Clinical Science and Molecular Medicine (1978) 55,105s-107s
Hypertension and brain catecholamine distribution in the
Hebrew University Sabra, H and N rats
N . Z A M I R , * Y. G U T M A N ?
AND
D. B E N - I S H A Y ( I )
Department of Pharmacology, The Hebrew University Hadassah School of Medicine and Pharmacy and
“’Department of Internal Medicine, Hadassah University Hospital, Jerusalem, Israel
Summary
Introduction
1. The concentration of catecholamines was
measured in several brain areas of the Hebrew
University Sabra rat (SB rat), and in two substrains
selected for their respective sensitivity (H) or
immunity (N) to hypertension.
2. Hypertension was induced in SB rats by
DOCA-salt, renal artery constriction and NaCl
1.7% drinking. The noradrenaline content was consistently elevated in the medulla oblongata of
hypertensive animals. In other brain areas the rise
in noradrenaline varied in the different types of
hypertension.
3. Administration of DOCA-salt to H and N
rats, while causing marked hypertension in the
former, had no effect on noradrenaline in either
strain.
4. Untreated, normotensive N rats had in the
medulla oblongata, significantly higher concentrations of noradrenaline than did H rats.
5. Differences in brain noradrenaline may
explain the inherited susceptibility or resistance to
hypertension in H and N rats.
In recent years, experimental evidence has been
produced that central catecholaminergic neurons
participate in the regulation of blood pressure
(Chalmers, 1975). A reduction in noradrenaline
concentration (Yamori, Lovenberg & Sjoerdsma,
1970) or turnover (Haeusler, Finch & Thoenen,
1972; Nakamura, Gerold & Thoenen, 1971), has
been reported in the brain stem and hypothalamus
in different models of experimental hypertension.
The purpose of this study was to determine the
effect of hypertension induced by various procedures, on the concentration of catecholamines
(CA) in brain areas of the Hebrew University
Sabra rat. Catecholamines were also studied in two
substrains derived from the SB rat which were
selected for their respective susceptibility (H) or
resistance (N) to hypertension (Ben-Ishay, Saliternick & Welner, 1972). The results of these studies
were presented at the 36th meeting of the Israel
Physiological and Pharmacological Society, June
1976 (Zamir, Gutman & Ben-Ishay, 1976).
Methods
Key words: brain catecholamines, genetic hypertensive rats.
Abbreviations; NA, noradrenaline; SB rat, Sabra
rat.
* Present address: Isotope Dept., Weizman Institute of
Science, Rehovot, Israel.
f’ Established Investigator of the Chief Scientist’s
Bureau, Israel Ministry of Health.
Correspondence: Drori Ben-Ishay, Department of
Medicine, Hadassah University Hospital, P.O. Box
24035, IL-91 240 Jerusalem, Israel.
105s
Hypertension was induced in male rats (150-200
g) by (a) uninephrectomy and administration of
DOCA (12.5 mg/kg subcutaneously) on alternate
days and 0.9% NaCl as drinking fluid; (b) renal
artery constriction with silver clips (internal
diameter 0.2 mm) and (c) administration of 1.7%
NaCl for 35 days as the sole drinking fluid.
Indirect systolic blood pressure was measured
under light ether anaesthesia by means of a pulse
transducer.
The animals were decapitated, the brains rapidly
106s
N. Zamir, Y. Gutman and D . Ben-Zshay
excised, chilled in ice, and dissected along natural
demarcation lines into: medulla oblongota, mesencephalon, hypothalamus, extrapyramidal nuclei
and cortex. Catecholamines were assayed by a
slight modification of the trihydroxyindole method
as described by Feurstein, Boonyaviroj & Gutman
(1977). Results are expressed as means f SEM.
For statistical analysis, Student’s t-test was used.
i lo8
Results
Brain catecholamine in various types of hypertension in SB rats
In DOCA-salt-treated rats the blood pressure
rose to 191 k 4 mmHg as compared with 121 k 1
mmHg in controls. The rise in blood pressure was
associated with a significant increase in NA concentration in the medulla oblongata (38%), mesencephalon (54%), hypothalamus (34%) and extrapyramidal nucleus (28%). Renal artery constriction caused a rise in blood pressure to 208 f 5
mmHg as compared with 117 f- 1 mmHg in
controls. The hypertensive animals had a significant increase in NA concentration in medulla
oblongata (33%), mesencephalon (35%), hypothalamus (43%) and cortex (26%). Rats subjected
to chronic saline drinking developed a moderate
degree of hypertension (133 k 2 mmHg vs 114 f
1 mmHg in controls). In these animals a significant
increase in NA was observed only in the medulla
oblongata (33%).
