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Journal ArticleDOI

α-Methylnoradrenaline induced hypotension and bradycardia after administration into the area of the nucleus tractus solitarii

01 Jun 1975-European Journal of Pharmacology (Elsevier)-Vol. 32, Iss: 2, pp 361-364

TL;DR: Bilateral injections of α-methylnoradrenaline into the area of the nucleus tractus solitarii of the brain stem caused a dose-dependent decrease of systemic arterial blood pressure and heart rate of anesthetized rats.

AbstractBilateral injections of α-methylnoradrenaline into the area of the nucleus tractus solitarii of the brain stem caused a dose-dependent decrease of systemic arterial blood pressure and heart rate of anesthetized rats. The effects were prevented and even reversed by a preceding injection of the α-adrenoceptor blocking agent phentolamine. Pressor doses of angiotensin II and of arginine-vasopressin at the same site failed to decrease blood pressure and heart rate.

Topics: Baroreceptor (61%), Angiotensin II (58%), Blood pressure (55%), Phentolamine (53%), Bradycardia (52%)

Summary (1 min read)

1. Introduction

  • The central blood pressure lowering effect of a-methyldopa may be mediated by its metabolite a-methylnoradrenaline (Henning and Rubenson, 1971 ).
  • Experiments in cats in which amethyldopa was infused into the vertebral artery indicate that the main site may be located in the medulla oblongata (Henning and Van Zwieten, 1968 ).
  • Administration of noradrenaline into the medulla oblongata in the area of the nucleus tractus solitarii in the rat decreased blood pressure and heart rate (De Jong, 1974} .
  • The present report describes the effect of local administration of a-methylnoradrenaline at the same medullary site on blood pressure and heart rate of anesthetized rats.

3. Results and discussion

  • A-Methylnoradrenaline presumably is the metabolite which mediates the blood pressure lowering effect of a-methyldopa (Henning and Rubenson, 1971) .
  • Central a-adrenoceptor blockade by intraventricularly administered phentolamine prevented the fall in blood pressure caused by a-methyldopa (Finch and Hauesler, 1973) .
  • In the present study injection of phentolamine into the area of the nucleus tractus solitarii inhibited both the hypotension and bradycardia induced by ~-methylnoradrenaline.
  • The present findings thus support the hypothesis that a-methyldopa acts through a-adrenoceptor stimulation in this particular region of the medulla oblongata (Van Zwieten, 1973) .

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European Journal of Pharmacology, 32 (1975) 361--364
© North-Holland Publishing Company, Amsterdam -- Printed in The Netherlands
Short communication
~-METHYLNORADRENALINE INDUCED HYPOTENSION AND BRADYCARDIA AFTER
ADMINISTRATION INTO THE AREA OF THE NUCLEUS TRACTUS SOLITARII
FRANS P. NIJKAMP and WYBREN DE JONG
Rudolf Magnus Institute for Pharmacology, Medical Faculty, University of Utrecht, Vondellaan 6, Utrecht,
The Netherlands
Received 1 April 1975, accepted 14 April 1975
F.P. NIJKAMP and W. DE JONG, a-Methylnoradrenaline induced hypotension and bradycardia after administra-
tion into the area of the nucleus tractus solitarii, European J. Pharmacol. 32 (1975) 361--364.
Bilateral injeetions of a-methylnoradrenaline into the area of the nucleus tractus solitarii of the brain stem
caused a dose-dependent decrease of systemic arterial blood pressure and heart rate of anesthetized rats. The
effects were prevented and even reversed by a preceding injection of the a-adrenoceptor blocking agent
phentolamine. Pressor doses of angiotensin II and of arginine-vasopressin at the same site failed to decrease blood
pressure and heart rate.
Nucleus tractus solitarii
Arginine-vasopressin
-Methylnoradrenaline
Blood pressure
Angiotensin II Heart rate
1. Introduction
The central blood pressure lowering effect of
a-methyldopa may be mediated by its metabo-
lite a-methylnoradrenaline (Henning and Ru-
benson, 1971). The brain structures at which
this action is exerted so far remain to be
identified. Experiments in cats in which a-
methyldopa was infused into the vertebral
artery indicate that the main site may be
located in the medulla oblongata (Henning and
Van Zwieten, 1968). Administration of nor-
adrenaline into the medulla oblongata in the
area of the nucleus tractus solitarii in the rat
decreased blood pressure and heart rate (De
Jong, 1974}. The present report describes the
effect of local administration of a-methylnor-
adrenaline at the same medullary site on blood
pressure and heart rate of anesthetized rats.
2. Materials and methods
The experiments were performed on male
Wistar rats (outbred stock, Wi/Cpb, TNO,
Zeist), weighing 200--250 g. The rats were
anesthetized with urethane (1.25 g/kg i.p.).
After fixation of the rat in a stereotaxic appara-
tus (David Kopf) with the head flexed to 45 °,
the dorsal surface of the lower brainstem was
exposed by a limited occipital craniotomy.
Bilateral injections into the nucleus tractus
solitarii (0.5 mm lateral of the obex and at a
depth of 1.0 ram) were carried out with a
stainless steel needle (outer diameter 0.2 mm)
connected via a polyethylene cannula with an
Agla micrometer syringe and a Shardlow mi-
crometer. Various doses of a-methylnoradrena-
line dissolved in 0.9% NaC1 solution were ad-
ministered bilaterally in a volume of 0.6 pl over

