Hypertension. 1995;25:139-145
(Hypertension. 1995;25:139-145.)
© 1995 American Heart Association, Inc.
Sustained Hypertension in Dahl Rats
Negative Correlation of Agonist Response to Blood Pressure
Jain-Qiang Kong;
David A. Taylor;
William W. Fleming
From the Department of Pharmacology and Toxicology, West Virginia
University, Robert C. Byrd Health Sciences Center, Morgantown.
 |
Abstract
|
|---|
Abstract The perfused mesenteric vasculature of Dahl
salt-sensitive
rats on a high salt diet for 5 days (prehypertensive or
early
hypertensive) is selectively supersensitive to norepinephrine.
The
present goal was to determine whether that supersensitivity
was
maintained as hypertension developed. Littermates of salt-sensitive
and
salt-resistant rats (Dahl Brookhaven strain) were followed
on low or
high salt for up to 6 weeks. Systolic blood pressure
was elevated in
the salt-sensitive, high salt rats after 3 or
6 weeks but not after 5
days of the diet. The perfused mesenteric
vascular beds from
salt-sensitive rats were supersensitive to
norepinephrine and nerve
stimulation but not to potassium chloride
when the rats had been
maintained for 5 days or 3 weeks on the
high salt diet. However,
responses to norepinephrine declined
after 6 weeks of the high salt
diet. To determine whether sustained
high blood pressure has a negative
effect on mesenteric vascular
responses, we conducted additional
experiments with perfused
mesenteric vascular beds from salt-sensitive
Brookhaven (high
salt, 5 weeks) and Rapp (high salt, 6 weeks) animals.
Both groups
exhibited significant negative correlations between in vivo
systolic
pressure and maximal responses of mesenteric vessels to
norepinephrine
and potassium chloride. We suggest that sustained
hypertension
in Dahl rats has a negative effect on the contractility of
the
mesenteric arterial system that, by 5 to 6 weeks, masks the
initial
supersensitivity to norepinephrine. No effects of any
diet on the
dilating responses of the mesenteric vessels to
acetylcholine were
observed in any group.
Key Words: hypertension blood pressure potassium sodium, dietary norepinephrine acetylcholine mesenteric arteries
 |
Introduction
|
|---|
Among the problems encountered in attempts
to relate vascular
responsiveness to hypertension in animal models have
been the
frequent use of conduit rather than resistance vessels and the
fact
that hypertension per se alters vascular structure and
responsiveness.
1 In an attempt to avoid both of these
problems, Kong et al
2 investigated the responsiveness of
the perfused mesenteric
vascular bed of Dahl salt-sensitive rats on a
high salt diet
for only 5 days, ie, during a prehypertensive or early
hypertensive
period. Kong et al found a selective supersensitivity to
norepinephrine
in the salt-sensitive, high salt group. The sensitivity
to potassium
chloride, angiotensin II, and 5-hydroxytryptamine was no
different
in this group than in control groups.
We undertook the work presented here to determine whether that
selective supersensitivity continued as hypertension developed with
longer exposures to high salt. The discovery that the supersensitivity
was no longer detected when the hypertension was well established (5 to
6 weeks of the high salt diet) led to an investigation of the relation
of the response of the vascular preparation to the in vivo blood
pressure of the animals from which the preparations were taken.
 |
Methods
|
|---|
Animals
Male salt-sensitive and salt-resistant rats (either Brookhaven
strain
[DS and DR] or Rapp strain [SS
JR and
SR
JR]) 3 to 4 weeks of
age were purchased from Harlan
Sprague Dawley (Indianapolis,
Ind) and maintained for approximately 5
days before any treatment.
After the acclimation period, systolic blood
pressures were
measured with tail-cuff plethysmography. All rats were
initially
fed a normal salt diet (0.45% NaCl, Teklad). One day after
blood
pressures were measured, salt-sensitive rats were randomly
assigned
to either normal salt (-) or high salt (+) groups. The normal
salt
group continued to receive normal rat chow, and the high salt
rats
were started on a diet in which NaCl was added to the regular
lab chow
to achieve a final content of 7% NaCl. The salt-resistant
rats were
given the high salt diet. Animals were maintained
on the respective
diets for 5 days to 6 weeks, and systolic
blood pressure measurements
were made by means of tail-cuff
plethysmography weekly and 1 day before
the rats were killed.
Animal use was in accordance with institutional
guidelines.
