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518
CIRCULATION RESEARCH
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VOL. 49, No. 2, AUGUST 1981
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Blood Pressure Response to Central and/or
Peripheral Inhibition of Phenylethanolamine
iV-Methyltransferase in Normotensive and
Hypertensive Rats
JESSIE BLACK, BERNARD WAEBER, MARGARET R. BRESNAHAN, IRENE GAVRAS, AND
HARALAMBOS GAVRAS
SUMMARY We studied the effects on blood pressure and heart rate of two different phenylethanolamine JV-methyltransferase (PNMT) inhibitors in normotensive, in two-kidney renal hypertensive, and
in deoxycorticosterone-salt (DOC-salt) hypertensive rats. One compound (SK&F 64139) blocks the
conversion of norepinephrine to epinephrine in both the central and the peripheral nervous system,
whereas the other (SK&F 26861) does not cross the blood-brain barrier and therefore is active mostly
in the adrenal glands. In the rats given SK&F 29661, practically no acute blood pressure changes were
observed. Central PNMT inhibition with SK&F 64139 induced only a minor blood pressure and heart
rate response in normotensive and two-kidney renal hypertensive rats. However, in DOC-salt hypertensive rats, it reduced arterial pressure to approximately normal levels and concomitantly glowed
pulse rate. There was a close correlation between the magnitude of the blood pressure response
observed in all SK&F 64139-treated animals and the control plasma norepinephrine (r = —0.795, P <
0.001) and epinephrine (r — -0.789, P< 0.001) levels. These results suggest an important role for central
epinephrine in regulating the peripheral sympathoadrenomedullary and the baroreceptor reflex activity, particularly when the maintenance of the high blood pressure is not renin-dependent. Circ Res 49:
618-524, 1981
CENTRAL catecholaminergic neurons are thought
to participate in the regulation of normal blood
pressure and in the development and maintenance
of high blood pressure in several types of experiFrom the Department of Medicine and the Thomdlke Memorial
Research Laboratories, Boston University Medical Center, Boston, M u sachuselLe.
Thra work was completed during the tenure of Dr. H. Gavras as an
Established Investigator of the American Heart Association. Supported
in pan by U.S. Public Health Service Grant HL-183ia Dr. Waeber is
supported by the Swiss National FoundationAddress for reprints: Dr H Gavraa, 80 E. Concord St., Boston,
Massachusetts 02118.
Received November 5. I960; accepted for publication April 7, 1981
mental hypertension (Chalmers, 1975). At least
some of the brain areas involved in cardiovascular
homeostasis are located in the brain stem (Doba
and Reis, 1974; Chalmers, 1975). Such areas not
only are innervated richly with catecholarninergic
cell bodies and terminals (Fuxe, 1965; Bolme et al.,
1972), but also have the highest activity of phenylethanolamine 7V-methyltransferase (PNMT) (Saavedra et al., 1974), the enzyme which catalyzes the
last step in epinephrine formation (Axelrod, 1962).
A neurogenic component has been proposed as a
pathogenic factor in the hypertension induced by
mineralocorticoids and salt (Nakamura et al., 1971;
PNMT INHIBITION IN EXPERIMENTAL HYPERTENSION/Btoc* et al.
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deChamplain and van Ameringen, 1972; Chalmers,
1975; Reid et al., 1975). In this model, rats with
established high blood pressure have increased
levels of PNMT activity in at least one region of
the brain stem, and demonstrate a decrease in blood
pressure to normotensive values following administration of a PNMT inhibitor (SK&F 7698) (Saavedra et al., 1976). However, the precise antihypertensive mechanism of that inhibitor remains unclear, particularly in view of the potent a-adrenergic-inhibiting properties of the compound (Pendleton et al., 1974).
The purpose of this study was to evaluate the
acute effect on blood pressure of two recently synthesized PNMT inhibitors in rats with experimental
hypertension induced by renal artery stenosis or
mineralocorticoid and salt excess, i.e., two forms of
hypertension considered to be, respectively, the
prototypes of renin-dependent (during the early
phases of hypertension) (Brunner et al., 1971; Leenen et al., 1973; Carretero and Gulati, 1978) and
non-renin-dependent hypertension (Gavras et al.,
1975). One of these compounds (SK&F 64139) inhibits PNMT activity in both the central nervous
system and the adrenal gland, and, in vitro, is a
weak a-adrenergic antagonist (Pendleton et al.,
1976; Pendleton et al., 1977); the other (SK&F
29661) does not cross the blood-brain barrier and
thus does not block the conversion of norepinephrine to epinephrine in the brain (Pendleton et al.,
1979).