362 F.P. NYKAMP, W. DE JONG
a period of 30 sec. Control rats received 0.6 pl
of vehicle only.
Blood pressure was continuously recorded
from a permanent indwelling iliac cannula (Nij-
kamp et al., 1975) with a Statham transducer
(Model P23-AC) connected to a Grass poly-
graph. The iliac cannula had been implanted
under ether anesthesia at least 24 hr prior to the
experiment. Heart rate was computed from the
blood pressure pulse wave by a cardiotachome-
ter (Narco Bio-systems, Model BT 1200). Drugs
given i.v. were dissolved in 0.2 ml 0.9% NaC1
solution and administered into the right jugular
vein. Control rats received 0.2 ml vehicle only.
After termination of th~ experiments, the
brains were fixed in 5% formalin. Frozen sec-
tions of 100 p were cut and stained with 0.1%
thionine. The injection sites were controlled
microscopically.
The following drugs were used: (+)-erythro-
a-methylnoradrenaline " HC1 (Cobrefin ®, Win-
throp Laboratories); phentolamine methane
sulphonate (Regitine ®, Ciba); 1-asp-5-val-angio-
tensin II am±de (Hypertensin ®, Ciba); arginine-
vasopressin (232 U/mg, Organon).
3. Results and discussion
Local injection of a-methylnoradrenaline
(5.8, 23.0, 92.0 nmol) into the area of the
nucleus tractus solitarii at the level of the obex
caused a dose-dependent decrease in mean
blood pressure and heart rate (table 1). Blood
pressure started to fall immediately after com-
pletion of the bilateral injections. The lowest
dose (5.8 nmol) caused a short lasting decrease
in blood pressure which reached a maximum
after 5 min. The higher doses (23.0 and 92.0
nmol) decreased blood pressure and heart rate
for over 30 min. Maximal effects were observed
after 5--10 min. Compared to the effect of
noradrenaline injected at the same site in doses
causing a similar degree of hypotensin (De
Jong, 1974), the effect of a-methylnoradrena-
line appears to be of longer duration.
Heise and Kroneberg (1972), showed that
the central inhibitory action on blood pressure
and heart rate of intraventricularly adminis-
tered a-methylnoradrenaline was blocked by
phentolamine given by the same route. In this
study, phentolamine in a dose of 23 nmol ad-
TABLE 1
Effect of graded doses of (~-methylnoradrenaline on mean blood pressure and heart rate after local administration
into the area of the nucleus tractus solitarii of the brain stem of anesthetized rats. Blood pressure and heart rate,
and the changes in these parameters are given in mm of mercury (mm Hg) and in beats per min (bpm). The means
-+ S.E.M. are listed. The numbers in parentheses indicate the number of animals used in each group.
Microinjection of n
Blood pressure in mm Hg (heart rate in bpm)
Basal values Changes after
5 rain 10 rain 20 min 30 rain
Vehicle 9 123+- 5 +6! 6 +5+ 6 +1+
391+ 18 -4-+ 9 +12+- 4 +39+
~-Methylnoradrenaline 5.8 nmol 7 122 -+ 5 -16 ± 2* -13 +- 2 -3 +
386 + 18 -27 +- 11 -12 -+ 14 +13 +
~-Methylnoradrenaline 23.0 nmol 6 117 +- 4 -33 -+ 6* -33 + 6* -23 +
423+ 5 -56±14" -66+ 7* -43+
~-Methylnoradrenaline 92.0 nmol 6 126 ± 6 -39 ± 5* -43 ± 4* -32 +-
4212 12 -38± 7 -75±11" -86±
4 -2 + 3
15 +39 + 17
2 +1 + 26
21 +42 -+ 26
5* -15 + 4*
7* -28 ± 9*
3* -20 -+ 3*
11" -74 + 14"
* c~-Methylnoradrenaline-induced changes that are significantly different (p < 0.01) from the respective control
values after the administration of vehicle (1 nmol of ~-methylnoradrenaline corresponds to 219.5 ng).