Tissue Preparation
The isolated perfused mesenteric vasculature was prepared
according to the method originally described by Castellucci et
al3 with modifications previously established in our
laboratory.2 4 This preparation involves the entire
isolated mesenteric vascular bed with the intestinal tract intact.
Preparations were obtained from three rats each day, one each from the
salt-sensitive, normal salt; salt-resistant, high salt; and
salt-sensitive, high salt groups. The rats were stunned and then killed
by cervical dislocation followed by decapitation. Heparin (10 U/100 g
IV) was administered approximately 5 minutes before the rats were
killed to reduce clotting in the fine resistance vessels of the
mesenteric vasculature.2 An incision was made in the
abdomen, the inferior mesenteric and superior pancreaticoduodenal
arteries were ligated, and the superior mesenteric artery was located.
A PE-90 cannula was inserted into the superior mesenteric artery at its
junction with the aorta and was tied in place. The entire mesenteric
vascular bed and intestinal tract were removed from the animal, and the
intestinal contents were flushed out with ice-cold Krebs' solution.
The cecum was identified, ligated, and removed. The preparation was
then mounted on a holding apparatus containing platinum stimulating
electrodes. One ring electrode encircled the proximal portion of the
mesenteric artery. At a position 2.5 cm distal from the ring electrode,
a hook electrode was embedded in the tissue fascia. The apparatus with
the preparation attached was then placed into a 50-mL water-jacketed
organ bath, and the preparation was perfused through the cannula with a
modified Krebs-Henseleit solution of the following composition
(mmol/L): NaCl 117, KCl 4.7, CaCl2 2.5,
KH2PO4 1.2, MgSO4 1.2,
NaHCO3 25, and glucose 11.5. The Krebs-Henseleit solution
was continuously bubbled with a 95% O2/5%
CO2 mixture, was maintained at 37°C, and was
delivered to the tissues at a constant flow of 4 mL/min by means of a
Gilson Minipuls 2 peristaltic pump (Rainin Instrument Co). A
T-tube was inserted between the preparation
and pump and was connected to a P23 AC pressure transducer (Statham
Co), which was used to monitor perfusion pressure. Changes in perfusion
pressure were recorded on a model 79D polygraph (Grass Instrument
Co).
Experimental Protocol
Noncumulative dose-response and frequency-response curves were
determined in individual preparations. Agonists were injected (in bolus
doses) intraluminally into the perfusion fluid near the cannula.
Frequency-response curves were obtained using a Grass model S44
stimulator that produced square-wave pulses of 0.5-millisecond duration
and supramaximal voltage from the platinum electrodes around the
superior mesenteric artery. Preparations were stimulated for 20 seconds
using increasing frequencies, with 2 minutes allowed after each return
to baseline between successive stimulation periods. Cocaine (1
µmol/L) and deoxycorticosterone acetate (30 µmol/L) were added to
the perfusion fluid 20 minutes before dose-response curves with
norepinephrine or frequency-response curves with nerve stimulation were
constructed to prevent any possible differences in neuronal or
extraneuronal uptake from affecting responses between experimental
groups. Responses of the preparations to nerve stimulation and
norepinephrine remain unchanged for up to 5 hours after the perfusion
procedure is begun.2 Multiple dose-response curves could
be constructed on an individual preparation without significant
alteration in responsiveness, permitting comparisons of dose-response
data among different agonists. Depressor responses to acetylcholine
were obtained in preparations in which vasoconstriction was maintained
by an infusion of 20 µmol/L norepinephrine.
Statistical Analysis
Body weight, systolic blood pressure, basal perfusion pressure,
and changes in perfusion pressure were calculated as arithmetic mean
values. The sensitivity of an individual preparation to a given
stimulus was calculated by constructing full dose-response or
frequency-response curves. From each norepinephrine dose-response
curve, the dose increasing perfusion pressure 150 mm Hg
(ED150mmHg) was calculated. From each stimulus-response
curve, the stimulus frequency increasing perfusion pressure 150 mm Hg
(EF150mmHg) was calculated. From each potassium chloride
(KCl) dose-response curve, the dose increasing perfusion pressure 50
mm Hg (ED50mmHg) was calculated, recognizing that the
maximal responses to KCl were much less than to norepinephrine or nerve
stimulation. From these individual data, geometric mean equieffective
doses or stimulus frequencies (the antilogs of the mean logs of the
individual doses or frequencies) were calculated and statistically
compared. For details and appropriateness of geometric means, see
Fleming et al.5 Mean maximal responses were compared using
arithmetic mean values of the maxima obtained for that agonist in that
treatment group.
