Tohoku
J.
exp.
Falsely by
Med.,
1979,
High
127, 63-69
Urinary
Catecholamines
Induced
Labetalol KIYOSHI KOBAYASHI,YUKIO MIURA, HIROSHI TOMIOKA.A, HISAICHISAKUMA,MAKI ADACHI, KEISHI ABE and KAORU YOSHINAGA The Second Department of Internal University School of Medicine, 980
Medicine,
Tohoku
KOBAYASHI, K., MIURA, Y., TOMIOKA,H., SAKUMA,H., ADACHI, M., ABE, K. and YOSHINAGA,K. Falsely High Urinary Catecholamines Induced by Labetalol. Tohoku J. exp. Med., 1979, 127 (1), 63-69 A preoperative patient with pheochromocytoma was satisfactorily treated with oral labetalol, while a con spicuous increase in urinary output of catecholamines (CA) and of vanillylmandelic acid (VMA) was observed after labetalol therapy. Exaggerated increases in urinary CA and in VMA were also confirmed in normal volunteers immediately after oral labetalol. These effects of labetalol on urinary CA and VMA, however, were proved to be largely due to the interference with the usual photometries rather than due to its stimulation of CA release. Therefore, it should be emphasized that clinical evaluations of CA and its metabolites must be performed before labetalol therapy to avoid an erroneous diagnosis of pheochromocytoma. labetalol; catecholamine; vanillylmandelic acid; pheochromocytoma
A newly
synthesized
competitive animals
and
action
in be
of
(Farmer
et
1972;
of
labetalol, sites
Richards
provide
a
clinical
types
agent,
and ƒÀ-adrenoceptor al.
to
Extensive
various
blocking
both ƒ¿
expected
medicine.
treatment
at
man
would
clinical
adrenergic
antagonist
et
potent
trials
unique
in
the
1974).
This
antihypertensive
have
hypertension
al.
is
proved
(Frick
being
new
of
in
usefulness
Porsti
a
profile
agent
its
and
in
experimental
the
in
1976;
Rosei
in
treatment
the et
al.
1976). The
present
report
pheochromocytoma.
A
labetalol,
while
(VMA),
measured
treatment.
An
persons. be
due
This to
concerns
the
urinary by
our
usual
had
methods, CA
on
with
also
and
of
remarkably
CA
after
output,
photometries
managed
widely
with acid
after
labetalol however,
used
of
vanillylmandelic
elevated
confirmed
urinary
the
the
satisfactorily
(CA) was
was
labetalol
been
catecholamines
labetalol
interference
with
patient of
of of
experiences
preoperative output
elevation effect
our
was for
labetalol in
normal
proved
CA
and
to VMA
assays.
SUBJECTS A patient The
case
of
Received
with
pheochromocytoma
pheochromocytoma
for publication,
AND and
was
April
five
a 26-year-old
13,
1978. 63
METHODS volunteers woman
were who
the was
subjects admitted
in this to
study. Tohoku
64
K. Kobayashi
University The
Hospital
blood
Laboratory
proteinuria
up
were
aortography
histologic Effects
of
during
the
oral
on
perature
and
for 6
N at
NE
4•Ž
and
(Miura
et
for
assay
the
in
1.0
al.
ml
1977).
of
External
0.1
M
were
prepared
through and
the
and
as
and
sample
of
Renzini
et
50-60
min
after
measured
on
a
7•~40
Urinary
in
at
with
absorbance -24)
fluorescence
mm)
VMA of
quartz
in
the
centrifuging activity determined
0.3 of
ml
0.1
M
faded
of
CA
sucrose
of
0 .05
an
for
with
the
was
the
using
mm)
an
homogenate
at was
aliquot of
the
procedure
developed
the
the
a
fresh
Axelrod
room
of the
Pisano
335
et
(1962)
in
452/490
al . (1962)
nm
same
at the
nm
and
800•~g same
the
, model
.
method
which
tissue
then
cuvettes
(Beckman
supernatant tumor
was
.
spectrophotometer
by
.0),
temperature
and
sensitivity
7
prepared
quartz
(410/490
wavelength
the
was
in
passed (pH
mixture
IV)
amines
solution
reaction
type
by
procedures.
without
at
used
oxidized
buffer
left
assay
were
THI
specimen
the
and
measured of
the
of
CA
directly
acid
was of
tem
a fortnight.
plasma
blank
urine
(PNMT) by
to
a
room
specimens
perchloric
reported
phenylethanolamine-N-methyltransferase by
M
, MPF
on
was
modification
was
a reagent
mixture
method
for
according
system
studied
containing
within
urine
wavelengths
measured
tumor
of
every
(Hitachi
its
assays
at
our
eluate
fluorescence
slit
jar
tetraborate-HCI
oxidized
adequate
glass urine)
devised
sodium
excitation/emission of
of
and
blank
The
a
with
ml
7 .0)
The and
serially VMA
performed
primarily
(pH
were and
24-hr
alumina-column
0.3
The
(10•~10•~40
urinary M
of
(1970).
mixture
content of
ml
in for
was
amine)
region. surgery
pheochromocytoma.