Methods
Animals
Male Wistar rats from Charles River Breeding
Laboratories were used in all experiments. They
were housed in a temperature- and humidity-controlled room with automatic lighting in 12-hour
cycles.
Normotensive Rats (Group A)
These animals were kept on a usual diet of Purina
Rat Chow and tap water ad libitum. At the time of
study, the rats weighed 260 ± 6 g (mean ± SE) .
Two-Kidney Renal Hypertensive Rats (Group B)
These rats underwent a left lateral flank incision
under ether anesthesia when they weighed 140-160
g, and a silver clip was applied, as previously described, to the left renal artery (Byrom, 1969). The
right kidney was left intact. The rats then were
allowed unrestricted access to laboratory chow and
tap water. On the day of the experiment 3-4 weeks
later, their weight averaged 284 ± 12 g.
Deoxycorticosterone (DOC)-Salt Hypertensive
Rats (Group C)
A left nephrectomy was performed under ether
anesthesia in rats weighing 140-160 g. One week
later, the DOC-salt regimen was started. The rats
were given subcutaneous injections of DOC (Percorten Pivalate, CIBA), 30 mg/kg body weight per
519
week in divided doses of 15 mg/kg body weight at
3- to 4-day intervals, and had free access to 1%
NaCl as drinking water and usual laboratory chow.
At the time of the study, 4 weeks following the
initiation of the DOC-salt regimen, the animals
weighed 293 ± 6 g.
Procedures and Analytical Methods
On the day of the experiment, under light ether
anesthesia, the right femoral vein was cannulated
with a PE-10 and the right external iliac artery with
a PE-50 catheter. Both catheters contained a heparinized 5% dextrose solution. Arterial pressure
then was monitored continuously with a HewlettPackard transducer (model P23 Db) and recorder
(model 7702). Pulse rates were derived from the
arterial pressure tracings. Upon awakening, the animals were maintained in a semirestrained position
on a light mesh screen for 60-90 minutes until blood
pressure rose to a steady baseline. At that time, 0.3
ml blood was withdrawn via the arterial catheter
for determination of plasma catecholamines. That
blood volume was replaced by an equivalent
amount of 5% dextrose, and 20 minutes later, the
first dose of the test drug was administered. Plasma
norepinephrine and epinephrine levels were assayed, as described elsewhere (Bresnahan et al.,
1980), with a modification of the method of Peuler
and Johnson (1977).
SK&F 64139 (7,8-dichloro-l,2,3,4-tetrahydroisoquinoline hydrochloride) and SK&F 29661 (1,2,3,4tetrahydroisoquinoline-7-sulfonamide) were supplied by Smith, Kline & French Laboratories. Both
drugs were diluted in 5% dextrose to achieve a final
concentration of 25 mg/ml. Each rat received two
5-mg doses of one inhibitor given 1 hour apart as a
0.2-ml solution injected over a 5-minute period.
The effect on blood pressure of the different
compounds was observed for 3 hours in all the
animals. Seven rats in group A, six in group B, and
eight in group C received SK&F 29661; whereas six
in group A, eight in group B, and seven in group C
were given SK&F 64139.
Data Analysis
Data are reported as means ± SE. Statistical
evaluation of the results was made using analysis of
variance for one group having repeated measures,
one-way analysis of variance followed by Scheffe
multiple comparison procedure, and Student's t-test
for nonpaired data as appropriate. Correlation coefficients of regression lines were calculated by the
method of least squares. A probability level of less
than 0.05 was considered significant.
Results
The control mean blood pressures and pulse rates
of these different groups of rats are summarized in
Table 1. Figure 1 depicts the time courses of the
effect on blood pressure of SK&F 29661 and SK&F
64139 administered to normotensive rats, two-kidney renal hypertensive rats, and DOC-salt hypertensive rats.
