a significant
followed
by a hypertension
(N
and
produced
choleretic
decreased
caused
increased
by DHC, and increased responses
by
of hepatic and sys a transient hypotension,
UDC
of the bile acids in doses of 1 and 3
PBF and LTBF were not significantly into the portal
vein, suggesting CDC produced,
in both PBF and LTBF, accompanied
that
changed DHC
The effects of the bile acids on biliary excretion
of biliary outflow,
but did not significantly
of 30 mg; kg i.v. of all the bile acids used increased
after close
and UDC
have
on the other hand, a marked
with a rise in systemic blood pressure. were not related to their effects on PBF.
A dose of 10 mg/kg i.v. of the bile acids was sufficient to cause a dramatic volume
only a transi
an increase in LTBF following
injections
hardly any direct effect on hepatic circulation. decrease
potency,
A dose of
increase in PBF and caused an acute marked
of intraportal
6 for each agent). of DHC
of
in a dose of 30 mg; kg.
Fig. 2 shows the results
injections
in hepatic circulation.
the bile acids used, CDC caused the strongest
temic circulation.
mg/k
volume
A dose of 30 mgikg moderately
LTBF for at least 30 min, while PBF was transiently UDC.
increased
The order of potency was as follorss: DHC~.UDC>CDC.
they produced
ent and slight change
blood flow, and N-4
change either
increase in the
PBF or LTBF.
LTBF for more than 60 min.
A dose
An increase
SHORT
COMMUNICATIONS
Japan. J. Pharmacol. 26, 275 (1976)
FIG. 2. Effects of intra-portal administrations of dehydrocholic acid, ursodesoxycholic acid and chenodesoxycholicacid on portal blood flow (P.B.F.), liver-tissue blood flow (L.T.B.F.) and systemic blood pressure (B.P.) in mongrel dogs. Each point represents the mean of six dogs. Vertical bars indicate the S.E. of means at 10 min after administration. Other conditions as in Fig. 1. in LTBF has been also observed by an i.v. injection of DHC in doses of more than 50 mg/kg in rats (3). Taking into consideration the fact that with the bile acids used, a prolonged increase of the effect on LTBF was seen with only relatively high doses, and that these effects on LTBF tended to increase progressively, it appears that the increase in LTBF is not a trigger to initiate choleresis, but rather a consequence of choleretic actions of the bile acids.
Drapanas, et al. (4) have shown that perfusions of pyruvic or lactic acid into the
isolated pig liver resulted in a marked increase in hepatic blood flow.
Activation of me
tabolism in the liver and an enhanced bile formation, therefore, may increase hepatic blood flow via such metabolic substances.
Intraportal injections of all the bile acids used caused
no increase in either PBF or LTBF; in fact, a decrease was seen with CDC and such is attributed to a contraction of the portal vein and intrahepatic blood vessels. These findings suggest that there is no significant relationship between the effects of bile acids on biliary excretion and hepatic blood flow. REFERENCES 1) GRODINS, F.S., OSBORNE, S.L., Ivy, A.C. ANDGOLDMAN, L.: Am. J. Physiol. 132, 375 (1941); 2) MIZUTA,M. ANDSHINOYAMA, T.: Acta hepatol.japan. 12, 416 (1971)(in Japanese); 3) KITA GAWA,H. ANDYANO,H.: Pharmacometrics, 7, 1315 (1973) (in Japanese); 4) DRAPANAS, T., ZEMEL,R., ANDVANG,J.O.: Ann. Surg. 164, 522 (1966)
OF
DOGS
SOME
BILE
-WITH
Yoshikazu
ACIDS
ON
REFERENCE
YAMATAKE,
Shigeru
HEPATIC
BLOOD
BILIARY
EXCRETION
TO ISHIKAWA
FLOW
and Saizo YANAURA
Department of Pharmacology. Hoshi College of Pharmacy, Shinagawa-kn, Tokyo 14?, Japan Accepted January 9, 1976
The relationship
between effects of bile acids on hepatic blood flow and on bile formation
has not been extensively salts on arterial study,
studied (1, 2).
the effects
(UDC)
and chenodesoxycholic
(LTBF)
and on bile formation,
Male mongrel
blood
of dehydrocholic
acid (CDC)
on portal
flow, animals
probe (Nihon
Kohden
Femoral
vein via a cannula were performed
dissolved
using a pressure
every 5 min with a drop counter
via a tracheal
In the
cannula.
electromagnetic
flow
PBF (basal
(Shincorder
transducer.
or into a small branch
(25 mg/kg i.v.) anesthesia. Biliary outflow
(basal secretion:
CTE-201,
with NaOH
In Fig. 1, the results of systemic
aqueous
Drugs were of the portal experiments The common
from the cannula
1.5-2.0 ml/30 min). Animals
saline, 25 ml/30 min, during the experiment.
out at a room temp. of 23 'C and at a humidity
and neutralized
flow
pentobarbital
In the studies on biliary secretion,
and the cystic duct was ligated.
were infused with physiological were carried
artificially
thermocouples
i.v. injections,
injections.
on dogs under sodium pentobarbital
bile duct was cannulated
blood
acid
into the free end of the left medial lobe of liver to measure
vein for systemic
for intraportal
liver-tissue
the portal vein to measure
and a wire element of crossed
blood pressure was also recorded
given into the cephalic
In the present
ursodesoxycholic
with i.v. sodium
A non-cannulating
Co., Ltd.) was placed around
Shin-ei Co., Ltd.) was implanted
and
response.
is discussed.
were anesthetised
was opened by a midline incision.
was measured
(PBF)
and s.c. Urethane (1.2 g/kg) and ventilated
flow: 190-260 inljmin),
(DHC),
out that effects of bile
9-13 kg were fasted for 18 hr before experiments.