CA
separately
1.0-10
of
of each
oxidation.
determined
cuvettes
assay
al.
sets
reaction
Catecholamine
ng
A
selection
was
the
ml)
spectrophotometer
two the
1.0
eluates.
for
uncorrected)
was
nitrogen,
years.
ml
assay
buffer
(25
20
.
Abdominal
by
CA
collected
and
specimens, 0.3
containing
(20-25•Ž)
(7•~
method
E
medium
column
oxidized
plasma
34
urea
adrenal
of
urinary
determined
which
blood
nature
973
mg/day)
classification)
normal.
removed
to
were
3.0-7.0
Barker's
right
admission. (NE,
remained
on
perspiration. on
clearance,
labetalol
Every
were
and
the
benign
28
urine
tetraborate-HC1
NE
in
from
assay.
(usually
sodium
the
alumina
of
aliquot
of in
the
normal,
and of
assays
timed
method
Instead an
standards
for
(E)
(THI)
and
VMA
ml
mg/day;
successfully the
and
beats/min
norepinephrine
sugar
symptoms
aged
epinephrine
trihydroxyindole
was
60
urine
creatinine
located
volunteers
was
Wagner
blood
origin,
influence
until
of
tumor
clinical
and
(2
Keith,
fasting
An
CA
HCl
(9-23
of
confirmed
both
healthy
stored
Urinary
in
palpitation
rate
24-hr
of VMA
levels
and
period.
five
of
the
examination
specimens
amount
but
episodic
pulse of
(grade ‡V
walnut-sized
labetalol
in
and
extra-adrenal
preoperative
Urine
the
g,
biochemical
examined
small
a
21
or
65 ƒÊg/day)
cholesterol
depicted
the
elevation
observed, serum
weighing
also
to
with and
marked
retinopathy
electrolytes,
tumor,
hypertension mmHg
revealed
hypertensive
serum
of
194/124
normal,
Advanced
by
was
studies
1730 ƒÊg/day;
and
because
pressure
et al.
as
was
described
obtained at
preparation
4•Ž
by .
The was
.
RESULTS Before the treatment, the patient showed remarkably fluctuating hypertension and complained of a variety of episodic symptoms including headache , palpitation, substernal discomfort, excessive sweating and so forth . Fig. 1 illustrates the circulatory effects in the patient following oral administration of several adreno ceptor antagonists. The patient was initially treated with a combination of phenoxybenzamine (POB, 20-60 mg daily) plus a small dose of propranolol (PRP , 20 mg daily). During these medications , neither clinical symptom nor hyperten sion had been ameliorated. Then , oral labetalol was tried at an initial dose of 300 mg daily in addition to the above medications . These combinations rendered her blood pressure significantly lowered and the fluctuation reduced , relieving the patient from any kind of episodic symptoms . A dose related reduction
Labetalol
Fig.
1.
Circulatory
patient upper
effects
and Catecholamine
of various
combinations
with pheochromocytoma. Daily frame. POB, phenoxybenzamine;
65
of
adrenoceptor
antagonists
in a
oral dosage of each agent is indicated PRP, propranolol; LAB, labetalol.
in the
TABLE 1.
Effect of various adrenoceptor antagonists on urinary catecholamines and vanillylmandelic acid (VMA) in a patient with pheoehromocytoma
Values LAB,
of
blood
patient
indicate
pressure was
surgical
was
of
mg/g
was
detected
in
the
Changes
of
mean
the
also
satisfactorily
removal
(9.02
were
mean•}S.E.M.
POB,
phenoxybenzamine;
PRP,
propranolol.
labetalol.
wet
summarized pre-treatment
obtained
by
managed
by
increment repeated
pheochromocytoma.
tissue)
rather
than
(0.49
labetalol
450
intravenous
The E
of
tumor No
and
VMA
daily.
labetalol
contained
mg/g).
mg
The
during
the
predominantly
significant
activity
NE of
PNMT
tumor. levels
in
Table
period
of 1. were
urinary
CA
Twenty-four 1080•}170 ƒÊg
hour
induced
urinary
(mean•}S.E.M.),
NE,
by E trace
various and
VMA and
therapy during 14.3•}1.8
66
K. Kobayashi
mg,
respectively.
and
PRP.