CIRCULATION RESEARCH
520
VOL. 49, No. 2, AUGUST
1981
TABLE 1 Control Blood Pressures and Heart Rates in Normotenswe, Two-Kidney
Hypertensive, and DOC-Salt Hypertensive Rats
Two-kjdney renal
hyperteruiive rata
Normotensive rats
Control mean
blood pressure
<mm Hg)
Control pulse
rate
(beats/min)
DOC-saJt
hypertensive rau>
SK&F 29661
in - 7)
SK&F 64139
(n - 6)
SK&F 29661
in - 6)
SKfcF 64139
(n - 8)
SK&F 29661
in - 8)
SK&F 64139
in - 7)
120 ± 1 . 5
120 ± 1 3
L89 ± 7
179 ± 6.9
176 ± 6.7
194 ± 6.8
480 ± 8
460 ± 13
470 ± 18
473 ± 8
443 ± 11
446 ± 18
Baseline hlood pressures and heart rates in the three groups (mean ± SE) are not flignificantly diiTerent between
animala that received SK&F 29G61 and those that received SK&F 64139.
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In normotensive rats, SK&F 29661 did not decrease the blood pressure, whereas SK&F 64139
caused a significant reduction in blood pressure (P
< 0.01) with a maximal drop of 12 mm Hg.
In two-kidney renal hypertensive rats, SK&F
29661 had only a minor antihypertensive effect.
SK&F 64139 produced a more pronounced blood
pressure response, which was still nonsignificant.
At the end of the experiment, rats which had received either agent were still hypertensive with
mean blood pressures of 181 ± 7.5 and 165 ± 6.9
mm Hg, respectively.
Although DOC-salt rats also responded poorly to
the administration of SK&F 29661, those given the
peripherally and centrally active PNMT inhibitor
SK&F 64139 showed a progressive decrease of blood
pressure toward approximately normal levels (P <
0.001). Three hours after initiation of the experiment, the mean arterial pressure was still low at 128
±6.1 mm Hg in these animals, whereas it remained
high at 165 ± 5.5 mm Hg in those treated with
SK&F 29661.
Figure 2 illustrates the changes in pulse rate
I 5mq IV
, 5mg IV
+ 2 0 - NORMOTENSIVE
induced by SK&F 29661 and SK&F 64139 in the
different groups of rats. With SK&F 29661, a trend
toward a slower pulse rate was observed only in the
DOC-salt hypertensive rats. The administration of
SK&F 64139 to normotensive and two-kidney renal
hypertensive rats induced only minor reductions in
heart rate. In contrast, in DOC-salt hypertensive
rats, a significant decrease in pulse rate from 446
± 18 to 326 ± 22 beats/min (P< 0.001) was observed
with SK&F 64139. A close correlation (r - 0.80, P
< 0.001) appeared between the blood pressure and
heart rate changes measured at the end of the
experiment in all animals given SK&F 64139.
The control plasma catecholamine levels for all
the rats are plotted individually in Figure 3. In the
normotensive rats, plasma norepinephrine and epinephrine levels averaged 0.689 ± 0.077 and 0.539 ±
0.088 ng/ml, respectively, whereas in the two-kidney renal hypertensive rats, the same parameters
were somewhat higher, at 0.912 ± 0.106 and 0.904
± 0.149 ng/ml, respectively, but the differences
were not significant. In the DOC-salt hypertensive
rats, both plasma norepinephrine (1.726 ±0.115 ng/
o SKSF 29661
• SK3F 64139
-+20
o--20
TWO-KIDNEY RENAL HYPERTENSIVE
°r
- —0
5
-0
;
--20
0. -40
I.
DOC-SALINE HYPERTENSIVE
-*•—--*—-+
^ -201-
4
-0
-"20
--40
--60
"60 r-
---80
Control
15
30
45
60
90
MINUTES
120
150
190
FIGURE 1 Blood pressure effects of
PNMT inhibition with SK&F 64139
and SK&F 29661 in normotensive rats,
two-kidney renal hypertensive, and
DOC-salt hypertensive rats.
PNMT INHIBITION IN EXPERIMENTAL HYPERTENSION/B/aeA et al.
521
5rnglV
SK3F 2966)
SK3F 64139
••40
-U40
_ NORMOTENSIVE
,
o
5
5
5-—
-40
Ho
-40
~TWO-KIONEY RENAL HYPERTENSfVE
+ 40
-40
DOC SALINE
HYPERTENSIVE
FIGURE 2 Puke rate response to PNMT
inhibition with SK&F 64139 and SK&F
29661 in normotensive rats, two-kidney
renal hypertensive, and DOC-salt hypertensive rats.