The abdomen
LTBF.
acid
and their relationship
dogs weighing
on hepatic
(15 mg/kg)
et al. (1) pointed
flow to the liver were not essential for a choleretic
we investigated
studies
Grodin,
of 65'),,/. ,Bile
All experiments acids used were
solution.
i.v. injections
of the bile acids in doses of 3, 10 and
SHORT
CO tt. 1U.VICATIOAS
Japan.
J. Pharmacol.
26, 274 (1976)
Fir,. I . Effects of systemic i.v. administrations of dehvdrocholic acid, ursodesox\cholic acid and chenodeso.xycholic acid on portal and liver-tissue blood flows, systemic blood pressure, and biliary now in mongrel dogs. C'holeretic activity is expressed as "„ increase in biliary flow. Administration of bile acids 30 mg kg, i.s. (0), 10 mg kg, i.v. ( ), 3 mg'kg, i.s. (A) was carried out at '0' time, respectisely. Each point represents the mean of six dogs in the experiments of hepatic circu lation, and of four dogs in those of hiliair excretion. Vertical bars indicate the S.E. of means at 10 and 30 min after administration. 30 mg/ kg are shown
(N
6 for each agent in the study on hepatic
in the study on biliary secretion). biliary outflow, dose-dependently. On the other
hand,
The three
bile acids used markedly
10 mg/kg of DHC and UDC, despite
different
responses
their strong
in both PBF and LTBF.
Among
CDC significantly
decrease.
produced
a significant
followed
by a hypertension
(N
and
produced
choleretic
decreased
caused
increased
by DHC, and increased responses
by
of hepatic and sys a transient hypotension,
UDC
of the bile acids in doses of 1 and 3
PBF and LTBF were not significantly into the portal
vein, suggesting CDC produced,
in both PBF and LTBF, accompanied
that
changed DHC
The effects of the bile acids on biliary excretion
of biliary outflow,
but did not significantly
of 30 mg; kg i.v. of all the bile acids used increased
after close
and UDC
have
on the other hand, a marked
with a rise in systemic blood pressure. were not related to their effects on PBF.
A dose of 10 mg/kg i.v. of the bile acids was sufficient to cause a dramatic volume
only a transi
an increase in LTBF following
injections
hardly any direct effect on hepatic circulation. decrease
potency,
A dose of
increase in PBF and caused an acute marked
of intraportal
6 for each agent). of DHC
of
in a dose of 30 mg; kg.
Fig. 2 shows the results
injections
in hepatic circulation.
the bile acids used, CDC caused the strongest
temic circulation.
mg/k
volume
A dose of 30 mgikg moderately
LTBF for at least 30 min, while PBF was transiently UDC.
increased
The order of potency was as follorss: DHC~.UDC>CDC.
they produced
ent and slight change
blood flow, and N-4
change either
increase in the
PBF or LTBF.
LTBF for more than 60 min.
A dose
An increase
SHORT
COMMUNICATIONS
Japan. J. Pharmacol. 26, 275 (1976)
FIG. 2. Effects of intra-portal administrations of dehydrocholic acid, ursodesoxycholic acid and chenodesoxycholicacid on portal blood flow (P.B.F.), liver-tissue blood flow (L.T.B.F.) and systemic blood pressure (B.P.) in mongrel dogs. Each point represents the mean of six dogs. Vertical bars indicate the S.E. of means at 10 min after administration. Other conditions as in Fig. 1. in LTBF has been also observed by an i.v. injection of DHC in doses of more than 50 mg/kg in rats (3). Taking into consideration the fact that with the bile acids used, a prolonged increase of the effect on LTBF was seen with only relatively high doses, and that these effects on LTBF tended to increase progressively, it appears that the increase in LTBF is not a trigger to initiate choleresis, but rather a consequence of choleretic actions of the bile acids.
Drapanas, et al. (4) have shown that perfusions of pyruvic or lactic acid into the
isolated pig liver resulted in a marked increase in hepatic blood flow.
Activation of me
tabolism in the liver and an enhanced bile formation, therefore, may increase hepatic blood flow via such metabolic substances.
Intraportal injections of all the bile acids used caused
no increase in either PBF or LTBF; in fact, a decrease was seen with CDC and such is attributed to a contraction of the portal vein and intrahepatic blood vessels. These findings suggest that there is no significant relationship between the effects of bile acids on biliary excretion and hepatic blood flow. REFERENCES 1) GRODINS, F.S., OSBORNE, S.L., Ivy, A.C. ANDGOLDMAN, L.: Am. J. Physiol. 132, 375 (1941); 2) MIZUTA,M. ANDSHINOYAMA, T.: Acta hepatol.japan. 12, 416 (1971)(in Japanese); 3) KITA GAWA,H. ANDYANO,H.: Pharmacometrics, 7, 1315 (1973) (in Japanese); 4) DRAPANAS, T., ZEMEL,R., ANDVANG,J.O.: Ann. Surg. 164, 522 (1966)