These But
Particularly, over
urinary
Fig.
the
2.
Changes
(VMA) area
of
of
before
urinary
urinary
increased after
50
limit
of
mg
of
CA
in
CA
assay,
of
HCl
410/490
and
but
main
peak
through measured,
of
E
whole which
were and
oral
(NE)
labetalol
in
POB
labetalol high
mg
of
.
levels
labetalol
,
CA.
and
vanillylmandelic
normal
in
were
0.924•}0.175 ƒÊg/hr
VMA
nm
,
respectively.
.15 ƒÊg/hr E
acid
persons.
was
five
Stippled
normal
volunteers
respective
73±19 ƒÊg/hr
distinctly
at
(mean•}S.E.M.),
Those and
with
as
.
This
nm,
in
values immediately
higher
calculated
the
.
assay
a
as
24
however
.
On
3).
ng
out
peak
at
than
of of
NE
, did not excitation/emission
other
of
420/490 10
CA and
at
the
upper
excitation
(Richards
et
alkaline
the
When
procedure
located
ammonium
carried
with (Fig
peak reported
fluorescence, was
respectively
of
a
previously
intensified
fluorescence
was
of
oral
extremely 450
determined
fluorescence
315/420
fluorimetry
course
to after
that
with
after
. 2).
fluorescence
CA
trace
increase
than
treatment
observed
norepinephrine of
Urinary
much
452/490
,
9.66•}4
medium the
significant
the
,
native of
acidic
to
mg
73•}19 ƒÊg/hr
(Fig
was
when
small
VMA
NE
showed
fluorescence
50
after
was
from
less
(E)
labetalol.
wavelength
than
and
range
Labetalol
This
oral
CA
increased
much
(•ü)
4.52•}2.58 ƒÊg/hr,
normal
emission
after
significantly
tended
was
and
to
urinary
range.
urinary
0.567•}0.067 ƒÊg/hr
vary
of
epinephrine
and
normal
position,
not
was VMA
increase
(•œ)
indicates
When supine
fraction
Urinary rate
did
elevation
E
500 ƒÊg/day.
although
values
a marked
et al.
hand,
mg
medium interfere
labetalol
nm
which
of
labetalol
, a considerable 56 ng of E
has is similar was
Further,
. 1977). rather
with wavelength
fluorescence .
and
al
the
another to
the
treated was labetalol
Labetalol
Fig.
3.
Excitation
mg
of
each
spectra
labetalol agent
in
1.0
conditions:
Energy
filter
Absorption
M
of
norepinephrine,
blank.
al.
(b)
These
sodium
et
spectra
The
Ex.
slit
10
ng
were
tetraborate-HCl 1977).
mode,
Sample
mg
2
buffer
nm,
Em.
and
of
(pH were
slit
epinephrine,
(c)
after
processing
obtained
fluorimetries
sensitivity•~10
of
only
each
oxidized
albetalol
spectra
15
(a)
and
agent
labetalol
(c)
via
a
14
nm,
Measuring
through
complete
from
the
whole
mg
plus
blank.
7.0)
through
carried Em.
voltage
a
out W.L. of
vanillylmandelic These
procedure
procedure
indistinguishable
passed
15
nonoxidized
through
compounds
spectrum
of
ng
67
0.5
THI
at
the
490
the
nm,
recorder
mV.
4.
its
35,
10
faded
1.0
following
processing
mg
of (Miura
labetalol
tion
ml
(a)
its
procedure
10
and
(d)
oxidation
Fluorescence
Fig.
of
and
and Catecholamine
of
Pisano
that
of
procedure
of
of
Pisano
et
al.
vanillin VMA
acid
spectra
were et
(1962) (Fig.
assay
al.
10 ƒÊg,
obtained (1962).
showed 4).
were
(b) after
an
absorp
Fifteen
mg
calculated
of
as
0.16
VMA.
DISCUSSION The
present
labetalol tion
is
study
useful
therapy
in
of ƒ¿-
be
achieved
the
treatment
of
and ƒÀ-antagonists
pheochromocytoma, must
confirmed the
Ross prior
to
et
al.
previous
has (1967)
the ƒÀ-adrenoceptor
report
(Rosei
pheochromocytoma. been
established
emphasized blockade,
that
et
al.