—5-40
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-80
-120
-160
Centre*
IS
ml) and epinephrine (1.349 ± 0.173 ng/ml) levels
were significantly higher (P < 0.05) than those
determined in the normotensive rate. Compared to
the two-kidney renal hypertensive rats, only the
plasma norepinephrine levels were significantly (P
< 0.05) increased in the DOC-salt hypertensive rats.
Figure 4 illustrates the relationship between
changes in blood pressure induced by SK&F 64139
and the control plasma catecholamine levels measured in all rate given that compound. A close
correlation emerged between the magnitude of the
blood pressure changes recorded at the end of the
experiment and both the corresponding control norepinephrine (r = -0.795, P < 0.001) (left panel) and
epinephrine (r = -0.789, P < 0.001) (right panel)
levels.
Discussion
Recent work has focused on a possible specific
involvement of the central adrenergic system in the
regulation of normal blood pressure, as well as in
the pathogenesis of some forms of hypertension
(Saavedra et aL, 1974, 1976). The existence of epinephrine-containing neurons in the brain has been
ascertained in two ways: either by demonstrating
the presence of PNMT by immunofluorescence
(Hokfelt et al., 1973, 1974) and biochemical techniques (Saavedra et al., 1974; Lew et al., 1977) or by
measuring directly the hormonal content (Koslow
and Schlumpf, 1974). Not surprisingly, since PNMT
is most likely localized in the epinephrine-producing
neurons, the brain PNMT and epinephrine were
found to be similarly distributed (Saavedra et al.,
1974; Koslow and Schlumpf, 1974). In normotensive
rats, the greatest central PNMT activity has been
detected in brain stem areas (Saavedra et al., 1974)
such as in the A, region which represents the catecholaminergic cell bodies projecting their axons
to the spinal cord and in the A2 region (Fuxe, 1965;
Bolme et al., 1972) which includes the nucleus tractus solitarii, the terminal of the majority of the
fibers originating from the carotid sinus (Crill and
Reis, 1968; Doba and Reis, 1974). In addition, both
noradrenergic nerve endings and catecholaminergic
cell bodies have been described at the level of the
A2 region (Fuxe, 1965; Bolme et al., 1972). Experimental evidence suggests that the same areas actively participate in blood pressure regulation
(Doba and Reis, 1974; Chalmers, 1975).
In the present study, we administered two different PNMT inhibitors, SK&F 29661 and SK&F
64139, to unanesthetized rats. Both compounds are
potent in vitro inhibitors of PNMT activity (Pendleton et al., 1976, 1977, 1979). However, unlike
SK&F 64139, which in vivo inhibits the brain stern,
as well as the adrenal PNMT activity (Pendleton
et al., 1976, 1977), SK&F 29661 does not cross the
blood-brain barrier (Pendleton et al., 1979). Therefore, when given orally up to a dose of at least 100
mg/kg, it remains without effect on brain stem
PNMT activity (Pendleton et al., 1979). The doses
used, i.e., two intravenous injections of 5 mg in each
rat at a 1-hour interval, were identical for the two
inhibitors and are thought, on the basis of previous
studies (Pendleton et al., 1976, 1977, 1979; Sauter et
al., 1977), to be sufficient to block effectively the
conversion of norepinephrine to epinephrine during
the observation period.
Although a 15-mm Hg blood pressure decrease
has been demonstrated in normotensive rate as the
CIRCULATION RESEARCH
522
i
p<005
p<005
NS
o
I
24-
OSK8F29661
• SK8F64139
o •
•
18-
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i. °:°
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^J
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06-
°
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o
o
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G
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18-
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S
06-
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O
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8
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o
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to
' •
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o
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1
WRMOTENSIVE
RATS
TWO KIONEr
DOC-SALINE
'—HYPERTENSIVE
RATS—'
3 Control plasma norepinephrine and epinephrine levels in normotenswe rats, two-kidney renal
hypertensive, and DOC-salt hypertensive rats.
FIGURE
immediate consequence of adrenalectomy (deChamplain and van Ameringen, 1972), the lack of
acute pressure changes observed in our normotensive rats given SK&F 29661 is not surprising, even
in the face of presumably effective blockade in
epinephrine generation, because it has been established that the adrenal epinephrine turnover is very
slow under normal conditions (Fuller et al., 1974).