Statistical analysis was performed using ANOVA followed by the
Newman-Keuls test for comparisons among multiple groups. In a few
instances, as appropriate, Student's t test for paired
samples was used. A value of P
.05 was considered to be
significant. Correlation coefficients obtained from linear regression
analysis were tested for statistical significance using Student's
t test.
 |
Results
|
|---|
Table 1
presents the mean systolic blood
pressures of all groups
of animals in the study. The mean pressure of
salt-sensitive
rats on the high salt diet was significantly greater
than that
of either control group at all treatment periods except 5
days.
The tendency for slightly higher pressure in the DS- versus
DR+
rats was significant only at 3 weeks. There was a tendency
of animals
on the high salt diet to be smaller than those on
a normal diet.
However, this difference in body weight was significant
only for the
salt-sensitive animals on the high salt diet for
6 weeks. The mean
basal perfusion pressures of the isolated
mesenteric vascular
preparations are presented in Table 2
. At
any given
time, basal perfusion pressure did not differ among
experimental
groups.
The first series of experiments examined the frequency-response or
dose-response relations among treatment groups to nerve stimulation,
norepinephrine, and KCl in perfused mesenteric vascular beds in matched
Brookhaven littermates after 5 days, 3 weeks, or 6 weeks of a normal or
high salt diet. The sensitivity of the perfused mesenteric vasculature
was increased in response to norepinephrine (Fig 1A,
Table 3; ED150mmHg for DS+, fourfold less
than either DS- or DR+, P<.05) in the salt-sensitive group
after 5 days of the high salt diet. Similarly, at that time the DS+
group demonstrated enhanced sensitivity to nerve stimulation
(approximately twofold, Table 4), although the
difference reached the .05 level of significance only compared with the
DS- group. After 5 days of the diets, sensitivity to the
vasoconstrictor effects of KCl did not differ among the groups (Table 5). These results are consistent with previous
results2 obtained by our laboratory in Dahl rats on a
5-day diet of high or normal salt. Similar results were obtained with
the same agonists after 3 weeks of the diets (Fig 1B; Tables 3, 4, and 5). The sensitivity to norepinephrine was fivefold greater in the DS+
group than in the DR+ group (Table 3); the DS- group also was
significantly more sensitive to norepinephrine (twofold) than the DR+
group. The DS+ group was statistically more sensitive to nerve
stimulation than either the DS- or DR+ group. However, after 6 weeks
of treatment, the supersensitivity to norepinephrine and nerve
stimulation was no longer apparent (Fig 1C; Tables 3, 4, and 5).
Consistent with the disappearance of supersensitivity, the maximal
responses to norepinephrine were less in the DS+ group at 6 weeks
(196±16 mm Hg) than in the DS+ group at 3 weeks (253±18 mm Hg) or 5
days (256±23 mm Hg) (P<.05). The maximal responses in the
other treatment groups did not vary with the duration of diet.
Dose-dependent depressor responses to acetylcholine were also measured
in the 3- and 6-week groups. As shown in Fig 2, the
responses to acetylcholine did not differ among the groups at either
time period.

View larger version (15K):
[in this window]
[in a new window]
|
Figure 1. Line graphs show effect of duration of normal (-)
vs high salt (+) diet on responses of perfused mesenteric vascular beds
of Dahl (Brookhaven) rats to norepinephrine. Values are mean±SEM of
four to seven preparations (see Table 2 for numbers of preparations per
group). DS indicates salt-sensitive rats; DR, salt-resistant rats. *DS+
mean different (P<.05) from mean in each control group;
**DS+ different (P<.05) from DS-; ***DS+ different
(P<.05) from DR+ group.
|
|
View this table:
[in this window]
[in a new window]
|
Table 4. Geometric Mean Equieffective Frequencies of Nerve
Stimulation for Dahl Brookhaven and Rapp Strains of Rats
|
|

View larger version (17K):
[in this window]
[in a new window]
|
Figure 2. Line graphs show effect of duration of normal (-)
vs high salt (+) diet on responses of perfused mesenteric vascular beds
of Dahl (Brookhaven) rats to acetylcholine. Values are mean±SEM of
four to seven preparations (see Table 2 for numbers of preparations per
group). DS indicates salt-sensitive rats; DR, salt-resistant rats.
|
|
An inspection of the maximal in vivo systolic pressures and maximal
responses to agonists in the preparations from the 6-week DS+ animals
did not suggest any relation between the two measures within the group.