Although in blockade otherwise
the
1976) a
that
combina
management
of
of ƒ¿-adrenoceptor hypertension
might
68
K. Kobayashi
et al.
be aggravated. Viewed from their opinion, labetalol may not be suitable in the beginning of the treatment. However, administration of a-antagonist elicits severe tachycardia in a majority of patients so that simultaneousprescription of j-antagonist is often required. These clinical experiencessupport the opinion that labetalol is not inconvenient, but adequate from the beginning of the management of pheo chromocytoma. The minimal effect of labetalol on the central nervous function (Martinet al. 1976)is an additional advantage, since larger doses are required quite often in these patients. A conspicuousincrease in urinary CA and VMA was observed after the administration of labetalol in our patient with pheochromocytoma. These increments might be due to an enhancementof CArelease from the chromaffintissues or due to the interference by a number of noncatecholamine fluorescencein the assay system. Blakeley and Summers (1977) reported that labetalol induces an enhancement of CA release from cat spleen by blocking neuronal uptake of NE . This mechanism may partly account for elevation of urinary CA and VMA. However, this explanation seems incompatible with the fact that a remarkable increase in both NE and E was observed after oral labetalol, while administration of both POB and PRP did not influence on urinary CA output in this patient. Exaggerated increase in E fraction after labetalol is also quite contradictory with the fact that NE fraction was exclusivelydetected in the tumor , and both E fraction and PNMT were negligible. These findings indicate that an elevation of values calculated as CA and VMA might be due largely to the biochemical properties of labetalol rather than its stimulation of CA release. This study disclosedthat labetalol, when processed through a complete course of CA or VMAassay, emits a considerablefluorescenceand has an absorbance in the similar areas of the spectrum as those of CA and VMA, respectively. It is beyond doubt that these biochemicalnatures of labetalol cause falsely higher values of CA and/or VMA. However, the interference with the assay by labetalol seems too weak to explain the great increase in values of CA, when the rate of interference is calculated on the basis of the data that 10 mg of labetalol are miscalculated as 24 ng of NE and 56 ng of E . Besides, unmetabolized labetalol in urine has been shownto account for 10% or less of the oral dose (Martin et al. 1976). From these reasons, it is most likely that a major portion of the interference is caused by urinary metabolites of labetalol rather than labetalol itself , although these fl uorescent metabolites remain speculative. Marked increase in urinary CA was also observed in normal subjects i mmediately after labetalol (Fig. 2). This findingis in line with recent correspon dence by Harris and Richards (1977), suggesting that the hypertensive patients under labetalol therapy may be erroneously diagnosed as pheochromocytoma. Therefore, it should be emphasized that clinical eval uations of CA and its metabolites have to be done prior to the treatment with l abetalol.
Labetalol
and
Catecholamine
69
Acknowledgments This study was supported by Grant-in-Aid for Scientific Research (Nos. 177193, 157228, 257245) and for Cancer Special Research from the Ministry of Education, Science and Culture, Japan. References 1)
Axelrod,
J.
ferase. 2)
(1962)
J.
biol.
Blakeley,
A.G.H.
adrenergic 3)
4)
&
L.B.,
and ƒÀ-adrenoceptors. M.H.
Kennedy,
& in
Harris,
R.J.
in
both ƒ¿-
the
I.,
Porsti,
&
& J.
med.
D.A.
alpha
of
labetalol
Pharmacol.,
Marshall,
J.,
(1977)
J.
Pharmacol.,
Combined
Brit.
effects
Brit.
G.P.
(1976)
Richards,
phenylethanolamine-N-methyltrans
The
speen.
Brit. P.
of
(1977)
cat
Levy,
hypertension.
D.
properties
1657-1660.
Summers,
Farmer,
Frick,
and
237,
transmission
labetalol 5)
Purification Chem.,
R.J.
(1972)
45,
660-675.
and
(AH 59,
5158)
on
the
which
blocks
643-650.
A
drug
beta-adrenoceptor
blockade
with
1,.1046-1048.
Labetalol
and
catecholamine.
Brit.
med.
J.,
2,
by
animal
1673. 6)
Martin,
L.E.,
and 7)
man.
Miura,
Y.,
via
an
Lab. 8)
Hopkins,
Brit.
J.
Campese,
Med.,
Crout,
V.,
Brunori,
method
for
the
10)
chirp.
D.A.,
Martin,
12)
L.E.
effects
of
Rosei,
E.A.,
Trust,
P.M.
Ross,
med.
J.,
J.
(1977)
Brown, (1976)
Prichard,
Preoperative
and 1,
Clin. Valori,
Meijer,
D.
(1977)
with
191-198.
D.
(1962)
chim.
Acta,
C.
of
E.P., a
an
labetalol
Plasma
catecholamines
enzymatic
method.