Following both peripheral and central PNMT
inhibition with SK&F 64139, the blood pressure
decrease in our normotensive rats was small, although presumably the brain stem PNMT activity
was still markedly suppressed. Indeed, other investigators, using doses of SK&F 64139 (about 12.5
VOL. 49, No. 2, AUGUST 1981
mg/rat, ip) very close to ours (10 mg/rat, iv), measured after a 3-hour interval a reduction of PNMT
activity of approximately 90% in selected regions of
the medulla oblongata (Sauter et al., 1977).
We investigated the blood pressure response to
PNMT inhibition with both compounds also in twokidney renal and DOC-salt hypertensive rats. These
two experimental models of high blood pressure
have been chosen because, in each one, different
mechanisms seem to be primarily responsible for
the development and the maintenance of the elevated blood pressure levels. Indeed, an activation
of the renin-angiotensin system has been proven to
be linked to t>.e increase in pressure levels observed
in the early phases of renovascular hypertension
(Brunner et al., 1971; Leenen et al., 1973; Carretero
and Gulati, 1978), but not in the DOC-salt model of
hypertension (Gavras et al., 1975). Blockade of the
renin axis with saralasin, a competitive inhibitor of
angiotensin II, markedly lowers arterial pressure in
the former (Brunner et al., 1971; Carretero and
Gulati, 1978), but not in the latter (Gavras et al.,
1975). On the other hand, the central and peripheral
catecholaminergic neurons, as well as the adrenal
medulla, seem to be involved in the pathogenesis of
DOC-salt hypertension (Nakamura et al., 1971;
deChamplain and van Ameringen, 1972; Chalmers,
1975; Reid et al., 1975). Interestingly, the plasma
norepinephrine levels determined in this model of
hypertension were reported to be significantly
higher than those measured in untreated controls
(Reid etal., 1975).
The time course of the blood pressure response
to the two PNMT inhibitors was similar in the twokidney renal hypertensive rats to that recorded in
the DOC-salt hypertensive animals. However, the
magnitude of the blood pressure reduction using
SK&F 64139 was far less pronounced in the renovascular hypertensive animals. In that model of
high blood pressure, rats remained hypertensive
despite peripheral and central inhibition of PNMT,
suggesting that overactivity of the central adrenergic system is not of major importance. In our DOCsalt hypertensive rats, an impressive blood pressure
fall was produced acutely by the centrally active
PNMT inhibitor only. In these rats, the antihypertensive effect of SK&F 64139 was already important
within the first 15 minutes of inhibition of PNMT,
and blood pressure normalization was progressively
achieved thereafter. Especially relevant to our
study is the fact that PNMT activity has been
reported to be elevated in the Ai brain stem areas
of adult mineralocorticoid salt hypertensive rats
and that oral administration of a PNMT inhibitor
(SK&F 7698) resulted in a decrease of blood pressure toward normal levels in these rats (Saavedra
et al., 1976). Unfortunately this compound has
about equal affinity for norepinephrine sites on the
epinephrine-synthesizing enzyme and the «-adrenergic receptors, thus confusing interpretation of its
effects (Pendleton et al., 1974).
ELECTROPHYSIOLOGICAL EFFECTS OF AUTONOMIC BLOCKADE/Prystowsky et at.
523
ng/ml
PLASMA NOREPINEPHRINE
PLASMA EPINEPHRINE
r =-0 789
p< 0 001
r=p< 0001
30
24
12
• Normotenave
* Two-Kidney Renol
Hypertensive
• OOC-Soline
Hypertensive
"120
-80
06
-40
0
-120
-80
-40
0
A MEAN BLOOD PRESSURE AFTER SKaF64f39(mmHg)
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4 Relationship between the control plasma norepinephrine and epinephrine levels and the magnitude of the
blood pressure response to PNMT inhibition with SK&F 64139 in normotensiue, two-kidney renal hypertensive, and
DOC-salt hypertensive rats.
FIGURE
In the SK&F 29661-treated rats of either model,
only a slight blood pressure decrease was observed
from the 90th minute of the experiment onwards.