However, the number of preparations was small, and the blood pressures
were relatively similar in all members of the DS+ group. Another
shipment of Brookhaven rats received high or normal salt diets for 5
weeks. Group by group, their mean blood pressures were similar to those
of the 6-week groups above (Table 1). However, the individual blood
pressures were more variable in the DS+ group. Dose-response curves for
norepinephrine (Table 3) indicated that mean ED150mmHg
values among the experimental groups were similar to those in the
6-week group (Fig 1), with the exception of a trend toward greater
sensitivity (P=NS) to norepinephrine in the DS- group.
There was no indication of increased responsiveness in the DS+ group. A
plot of in vivo systolic pressure versus maximal response to
norepinephrine of the isolated preparations from the same DS+ rats
indicated a negative correlation between pressure and maximal responses
to norepinephrine (Fig 3, Table 6), nerve
stimulation (Table 6), and KCl (Table 6). However, there was no such
correlation between in vivo pressure and the maximal depressor effect
of acetylcholine (Table 6). There was also no correlation between
systolic pressure and maximal response to any agonist in the DS- or
DR+ groups at any time. These groups, of course, were not hypertensive
and exhibited little variability in systolic pressure.

View larger version (19K):
[in this window]
[in a new window]
|
Figure 3. Line graph shows negative correlation of in vivo
systolic pressure vs maximal response to norepinephrine (NE) in
isolated mesenteric vascular preparation of salt-sensitive (Brookhaven)
rats after 5 weeks of high salt diet. R=-.70.
|
|
View this table:
[in this window]
[in a new window]
|
Table 6. Correlations Between In Vivo Systolic Pressure and
Maximal Response of Isolated Mesenteric Vasculature to Agonists After 5
or 6 Weeks of High Salt Diet to Salt-Sensitive Rats
|
|
To determine whether this surprising negative correlation
between in vitro maximal pressor response and in vivo systolic pressure
was limited to hypertensive animals of the Brookhaven strain, we
carried out similar experiments with salt-sensitive and salt-resistant
animals of the Rapp strain on high and low salt diets for 6 weeks. As
can be seen in Table 1, the subgroups of the Rapp strain on high or low
salt diets had blood pressures similar to those of the same subgroups
of the Brookhaven strain after 5 or 6 weeks of the diets. Just as in
the Brookhaven DS rats on a high salt diet for 5 or 6 weeks, there was
no indication of enhanced responses in the SSJR+ group to
norepinephrine, nerve stimulation, or KCl (Tables 3, 4, and 5). As is
apparent from Fig 4 and Table 6, the same negative
correlations existed between in vivo systolic pressure and maximal
response of the isolated mesenteric vascular bed to pressor agonists.
Again, as in the Brookhaven preparations, no correlation was detected
between in vivo blood pressure and the maximal depressor effect of
acetylcholine in the mesenteric vascular bed (Table 6). There was also
no correlation between in vivo systolic pressure and responses of the
mesenteric vasculature in SSJR- or SRJR+
rats.

View larger version (19K):
[in this window]
[in a new window]
|
Figure 4. Line graph shows negative correlation of in vivo
systolic pressure vs maximal response to norepinephrine (NE) in
isolated mesenteric vascular preparation of salt-sensitive (Rapp) rats
after 6 weeks of high salt diet. R=-.98.
|
|
Differences in basal perfusion pressure did not contribute to
differences in the responses detailed above. For example, basal
perfusion pressure did not differ among the experimental groups at any
time period (Table 2). Furthermore, in the groups in which maximal
response negatively correlated with in vivo systolic pressure (Figs 3 and 4, Table 6), there was absolutely no correlation between in vivo
systolic pressure and basal perfusion or between basal perfusion
pressure and maximal response (Table 7). Finally, basal
perfusion pressure did not differ between the litter-matched rats in
the 3- or 6-week groups, although the DS+ group demonstrated
selectively enhanced responses to norepinephrine and nerve stimulation
at 3 weeks but not at 6 weeks.