(1970)
Determination 7, A
noradrenalin
J.
clin.
of
3-methoxy-4
285-291.
sensitive and
clin.
Stephens,
combined ƒ¿-
and
specific
adrenalin
in
fluorimetric
human
plasma.
J.
J.J.,
Fraser,
clin.
B.N.C., operative
R.E.,
of Brit.
Maconochie,
J.
Kaufman, management
J.G. antagonists,
Hopkins,
plasma
Pharmacol., R.,
Treatment
&
(1974) in
The healthy
505-510.
Bland, between
Europ.
labetalol.
1,
J.G.,
Relatioship
M.D.B. and ƒÀ-adrenoceptors
Pharmacol.,
Maconochie,
with
E.J.,
&
of
695-710.
587-594.
5158,
labetalol.
hypertension 13)
AH
Brit.
Richards,
&
Woodings,
oral
volunteers. 11)
Metabolism 3,
comparison
Abraham,
urine.
C.A.
39,
D.A., of
& in
determination
Acta,
Richards, effects
(1976)
Suppl. V.
assay:
J.R. acid
Renzini,
Clin.
R. 3,
421-427.
- hydroxymandelic 9)
Bland,
DeQuattro,
fluorimetric
89, J.,
&
Pharmcol., V.,
improved
Pisano,
R.
clin.
11,
Lever,
A.F.,
Pharmacol., L.,
Robertson, of
Woodings,
patients
and
E.P.
&
pharmacological
85-90. Morton,
pheochromocytoma clin.
R.,
concentrations
J.J.,
Robertson,
and 3,
Suppl.
A.I.G. with
clonidine 3, &
J.I.S.
&
withdrawal
809-815.
Harries,
pheochromocytoma.
B.J.
(1967) Brit.
J.
exp.
Falsely by
Med.,
1979,
High
127, 63-69
Urinary
Catecholamines
Induced
Labetalol KIYOSHI KOBAYASHI,YUKIO MIURA, HIROSHI TOMIOKA.A, HISAICHISAKUMA,MAKI ADACHI, KEISHI ABE and KAORU YOSHINAGA The Second Department of Internal University School of Medicine, 980
Medicine,
Tohoku
KOBAYASHI, K., MIURA, Y., TOMIOKA,H., SAKUMA,H., ADACHI, M., ABE, K. and YOSHINAGA,K. Falsely High Urinary Catecholamines Induced by Labetalol. Tohoku J. exp. Med., 1979, 127 (1), 63-69 A preoperative patient with pheochromocytoma was satisfactorily treated with oral labetalol, while a con spicuous increase in urinary output of catecholamines (CA) and of vanillylmandelic acid (VMA) was observed after labetalol therapy. Exaggerated increases in urinary CA and in VMA were also confirmed in normal volunteers immediately after oral labetalol. These effects of labetalol on urinary CA and VMA, however, were proved to be largely due to the interference with the usual photometries rather than due to its stimulation of CA release. Therefore, it should be emphasized that clinical evaluations of CA and its metabolites must be performed before labetalol therapy to avoid an erroneous diagnosis of pheochromocytoma. labetalol; catecholamine; vanillylmandelic acid; pheochromocytoma
A newly
synthesized
competitive animals
and
action
in be
of
(Farmer
et
1972;
of
labetalol, sites
Richards
provide
a
clinical
types
agent,
and ƒÀ-adrenoceptor al.
to
Extensive
various
blocking
both ƒ¿
expected
medicine.
treatment
at
man
would
clinical
adrenergic
antagonist
et
potent
trials
unique
in
the
1974).
This
antihypertensive
have
hypertension
al.
is
proved
(Frick
being
new
of
in
usefulness
Porsti
a
profile
agent
its
and
in
experimental
the
in
1976;
Rosei
in
treatment
the et
al.
1976). The
present
report
pheochromocytoma.
A
labetalol,
while
(VMA),
measured
treatment.
An
persons. be
due
This to
concerns
the
urinary by
our
usual
had
methods, CA
on
with
also
and
of
remarkably
CA
after
output,
photometries
managed
widely
with acid
after
labetalol however,
used
of
vanillylmandelic
elevated
confirmed
urinary
the
the
satisfactorily
(CA) was
was
labetalol
been
catecholamines
labetalol
interference
with
patient of
of of
experiences
preoperative output
elevation effect
our
was for
labetalol in
normal
proved
CA
and
to VMA
assays.