CENTRAL HYPOTENSIVE ACTION OF ~-METHYLNORADRENALINE 363
ministered into the area of the nucleus tractus
solitarii followed after 10 min by a dose of 23
nmol of ~-methylnoradrenaline applied at the
same site completely prevented and even re-
versed the fall in blood pressure and heart rate,
with a maximum reached within approximate-
ly 2 min. The mean changes S.E.M.) ob-
served in 6 rats at this time were +31 ± 6 mm Hg
and +27 ± 9 bpm in the phentolamine-treated
rats compared to --14 ± 5 mm Hg and --28 +- 15
bpm for the controls which had received 0.9%
NaC1 10 min prior to a-methylnoradrenaline.
In the control group a maximal decrease in
blood pressure and heart rate of the same
magnitude as that shown in table 1 was reached
within 10 min. In the phentolamine-treated
animals no secondary decrease in blood pres-
sure and heart rate occurred. Phentolamine by
itself caused no significant change in blood
pressure but reduced heart rate by 20% within
2--3 min.
In order to establish the specificity of the
structures in the medulla oblongata for a-meth-
ylnoradrenaline, the effect of the 2 pressor
peptides angiotensin II and arginine-vasopres-
sin was studied in equipressor amounts. I.v.
administration of the 3 different doses of
a-methylnoradrenaline used caused a dose-
dependent increase in mean blood pressure of
urethanized rats of 20--60 mm Hg (unpub-
lished data). Basal values of blood pressure and
heart rate in these groups of rats (table 2) did
not differ from those reported in table 1. I.v.
administration of the 2 peptides caused a dose-
dependent increase in blood pressure. Only the
highest dose of vasopressin (480 pmol) de-
creased heart rate. However, bilateral applica-
tion of these doses into the area of the nucleus
tractus solitarii in another group of rats failed
to cause cardiovascular changes (table2).
These observations suggest therefore that the
observed inhibitory cardiovascular action of
a-methylnoradrenaline cannot be explained by
local vasoconstriction.
a-Methylnoradrenaline presumably is the
metabolite which mediates the blood pressure
lowering effect of a-methyldopa (Henning and
Rubenson, 1971). Central a-adrenoceptor
TABLE 2
Effect of graded doses of angiotensin II and of
arginine-vasopressin on mean blood pressure and heart
rate after local administration into the area of the
nucleus tractus solitarii and after i.v. administration.
Maximal changes in blood pressure and heart rate
which were observed within 5 rain are given in mm of
mercury (mm Hg) and in beats per min (bpm). The
means +- S.E.M. of 4--5 anesthetized rats are listed.
Treatment Blood pressure in mm Hg
Heart rate in bpm
Nucleus tractus Intravenous
solitarii
Vehicle -5 + 4 +2 + 2
-16-+ 6 -31-+11
Angiotensin II -6 +- 8 +18 + 3**
39 pmol -13 + 13 -33 + 10
Angiotensin II +5 +- 5 +41 + 7**
117pmol -28+- 7 -31± 8
Angiotensin II +17 +- 7 +68 + 5**
351pmol -31+ 6 -38 +13
Arg-vasopressin 0 + 12 +22 -+ 5**
41 pmol -30 +- 14 -38 +- 4
Arg-vasopressin -1 + 5 +47 + 11"*
164 pmol -21 + 11 -52 + 18
Arg-vasopressin 0 ± 11 +54 + 3**
656pmol -20+ 8 -128+32"
* p ( 0.05
**p ~ 0.01 ~ compared to the control values after
the administration of vehicle (1 pmol of angio-
tensin II corresponds to 1030 pg and 1 pmol of
arg-vasopressin corresponds to 1051 pg = 0.244
mU).
blockade by intraventricularly administered
phentolamine prevented the fall in blood pres-
sure caused by a-methyldopa (Finch and
Hauesler, 1973). In the present study injection
of phentolamine into the area of the nucleus
tractus solitarii inhibited both the hypotension
and bradycardia induced by ~-methylnoradren-
aline. The present findings thus support the
hypothesis that a-methyldopa acts through