View this table:
[in this window]
[in a new window]
|
Table 7. Lack of Correlation Between Basal Perfusion Pressure
in Perfused Mesenteric Vasculature and Either In Vivo Systolic Pressure
or Maximal Response to Agonists After 5 or 6 Weeks of High Salt Diet to
Salt-Sensitive Rats
|
|
 |
Discussion
|
|---|
The isolated perfused mesenteric vascular preparation has proved
to
be very useful for studies of vascular responsiveness in models
of
hypertension. Since it represents a virtually complete arterial
bed,
changes in perfusion pressure represent the composite effect
of
a number of resistance vessels. Yet, as an isolated preparation,
it
is free of complications caused by reflexes or circulating
vasoactive
substances. Furthermore, it provides highly reproducible
responses to a
variety of agonists over a period of several
hours.
2
Using the perfused mesenteric vascular preparation, this laboratory has
demonstrated that the arterial resistance vessels are selectively
supersensitive to norepinephrine-mediated vasoconstriction
in hypertensive rat models before or early in the appearance of
hypertension (Dahl rats2 and spontaneously hypertensive
rats [SHR]6 ). The responses to norepinephrine are
limited to
1-adrenoceptors,2 7 and the
supersensitivity is independent of endothelial relaxant factors,
extraneuronal uptake, and neuronal uptake.2 6 Although
there is evidence of altered neuronal uptake of norepinephrine in Dahl
salt-sensitive, high salt animals2 and SHR,8
the selective supersensitivity in salt-sensitive, high salt rats is
demonstrable even when uptake is blocked in all groups.2
Furthermore, the supersensitivity is not related to differences in the
amount of released neurotransmitter.9 The early appearance
of the supersensitivity of the smooth muscle to
1-adrenoceptor agonists suggests that the
supersensitivity may contribute to the development of the
hypertension.
The present results also indicate that there is a tendency for the
mesenteric vasculature of the DS- group to be more sensitive to
norepinephrine relative to the DR+ group at some time periods. This
enhanced responsiveness is not as pronounced or consistent as it is in
the DS+ group. This tendency in the DS- group may indicate that even
the 0.45% NaCl diet represents a modest overload of salt for DS
rats. Alternatively, it may represent a genetic difference that is
marginally expressed even in the absence of salt load that is
additionally expressed in the presence of a persistent high salt diet.
DS- rats do tend to have somewhat elevated systolic blood pressure, as
is found here and in other reports,2 10 11 when fed a
"normal" diet of 0.45% NaCl. The DS- group, at least on the
normal salt diet, appears to represent a borderline hypertensive
group with characteristics intermediate between the DS+ and DR+
groups.
Responsiveness in blood vessels after hypertension has developed is
more complex. Established hypertension can induce structural changes in
blood vessel walls characterized by an increase in arterial wall
thickness and/or the wall-to-lumen ratio. As reviewed by Heagerty et
al,12 this relation has been demonstrated in hypertensive
humans as well as several rat models, including SHR; coarctation of the
aorta; deoxycorticosterone acetatesalt; chronic angiotensin infusion;
one-kidney, one clip; and two-kidney, one clip. In an extensive
morphometric analysis, Lee and Triggle10 documented
medial thickening in the superior mesenteric artery as well as its
large and small branches in DS rats on a high salt diet for 6 to 7
weeks. The altered geometry of the vascular wall is generally
considered to result in enhanced nonspecific responsiveness from an
increase in slope and maxima of concentration-response curves to
unrelated pressor agonists without alterations in threshold or median
effective concentration.1 13 Such an effect has been
reported in the isolated mesenteric vascular bed of SHR.14
Indeed, in SHR, which have a genetic predisposition for an altered
wall-to-lumen ratio, the increase in slope and maxima of agonist
concentration-response curves is clearly demonstrable at an early age,
when the development of hypertension is marginal.6
We undertook the present experiments to determine what happens to
agonist dose-response curves in Dahl salt-sensitive rats on a high salt
diet as the hypertensive state advances. The results confirmed the
selectively enhanced responses to norepinephrine and to sympathetic
nerve stimulation in young DS rats on a high salt diet for only 5
days,2 a time when the blood pressure, as measured by tail
cuff, of the DS+ rats was not different from that of control groups. In
contrast to the earlier study, the present results included an
increased maximal response to norepinephrine. The selective
supersensitivity to norepinephrine was maintained in the DS rats on the
high salt diet for 3 weeks but was no longer apparent after 6 weeks of
the diet. Indeed, at 5 or 6 weeks, neither the selective
supersensitivity to norepinephrine, present after 5 days or 3 weeks
of the high salt diet, nor the nonselective enhanced responses to
agonists expected from structural changes of established hypertension
was demonstrable. Therefore, one must conclude that although enhanced
responsiveness to sympathetic nerve stimulation and circulating
catecholamines may contribute to the development of hypertension in DS+
rats, they do not contribute to the maintenance of vasoconstriction in
the mesenteric vascular bed in rats with chronic hypertension. If the
mesenteric bed is typical of other resistance vessels in this model,
the maintenance of hypertension must depend on other factors (such as
increased sympathetic nerve activity, renin, or fluid volume).