SUBJECTS A patient The
case
of
Received
with
pheochromocytoma
pheochromocytoma
for publication,
AND and
was
April
five
a 26-year-old
13,
1978. 63
METHODS volunteers woman
were who
the was
subjects admitted
in this to
study. Tohoku
64
K. Kobayashi
University The
Hospital
blood
Laboratory
proteinuria
up
were
aortography
histologic Effects
of
during
the
oral
on
perature
and
for 6
N at
NE
4•Ž
and
(Miura
et
for
assay
the
in
1.0
al.
ml
1977).
of
External
0.1
M
were
prepared
through and
the
and
as
and
sample
of
Renzini
et
50-60
min
after
measured
on
a
7•~40
Urinary
in
at
with
absorbance -24)
fluorescence
mm)
VMA of
quartz
in
the
centrifuging activity determined
0.3 of
ml
0.1
M
faded
of
CA
sucrose
of
0 .05
an
for
with
the
was
the
using
mm)
an
homogenate
at was
aliquot of
the
procedure
developed
the
the
a
fresh
Axelrod
room
of the
Pisano
335
et
(1962)
in
452/490
al . (1962)
nm
same
at the
nm
and
800•~g same
the
, model
.
method
which
tissue
then
cuvettes
(Beckman
supernatant tumor
was
.
spectrophotometer
by
.0),
temperature
and
sensitivity
7
prepared
quartz
(410/490
wavelength
the
was
in
passed (pH
mixture
IV)
amines
solution
reaction
type
by
procedures.
without
at
used
oxidized
buffer
left
assay
were
THI
specimen
the
and
measured of
the
of
CA
directly
acid
was of
tem
a fortnight.
plasma
blank
urine
(PNMT) by
to
a
room
specimens
perchloric
reported
phenylethanolamine-N-methyltransferase by
M
, MPF
on
was
modification
was
a reagent
mixture
method
for
according
system
studied
containing
within
urine
wavelengths
measured
tumor
of
every
(Hitachi
its
assays
at
our
eluate
fluorescence
slit
jar
tetraborate-HCI
oxidized
adequate
glass urine)
devised
sodium
excitation/emission of
of
and
blank
The
a
with
ml
7 .0)
The and
serially VMA
performed
primarily
(pH
were and
24-hr
alumina-column
0.3
The
(10•~10•~40
urinary M
of
(1970).
mixture
content of
ml
in for
was
amine)
region. surgery
pheochromocytoma.
CA
separately
1.0-10
of
of each
oxidation.
determined
cuvettes
assay
al.
sets
reaction
Catecholamine
ng
A
selection
was
the
ml)
spectrophotometer
two the
1.0
eluates.
for
uncorrected)
was
nitrogen,
years.
ml
assay
buffer
(25
20
.
Abdominal
by
CA
collected
and
specimens, 0.3
containing
(20-25•Ž)
(7•~
method
E
medium
column
oxidized
plasma
34
urea
adrenal
of
urinary
determined
which
blood
nature
973
mg/day)
classification)
normal.
removed
to
were
3.0-7.0
Barker's
right
admission. (NE,
remained
on
perspiration. on
clearance,
labetalol
Every
were
and
the
benign
28
urine
tetraborate-HC1
NE
in
from
assay.
(usually
sodium
the
alumina
of
aliquot
of in
the
normal,
and of
assays
timed
method
Instead an
standards
for
(E)
(THI)
and
VMA
ml
mg/day;
successfully the
and
beats/min
norepinephrine
sugar
symptoms
aged
epinephrine
trihydroxyindole
was
60
urine
creatinine
located
volunteers
was
Wagner
blood
origin,
influence
until
of
tumor
clinical
and
(2
Keith,
fasting
An
CA
HCl
(9-23
of
confirmed
both
healthy
stored
Urinary
in
palpitation
rate
24-hr
of VMA
levels
and
period.
five
of
the
examination
specimens
amount
but
episodic
pulse of
(grade ‡V
walnut-sized
labetalol
in
and
extra-adrenal
preoperative
Urine
the
g,
biochemical
examined
small
a
21
or
65 ƒÊg/day)
cholesterol
depicted
the
elevation
observed, serum
weighing
also
to
with and
marked
retinopathy
electrolytes,
tumor,
hypertension mmHg
revealed
hypertensive
serum
of
194/124
normal,
Advanced
by
was
studies
1730 ƒÊg/day;
and
because
pressure
et al.
as
was
described
obtained at
preparation
4•Ž
by .
The was
.