This blood pressure response may not necessarily
be due to the inhibited formation of epinephrine in
the peripheral sympathetic nervous system, ie., in
the adrenal glands, which are almost exclusively
the site of epinephrine secretion. Indeed, it cannot
be ruled out that SK&F 29661, which does not reach
the brain in the normotensive state, may be able to
cross the blood-brain barrier in some animals if the
barrier has been more or less disrupted by high
pressure levels (Hatzinikolaou et al., 1980).
SK&F 64139 has been demonstrated in studies in
vitro to have only a weak affinity for both a-adrenoceptors and monamine oxidase (MAO) (Pendleton et al., 1976). In our rats given this compound, it
is unlikely that the parallel changes in blood pressure and pulse rate were due to a-blockade alone.
The decelerating effect on pulse rate of SK&F 64139
contrasts with the dose-dependent tachycardia
which in normotensive dogs accompanied a small
decrease in blood pressure induced by another
PNMT inhibitor with important a-blocking action
(SK&F 7698) (Pendleton et al., 1974). On the other
hand, a significant inhibition of MAO seems not to
occur in intact animals since no potentiation of the
pressor effect of tyramine or of tryptamine-induced
convulsive activity was found in rats treated with
three oral doses of 100 mg/kg of SK&F 64139 administered over a 24-hour period (Pendleton, 1979).
The antihypertensive action of SK&F 64139 may
be due primarily to the suppression of epinephrine
synthesis in specific brain vasomotor centers. In our
rats, a close correlation was found between the
control plasma norepinephrine and epinephrine
levels and the magnitude of the SK&F 64139-induced blood pressure drop. This correlation sup-
ports the concept that central adrenergic neurons
play a key role in controlling the sympathoadrenomedullary activity. In addition, the fact that the
cardiac decelerating effect of SK&F 64139 was most
marked in the rats with the greatest blood pressure
fall, in which a tachycardia rather than a bradycardia would be expected, is consistent with an inhibition of the baroreceptor reflex by central PNMT
inhibition. This tends to confirm an active participation of epinephrine as a neurotransmitter also in
the central part of the baroreceptor reflex arc, most
likely at the level of the nucleus tractus solitarii.
A concomitant reduction in blood pressure and
heart rate previously has been demonstrated to
occur after microinjection of norepinephrine in the
area of the nucleus tractus solitarii (DeJong et al.,
1975), as well as following administration of clonidine (Kobinger and Pichler, 1974) or injection of
tyrosine (Bresnahan et al., 1980). In these circumstances, the changes in both blood pressure and
pulse rate generally were thought to be the consequence of a central a-catecholaminergic receptor
stimulation. In our rats, there is no evidence that
the cardiovascular response to central PNMT inhibition was promoted by an enhanced noradrenergic receptor stimulation. Indeed, no accumulation
of norepinephrine has been detected in brain stem
despite effective blockade of epinephrine formation
induced by SK&F 64139 (Pendleton, 1979). Notwithstanding, it cannot be proven that this unchanged norepinephrine content corresponds to an
unchanged norepinephrine turnover in the same
areas. Interestingly, recent studies have also
pointed out the possible role of central epinephrine
in cardiovascular regulation. The reported findings
have shown that one of the final effects of a-agonistic properties of clonidine on adrenoceptors is a
decrease of epinephrine turnover in some brain
524
CIRCULATION RESEARCH
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stem areas (Fuxe et al., 1979; Scatton et al., 1979),
an effect which, in turn, might be important for the
cadiovascular response to the drug. Although a
similar relationship between central norepinephrine
a-receptor stimulation and epinephxine turnover
cannot be extrapolated with certainty from these
studies, it is intriguing that, in the DOC-salt hypertensive rats, in which blood pressure can be normalized by the central PNMT inhibitor, a decreased
turnover of norepinephrine was measured in the
medulla oblongata, while in other parts of the brain,
it was comparable to control values (Nakamura et
al., 1971).
In conclusion, our findings suggest that experimental hypertension induced by sodium and mineralocorticoid excess may be greatly dependent
upon central catecholamine levels. Indeed, inhibition of an enzyme controlling epinephrine synthesis
can reverse established hypertension of this type,
but not of a renin-dependent type.
References
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Bolme P, Fuxe K, Lidbrink P (1972) On the function of central
catecholamine neurons—Their role in cardiovascular and
arousal mechanisms. Res Commun Chem Pathol Pharmacol
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Circ Res. 1981;49:518-524
doi: 10.1161/01.RES.49.2.518
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