364 F.P. NYKAMP, W. DE JONG
a-adrenoceptor stimulation in this particular
region of the medulla oblongata (Van Zwieten,
1973).
Acknowledgement
We thank Dr. F.C. Nachod of Sterling--Winthrop
Research Institute for providing us with a-methylnor-
adrenaline HC1 (Cobrefin ®).
References
De Jong, W., 1974, Noradrenaline: Central inhibitory
control of blood pressure and heart rate, European
J. Pharmacol. 29, 179.
Finch, L. and G. Hauesler, 1973, Further evidence for
a central hypotensive action of a-methyldopa in
both rat and cat, Brit. J. Pharmacol. 47,217.
Heise, A. and G. Kroneberg, 1972, a-Sympathetic
receptor stimulation in the brain and hypotensive
activity of a-methyldopa, European J. Pharmacol.
17,315.
Henning, M. and A. Rubenson, 1971, Evidence that
the hypotensive action of methyldopa is mediated
by central actions of methylnoradrenaline, J.
Pharm. Pharmacol. 23, 407.
Henning, M. and P.A. Van Zwieten, 1968, Central
hypotensive effect of a-methyldopa, J. Pharm.
Pharmacol. 20, 409.
Nijkamp, F.P., J. Ezer and W. De Jong, 1975, Central
inhibitory effect of a-methyldopa on blood pres-
sure, heart rate and body temperature of renal
hypertensive rats, European J. Pharmacol. 31,243.
Van Zwieten, P.A., 1973, The central action of anti-
hypertensive drugs, mediated via central a-recep-
tor, J. Pharm. Pharmacol. 25, 89.
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Cites result from "α-Methylnoradrenaline induced hypot..."

  • ...This contention is supported by the findings of others obtained in anesthetized animals that reflex bradycardia produced by elevation of arterial pressure is facilitated by the intracisternal administration of clonidine, an a-adrenergic agonist,(34)'(35) that norepinephrine injected directly into NTS acutely and transiently lowers blood pressure and HR (an effect, blocked by a-adrenergic antagonists),(7) and that the depressor effects of a-methylnorepinephrine is mediated, in part, through a-adrenergic receptors within the NTS itself.(36)...

    [...]