RESULTS Before the treatment, the patient showed remarkably fluctuating hypertension and complained of a variety of episodic symptoms including headache , palpitation, substernal discomfort, excessive sweating and so forth . Fig. 1 illustrates the circulatory effects in the patient following oral administration of several adreno ceptor antagonists. The patient was initially treated with a combination of phenoxybenzamine (POB, 20-60 mg daily) plus a small dose of propranolol (PRP , 20 mg daily). During these medications , neither clinical symptom nor hyperten sion had been ameliorated. Then , oral labetalol was tried at an initial dose of 300 mg daily in addition to the above medications . These combinations rendered her blood pressure significantly lowered and the fluctuation reduced , relieving the patient from any kind of episodic symptoms . A dose related reduction
Labetalol
Fig.
1.
Circulatory
patient upper
effects
and Catecholamine
of various
combinations
with pheochromocytoma. Daily frame. POB, phenoxybenzamine;
65
of
adrenoceptor
antagonists
in a
oral dosage of each agent is indicated PRP, propranolol; LAB, labetalol.
in the
TABLE 1.
Effect of various adrenoceptor antagonists on urinary catecholamines and vanillylmandelic acid (VMA) in a patient with pheoehromocytoma
Values LAB,
of
blood
patient
indicate
pressure was
surgical
was
of
mg/g
was
detected
in
the
Changes
of
mean
the
also
satisfactorily
removal
(9.02
were
mean•}S.E.M.
POB,
phenoxybenzamine;
PRP,
propranolol.
labetalol.
wet
summarized pre-treatment
obtained
by
managed
by
increment repeated
pheochromocytoma.
tissue)
rather
than
(0.49
labetalol
450
intravenous
The E
of
tumor No
and
VMA
daily.
labetalol
contained
mg/g).
mg
The
during
the
predominantly
significant
activity
NE of
PNMT
tumor. levels
in
Table
period
of 1. were
urinary
CA
Twenty-four 1080•}170 ƒÊg
hour
induced
urinary
(mean•}S.E.M.),
NE,
by E trace
various and
VMA and
therapy during 14.3•}1.8
66
K. Kobayashi
mg,
respectively.
and
PRP.
These But
Particularly, over
urinary
Fig.
the
2.
Changes
(VMA) area
of
of
before
urinary
urinary
increased after
50
limit
of
mg
of
CA
in
CA
assay,
of
HCl
410/490
and
but
main
peak
through measured,
of
E
whole which
were and
oral
(NE)
labetalol
in
POB
labetalol high
mg
of
.
levels
labetalol
,
CA.
and
vanillylmandelic
normal
in
were
0.924•}0.175 ƒÊg/hr
VMA
nm
,
respectively.
.15 ƒÊg/hr E
acid
persons.
was
five
Stippled
normal
volunteers
respective
73±19 ƒÊg/hr
distinctly
at
(mean•}S.E.M.),
Those and
with
as
.
This
nm,
in
values immediately
higher
calculated
the
.
assay
a
as
24
however
.
On
3).
ng
out
peak
at
than
of of
NE
, did not excitation/emission
other
of
420/490 10
CA and
at
the
upper
excitation
(Richards
et
alkaline
the
When
procedure
located
ammonium
carried
with (Fig
peak reported
fluorescence, was
respectively
of
a
previously
intensified
fluorescence
was
of
oral
extremely 450
determined
fluorescence
315/420
fluorimetry
course
to after
that
with
after
. 2).
fluorescence
CA
trace
increase
than
treatment
observed
norepinephrine of
Urinary
much
452/490
,
9.66•}4
medium the
significant
the
,
native of
acidic
to
mg
73•}19 ƒÊg/hr
(Fig
was
when
small
VMA
NE
showed
fluorescence
50
after
was
from
less
(E)
labetalol.
wavelength
than
and
range
Labetalol
This
oral
CA
increased
much
(•ü)
4.52•}2.58 ƒÊg/hr,
normal
emission
after
significantly
tended
was
and
to
urinary
range.
urinary
0.567•}0.067 ƒÊg/hr
vary
of
epinephrine
and
normal
position,
not
was VMA
increase
(•œ)
indicates
When supine
fraction
Urinary rate
did
elevation
E
500 ƒÊg/day.
although
values
a marked
et al.
hand,
mg
medium interfere
labetalol
nm
which
of
labetalol
, a considerable 56 ng of E
has is similar was
Further,
. 1977). rather
with wavelength
fluorescence .
and
al
the
another to
the
treated was labetalol
Labetalol
Fig.
3.
Excitation
mg
of
each
spectra
labetalol agent
in
1.0
conditions:
Energy
filter
Absorption
M
of
norepinephrine,
blank.
al.