Our findings of an enhanced response to nerve stimulation and greater
neuronal uptake in the mesenteric vascular beds from prehypertensive or
early hypertensive Dahl salt-sensitive rats fed a high salt diet for 5
days2 and the supersensitivity in early hypertension (3
weeks, present results) are consistent with existing evidence of
altered adrenergic mechanisms in hypertensive Dahl
rats.15 16 Takeshita and Mark15 determined
that 50% of the elevated vasoconstriction in the perfused hindquarters
of DS+ rats with established hypertension was neurogenically
maintained. In a subsequent study from the same
laboratory,16 it was found that destruction of the
sympathetic nervous system with 6-hydroxydopamine
prevented the development of hypertension in the animals and the
development of elevated resistance in the perfused hindquarters. In
addition, DS rats demonstrate a greater rate of adrenal synthesis of
catecholamines compared with DR rats.17 Genain et
al11 reported that salt loading fails to inhibit
norepinephrine turnover in heart and brown fat of prehypertensive DS
rats but not of DR rats. Thus, the overall picture is one of increased
supply of norepinephrine combined with enhanced responsiveness to
norepinephrine contributing to the development of hypertension in
salt-sensitive rats.
The absence of enhanced responses in the mesenteric vasculature of DS
animals after 6 weeks of a high salt diet is therefore surprising.
However, the investigation of the relation between blood pressure and
maximal response of the mesenteric vasculature to norepinephrine, nerve
stimulation, and KCl in both DS and SSJR rats on 5 to 6
weeks of a high salt diet shows that higher pressures are associated
with lesser responses to all three pressor procedures. These results
suggest that, at least in the mesenteric arterial bed, prolonged high
pressure leads to a nonspecific loss of responsiveness to
vasoconstrictors that masks the earlier supersensitivity to
norepinephrine in salt-sensitive rats on a high salt diet.
Existing evidence indicates that prolonged hypertension in Dahl
salt-sensitive rats on a high salt diet induces vascular hypertrophy
and/or luminal narrowing of mesenteric,10
renal,18 19 and retinal vessels,20 21 as
observed in vessels of other models of hypertension. These structural
changes are commonly associated with nonspecific increases in slopes
and maxima of vasoconstrictor concentration-response curves. The
absence of such changes in slope and maxima in the mesenteric
vasculature may be due to the nonspecific loss of contractility in
chronic hypertensive Dahl animals reported here. Since this loss of
contractility is in contrast to what is observed in SHR (see, for
example, Longhurst et al14 ), it seems that the loss of
responsiveness is a consequence either of the genetics of the Dahl rat
or of the prolonged effect of the high salt diet interacting with the
elevated pressure.
A recent report has documented the fact that Dahl SSJR rats
have been genetically contaminated such that some of them do not become
hypertensive despite a high salt diet.22 This is likely to
be the reason that some SSJR rats on the high salt diet for
6 weeks did not become hypertensive in the present study. However,
this cannot explain the fact that in both Dahl Brookhaven and Rapp
animals, those rats that did become hypertensive had clearly depressed
responses to norepinephrine, nerve stimulation, and KCl.
There is evidence that DS+ rats with established hypertension
experience endothelial damage in the mesenteric artery10
and that inhibitory responses to acetylcholine, which acts by the
release of endothelium-dependent relaxing factor, are
depressed in aortic preparations from Dahl animals with established
hypertension.23 Aortic rings from hypertensive Dahl rats
fed a high salt diet for 3 weeks demonstrated maximal relaxations to
acetylcholine inversely related to in vivo pressures.24 In
contrast, no such inverse relation was observed in the present
experiments between depressor responses to acetylcholine in the
mesenteric vasculature and in vivo systolic pressures in preparations
from either Brookhaven or Rapp animals with established hypertension.
Prior work2 had already established that 5 days of a high
salt diet did not alter responses to acetylcholine. Thus, the depressed
response to acetylcholine associated with high pressure in the
mesenteric circulation is apparently limited to pressor substances.