References
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Journal ArticleDOI
L. Finch1, G. Haeusler1
TL;DR: The results strongly suggest that the central actions of α‐methyldopa are important for its hypotensive effect, although a possible peripheral effect cannot be excluded.
Abstract: 1. α-Methyldopa (300 mg/kg i.p.) produced a fall in blood pressure in conscious genetic hypertensive rats. Pretreatment with intraventricular 6-hydroxydopamine prevented this hypotensive effect of α-methyldopa, whilst intravenous 6-hydroxydopamine reduced but did not prevent the hypotension. 2. The hypotensive effect of α-methyldopa was prevented or reversed by intraventricular injection of phentolamine (200 μg/rat). 3. Pressor responses obtained by stimulation of the entire sympathetic outflow in the Gillespie & Muir preparation, were unaffected by pretreatment with α-methyldopa (300 mg/kg i.p.). 4. Vasoconstrictor responses to periarterial nerve stimulation of the isolated renal artery preparation of the rat were markedly reduced by pretreatment with α-methyldopa. Furthermore, α-methylnoradrenaline was found to have one-eighth the vasoconstrictor potency of noradrenaline in this particular artery preparation. 5. Pressor responses obtained by stimulation of the posterior hypothalamus or midbrain reticular formation in the rat anaesthetized with urethane were markedly reduced by pretreatment with α-methyldopa. FLA-63, a selective dopamine-β-hydroxylase inhibitor, prevented the reduction of the pressor responses to hypothalamic stimulation produced by α-methyldopa. 6. Stimulation of the posterior hypothalamus in the anaesthetized cat caused both an increase in sympathetic nerve activity and a rise in blood pressure. These responses were markedly reduced 3-4 h after the injection of α-methyldopa (100 mg/kg i.v.). 7. These results strongly suggest that the central actions of α-methyldopa are important for its hypotensive effect, although a possible peripheral effect cannot be excluded.

95 citations


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TL;DR: The formation ofα‐methylnoradrenaline from α‐MD was prevented after FLA‐63 but there was a significant increase in the amounts of α‐methyldopamine formed.
Abstract: Mean arterial blood pressure was recorded in conscious normotensive rats through indwelling arterial catheters. The effect of l-α-methyldopa (α-MD) (400 mg/kg, i.p.) was studied in animals pretreated with α-methyl-m-tyrosine (400 mg/kg i.p.) 27 and 15 h before α-MD, α-methyl-p-tyrosine methylester (H 44/68) (250 mg/kg, i.p.) 1 h before α-MD, and dl-α-hydrazino-α-methyl-β-(3,4-dihydroxyphenyl) propionic acid (MK 485, 100 mg/kg, i.p.) 30 min before α-MD. This pretreatment, which resulted in a severe depletion of endogenous catecholamines, did not alter the hypotensive effect of α-MD. The effect of α-MD (200 mg/kg, i.p.) was studied 30 min after pretreatment with the dopamine β-hydroxylase inhibitor, bis (4-methyl-l-homopiperazinyl-thiocarbonyl) disulphide (FLA-63) (25 mg/kg, i.p.). The hypotensive response to α-MD was completely abolished in these experiments. The formation of α-methylnoradrenaline from α-MD was prevented after FLA-63 but there was a significant increase in the amounts of α-methyldopamine formed.

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Journal ArticleDOI
TL;DR: The results suggest an inhibitory role of an α-adrenoceptor in the area of the nucleus tractus solitarii in the central control of blood pressure in anesthetized rats.
Abstract: Noradrenaline injected bilaterally into the brainstem in the area of the nucleus tractus solitarii decreased systemic arterial blood pressure and heart rate of anesthetized rats. The effect of noradrenaline was prevented by a preceding injection of the α-adrenergic blocking agent phentolamine, at the same site. The results suggest an inhibitory role of an α-adrenoceptor in the area of the nucleus tractus solitarii in the central control of blood pressure.

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Journal ArticleDOI
A. Heise1, G. Kroneberg1
TL;DR: It was concluded that α-methyldopa exerts its blood pressure decreasing effect at least partly by the stimulation of central α-sympathetic receptors.
Abstract: Part of the third and the entire fourth ventricle of cats were perfused with physiological saline containing α-methyldopa, α-methyldopamine or α-methylnoradrenaline. α-Methylnoradrenaline had the greatest depressor effect on blood pressure of these substances. The depressor effect was significantly inhibited by the α-blocking agents yohimbine and phentolamine. It was concluded that α-methyldopa exerts its blood pressure decreasing effect at least partly by the stimulation of central α-sympathetic receptors.

84 citations