(b)
These
sodium
et
spectra
The
Ex.
slit
10
ng
were
tetraborate-HCl 1977).
mode,
Sample
mg
2
buffer
nm,
Em.
and
of
(pH were
slit
epinephrine,
(c)
after
processing
obtained
fluorimetries
sensitivity•~10
of
only
each
oxidized
albetalol
spectra
15
(a)
and
agent
labetalol
(c)
via
a
14
nm,
Measuring
through
complete
from
the
whole
mg
plus
blank.
7.0)
through
carried Em.
voltage
a
out W.L. of
vanillylmandelic These
procedure
procedure
indistinguishable
passed
15
nonoxidized
through
compounds
spectrum
of
ng
67
0.5
THI
at
the
490
the
nm,
recorder
mV.
4.
its
35,
10
faded
1.0
following
processing
mg
of (Miura
labetalol
tion
ml
(a)
its
procedure
10
and
(d)
oxidation
Fluorescence
Fig.
of
and
and Catecholamine
of
Pisano
that
of
procedure
of
of
Pisano
et
al.
vanillin VMA
acid
spectra
were et
(1962) (Fig.
assay
al.
10 ƒÊg,
obtained (1962).
showed 4).
were
(b) after
an
absorp
Fifteen
mg
calculated
of
as
0.16
VMA.
DISCUSSION The
present
labetalol tion
is
study
useful
therapy
in
of ƒ¿-
be
achieved
the
treatment
of
and ƒÀ-antagonists
pheochromocytoma, must
confirmed the
Ross prior
to
et
al.
previous
has (1967)
the ƒÀ-adrenoceptor
report
(Rosei
pheochromocytoma. been
established
emphasized blockade,
that
et
al.
Although in blockade otherwise
the
1976) a
that
combina
management
of
of ƒ¿-adrenoceptor hypertension
might
68
K. Kobayashi
et al.
be aggravated. Viewed from their opinion, labetalol may not be suitable in the beginning of the treatment. However, administration of a-antagonist elicits severe tachycardia in a majority of patients so that simultaneousprescription of j-antagonist is often required. These clinical experiencessupport the opinion that labetalol is not inconvenient, but adequate from the beginning of the management of pheo chromocytoma. The minimal effect of labetalol on the central nervous function (Martinet al. 1976)is an additional advantage, since larger doses are required quite often in these patients. A conspicuousincrease in urinary CA and VMA was observed after the administration of labetalol in our patient with pheochromocytoma. These increments might be due to an enhancementof CArelease from the chromaffintissues or due to the interference by a number of noncatecholamine fluorescencein the assay system. Blakeley and Summers (1977) reported that labetalol induces an enhancement of CA release from cat spleen by blocking neuronal uptake of NE . This mechanism may partly account for elevation of urinary CA and VMA. However, this explanation seems incompatible with the fact that a remarkable increase in both NE and E was observed after oral labetalol, while administration of both POB and PRP did not influence on urinary CA output in this patient. Exaggerated increase in E fraction after labetalol is also quite contradictory with the fact that NE fraction was exclusivelydetected in the tumor , and both E fraction and PNMT were negligible. These findings indicate that an elevation of values calculated as CA and VMA might be due largely to the biochemical properties of labetalol rather than its stimulation of CA release. This study disclosedthat labetalol, when processed through a complete course of CA or VMAassay, emits a considerablefluorescenceand has an absorbance in the similar areas of the spectrum as those of CA and VMA, respectively. It is beyond doubt that these biochemicalnatures of labetalol cause falsely higher values of CA and/or VMA. However, the interference with the assay by labetalol seems too weak to explain the great increase in values of CA, when the rate of interference is calculated on the basis of the data that 10 mg of labetalol are miscalculated as 24 ng of NE and 56 ng of E . Besides, unmetabolized labetalol in urine has been shownto account for 10% or less of the oral dose (Martin et al. 1976). From these reasons, it is most likely that a major portion of the interference is caused by urinary metabolites of labetalol rather than labetalol itself , although these fl uorescent metabolites remain speculative. Marked increase in urinary CA was also observed in normal subjects i mmediately after labetalol (Fig. 2). This findingis in line with recent correspon dence by Harris and Richards (1977), suggesting that the hypertensive patients under labetalol therapy may be erroneously diagnosed as pheochromocytoma. Therefore, it should be emphasized that clinical eval uations of CA and its metabolites have to be done prior to the treatment with l abetalol.
Labetalol
and
Catecholamine
69
Acknowledgments This study was supported by Grant-in-Aid for Scientific Research (Nos. 177193, 157228, 257245) and for Cancer Special Research from the Ministry of Education, Science and Culture, Japan. References 1)
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R.J.
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Marshall,
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(1977)
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