Thus a significant increase in NA content in the
medulla oblongata was a consistent finding in three
models of experimental hypertension, whereas in
the other brain regions variable results were
obtained. No significant changes in dopamine
content were observed in any brain region in these
or subsequent experiments.
Brain NA in DOCA-salt-treated H and N rats
As previously reported (Ben-Ishay et al., 1972),
untreated H rats have significantly higher blood
pressure than N rats (130 k 2 mmHg vs 1 16 i I
mmHg respectively). In DOCA-salt treated H rats,
the blood pressure rose to 187 +_ 4 mmHg (142 +_ 1
mmHg in H controls). Similarly treated N rats
showed a slight elevation in blood pressure (138 k
3 mmHg) compared with controls (120 +_ 3
mmHg).
In sharp contrast to the rise in NA observed in
DOCA-salt-treated SB rats, H and N rats showed
no significant changes in NA concentration in any
FIG. 1. NA concentration in brain areas of untreated
rats. Blood pressures were as follows: H, 134 mmHg; N,
119 mmHg; Sabra (S), 120 mmHg. ***P < 0.001; **P
< 0.02; *P < 0.05. M.O., medulla oblongata; Mes,
mesencephalon; E.P.N., extrapyramidal nuclei; Cor,
cortex; Hyp, hypothalamus.
of the examined brain regions, following the above
treatment.
Brain NA in untreated H , N a n d S B rats
The distribution of NA was determined in the
brains of untreated rats of the three strains. Their
respective blood pressures were: H, 134 ? 1
mmHg; N, 119 f 2 mmHg; SB, 120 & 1 mmHg.
The most remarkable finding was that for the
region of the medulla oblongata (Fig. 1). The
concentration of NA in N rats was 30% higher
than in SB rats (P< 0.02), whereas in H rats it was
49% lower than in SB rats (P < 0.001). A
comparison of H and N rats showed a striking
difference of 90% between the two strains (P <
0.001). In the other brain areas, the content of N A
was similar in the three strains except for the hypothalamus where an elevation of borderline significance was found in N rats, when compared with
SB rats (P < 0.05).
Discussion
The distribution pattern of N A and dopamine in
SB, H and N rats was found to be generally in
good agreement with previous reports (Holman,
Angwin & Barchas, 1976). The relatively lower
NA values obtained in this study may be ascribed
to differences in strain and/or assay specificity.
Induction of hypertension in the SB rat by three
different methods was generally associated with an
Hypertension and brain catecholamine
increase in N A concentration in the brain,
particularly in the medulla oblongata where a
significant increase in N A was found in every
experiment. In the other brain areas the increase in
NA varied in the different experimental models.
Administration of DOCA-salt produced a marked
hypertensive response in the H rats as opposed to
N rats. The NA concentration, however, was not
affected by this treatment in either strain.
The outstanding finding in this study was the
high N A content in the medulla oblongata of
untreated N rats, as compared with H rats. The
role of the medulla oblongata in the control of
blood pressure has been studied by numerous
investigators, and evidence has been presented in
support of a sympatho-inhibitory noradrenergic
mechanism located in this area (Haeusler, 1973).
Our findings in the H rat are in agreement with
earlier studies in which a decreased catecholaminergic activity was reported in the brain stem of
spontaneously hypertensive rats (Yamori et al.,
1970). More recently a decreased NA turnover was
reported in the brain stem of DOCA hypertensive
rats, which was interpreted as a primary dysfunction in vasomotor centres of baroreceptor
functions (Van Ameringen, De Champlain &
Imbeault, 1977). In the light of present knowledge,
it is possible that the elevated NA content in the
medulla oblongata of untreated N rats provides
these animals with an inherited defence mechanism
against hypertension.
Conversely, the low N A content in the medulla
oblongata of untreated H rats may explain, at least
in part, their inherited predisposition to hyper-
107s
tension. According to this concept, the increased
N A in the medulla oblongata of SB rats, made
hypertensive by various procedures, may represent
a defence mechanism against hypertension rather
than its cause.
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