Although the mesenteric arterial system shows physical signs of
endothelial damage,10 it is apparently less susceptible to
the deleterious effects of sustained hypertension on
endothelium-induced relaxation than the aorta.
The nonspecific nature of the depressed responses of the vessels of
rats on a high salt diet with sustained hypertension to contractile
agents suggests a defect in the contractile mechanism or in the
regulation of intracellular free calcium rather than alterations in
receptors or specific transduction processes. It has been
reported25 that single-channel potassium current in aortic
smooth muscle membranes of SHR with sustained hypertension is enhanced.
However, in SHR responses to norepinephrine are
enhanced8 14 because of the structural changes in the
arteries1 despite the increased K+
conductance. Thus, even if enhanced K+ conductance were to
be found in the mesenteric vascular smooth muscle of hypertensive Dahl
rats, such a finding could not by itself explain why the responses to
agonists are depressed in the presence of similar structural changes in
the arterial wall. Clearly, the identification of the mechanism of the
depressed responses unique to sustained hypertension in Dahl animals
can only occur with further experiments at the cellular level.
 |
Acknowledgments
|
|---|
This work was supported by grant 5 R01 GM29840 from the National
Institutes
of Health, Bethesda, Md.
 |
Footnotes
|
|---|
Reprint requests to William W. Fleming, PhD, Department of Pharmacology
and Toxicology, West Virginia University, Robert C. Byrd Health
Sciences Center, PO Box 9223, Morgantown, WV 26506-9223.
Received January 24, 1994;
first decision March 9, 1994;
accepted August 30, 1994.
 |
References
|
|---|
-
Folkow B. `Structural factor' in primary and
secondary hypertension. Hypertension. 1990;16:89-100.
-
Kong JQ, Taylor DA, Fleming WW, Kotchen TA. Specific
supersensitivity of the mesenteric vascular bed of Dahl salt-sensitive
rats. Hypertension. 1991;17:349-356. [Abstract/Free Full Text]
-
Castellucci A, Bacciarelli C, Boni P, Fedi M. The rat
mesenteric artery-intestinal loop preparation.
Arzneimittelforschung. 1981;31:54-58. [Medline]
[Order article via Infotrieve]
-
Longhurst PA, Rice PJ, Taylor DA, Fleming WW. Sensitivity of
caudal arteries and the mesenteric vascular bed to norepinephrine in
DOCA-salt hypertension. Hypertension. 1988;12:133-142. [Abstract/Free Full Text]
-
Fleming WW, Westfall DP, DeLaLande IS, Jellett LB. Log-normal
distribution of equieffective doses of norepinephrine and acetylcholine
in several tissues. J Pharmacol Exp Ther. 1972;181:339-345. [Abstract/Free Full Text]
-
Kong JQ, Taylor DA, Fleming WW. Mesenteric vascular responses
of young spontaneously hypertensive rats. J Pharmacol Exp
Ther. 1991;258:13-17. [Abstract/Free Full Text]
-
Kong JQ, Taylor DA, Fleming WW. Antagonism of norepinephrine
by clonidine in the isolated rat mesenteric vascular bed. J
Pharmacol Exp Ther. 1991;259:653-658. [Abstract/Free Full Text]
-
Head RJ. Hypernoradrenergic innervation: its relationship to
functional and hyperplastic changes in the vasculature of the
spontaneously hypertensive rat. Blood Vessels. 1989;26:892-897.
-
Kong JQ, Curto KA, Fleming WW, Kotchen TA, Taylor DA.
Catecholamine and neuropeptide Y levels in tissues from young Dahl rats
following 5 days low- or high-salt diet. Blood Vessels. 1991;28:442-451. [Medline]
[Order article via Infotrieve]
-
Lee RMKW, Triggle CR. Morphometric study of mesenteric
arteries from genetically hypertensive Dahl strain rats. Blood
Vessels. 1986;23:199-224. [Medline]
[Order article via Infotrieve]
-
Genain CP, Reddy SR, Ott CE, Van Loon GR, Kotchen TA. Failure
of salt loading to inhibit tissue norepinephrine turnover in
prehypertensive Dahl salt-sensitive rats.
Hypertension. 1988;12:568-573. [Abstract/Free Full Text]
-
Heagerty AM, Aalkjaer C, Bund SJ, Korsgaard N, Mulvany
MJ. Small artery structure in hypertension: dual processes of
remodeling and growth. Hypertension. 1993;21:391-397. [Free Full Text]
-
Folkow B, Karlstrom G. Vascular reactivity in hypertension:
importance of structural influences. J Cardiovasc Pharmacol. 1987;4:525-530.
-
Longhurst PA, Stitzel RE, Head RJ. Perfusion of the
intact and partially isolated rat mesenteric vascular bed: application
to vessels from hypertensive and normotensive rats. Blood
Vessels. 1986;23:288-296. [Medline]
[Order article via Infotrieve]
-
Takeshita A, Mark AL. Neurogenic contribution to hindquarters
vasoconstriction during high sodium intake in Dahl strain of
genetically hypertensive rat. Circ Res.
1978;43(suppl I):I-86-I-91.
-
Takeshita A, Mark AL, Brody MJ. Prevention of salt-induced
hypertension in the Dahl strain by 6-hydroxydopamine.
Am J Physiol. 1979;236:H48-H52.
-
Racz K, Kuchel O, Buu NT. Abnormal adrenal catecholamine
synthesis in salt-sensitive Dahl rats.
Hypertension. 1987;9:76-80. [Abstract/Free Full Text]
-
Uehara Y, Numabe A, Hirawa N, Kawabata Y, Iwai J, Ono H,
Matsuoka H, Takabatake Y, Yagi S, Sugimoto T. Antihypertensive effects
of cicletanine and renal protection in Dahl salt-sensitive rats.
J Hypertens. 1991;9:719-728. [Medline]
[Order article via Infotrieve]
-
Uehara Y, Numabe A, Kawabata Y, Nagata T, Iwai J, Matsuoka H,
Yagi S, Takabatake Y, Sugimoto T. Evidence of medial-mass regression in
the vascular wall of Dahl hypertensive rats by cicletanine treatment.
J Cardiovasc Pharmacol. 1991;18:158-166. [Medline]
[Order article via Infotrieve]
-
Cristofori P, Terron A, Micheli D, Bertolini G, Gaviraghi G,
Carpi C. Vascular protection of lacidipine in salt-loaded Dahl-S rats
at nonsustained antihypertensive doses. J Cardiovasc
Pharmacol. 1991;17(suppl 4):S75-S86.
-
Gaviraghi G, Micheli D, Terron A, Cristofori P. Lacidipine:
prevention of vascular damage induced by hypertension. J
Cardiovasc Pharmacol. 1991;18(suppl 11):S7-S12.
-
Lezin EM, Pravenec M, Wong A, Wang J-M, Merriouns T, Newton S,
Stec DE, Roman RJ, Lau D, Morris RC, et al. Genetic contamination of
Dahl SS/JR rats: impact on studies of salt-sensitive hypertension.
Hypertension. 1994;23:786-790. [Abstract/Free Full Text]
-
Luscher TF, Raij L, Vanhoutte PM. Endothelium-dependent
vascular responses in normotensive and hypertensive Dahl rats.
Hypertension. 1987;9:157-163. [Abstract/Free Full Text]
-
Krishnankutty S, Kurtz TW, Yock PG, Connolly AJ, Morris RC Jr.
Potassium preserves endothelial function and enhances aortic compliance
in Dahl rats. Hypertension. 1993;22:315-322. [Abstract/Free Full Text]
-
England SK, Wooldridge TA, Stekiel WJ, Rusch NJ. Enhanced
single-channel K+ current in arterial membranes from
genetically hypertensive rats. Am J Physiol. 1993;264:H1337-H1345.[Abstract/Free Full Text]
This article has been cited by other articles:

|
 |

|
 |
 
G. D'Angelo, J. S. Pollock, and D. M. Pollock
Endogenous endothelin attenuates the pressor response to acute environmental stress via the ETA receptor
Am J Physiol Heart Circ Physiol,
April 1, 2005;
288(4):
H1829 - H1835.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
T. Ikeda, H. Ohta, M. Okada, N. Kawai, R. Nakao, P. K. S. Siegl, T. Kobayashi, S. Maeda, T. Miyauchi, and M. Nishikibe
Pathophysiological Roles of Endothelin-1 in Dahl Salt-Sensitive Hypertension
Hypertension,
September 1, 1999;
34(3):
514 - 519.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
L. V. d'Uscio, M. Barton, S. Shaw, P. Moreau, and T. F. Luscher
Structure and Function of Small Arteries in Salt-Induced Hypertension : Effects of Chronic Endothelin-Subtype-A–Receptor Blockade
Hypertension,
October 1, 1997;
30(4):
905 - 911.
[Abstract]
[Full Text]
|
 |
|