Download Contrasting Regression of Blood Pressure and

Contrasting Regression of Blood Pressure and Cardiovascular
Structure in Declipped Renovascular Hypertensive Rats
Stinne Kvist, Michael J. Mulvany
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Abstract—We investigated the time relationship between changes in blood pressure and changes in the structure of
the resistance vasculature. Blood pressure, heart/body weight ratio, and morphology and function of mesenteric
resistance arteries from 1-kidney, 1-clip renovascular hypertensive rats were followed before and after declipping
at age 14 weeks. The rats were divided into 5 groups, which were investigated 6 hours, 24 hours, 1 week, 4 weeks,
and 8 weeks after declipping and compared with 2 normotensive and 2 renovascular hypertensive control groups
at 14 weeks and 18 weeks. Systolic blood pressure was elevated 2 weeks after application of the clip and stabilized
after 6 weeks. Declipping induced a prompt fall in blood pressure within 6 hours, and blood pressure was
normalized within 1 week. Heart/body weight ratio was increased in renovascular hypertensive rats, and declipping
induced a gradual decrease in the ratio, which was normalized within 4 weeks. Media/lumen ratio and media area
of mesenteric resistance arteries were increased in renovascular hypertensive rats, and declipping did not affect
media/lumen ratio and media area within 8 weeks, although there was a tendency for some regression of
media/lumen ratio. There were no differences in response to high potassium, noradrenaline, or acetylcholine. Thus,
these findings show definitively that declipping causes rapid reversal of renovascular hypertension in rats
accompanied by gradual reduction of the heart/body weight ratio but lack of normalization in the mesenteric
resistance vessels. This provides clear evidence that neither vascular nor cardiac structural changes are capable of
keeping rats hypertensive. (Hypertension. 2003;41:540-545.)
Key Words: hypertension, renal 䡲 rats 䡲 hypertrophy 䡲 arteries 䡲 blood pressure 䡲 heart 䡲 kidney 䡲 remodeling
H
ypertension is complicated by hypertrophy of the heart
and abnormal structure of peripheral arteries in renovascular hypertensive rats1 and spontaneously hypertensive rats
(SHR),2 as well as in humans with essential3 or renovascular
hypertension.4 Hypertension and the abnormal structure of
the heart and vessels in SHR and essential hypertension can
be reversed by pharmacological treatment,2,5–7 but the cause
of the disease has not been treatable. In contrast, the cause of
renovascular hypertension is known and can be removed and
indeed appears to be the only way to normalize the blood
pressure, as pharmacological treatment is difficult and seldom
effective. Because the structural changes of heart and vessels
occur in parallel with the high blood pressure in all forms of
hypertension,8 it has been suggested that the structural
changes may be one of the causes of hypertension, or at least
contribute to the maintenance of hypertension.8,9 However,
there are a number of reports indicating that after an intervention, vascular structure and pressure are not correlated.10,11 For example, when the renal artery stenosis is removed in 1-kidney, 1-clip (1K-1C) rats, blood pressure
returns to normotensive levels almost immediately,12 whereas
similar observations have been made concerning the angiotensin II infusion model of hypertension after cessation of
infusion.13 In both cases, the rapidity of the blood pressure
fall makes it likely that the fall occurs before any regression
of resistance vessel structure,14 –16 but there is no direct
evidence on this point. Stacy and Prewitt16 found little change
in cremaster arteriole structure either before or 4 weeks after
declipping measured histologically, although in vivo measurements indicated that 1K-1C hypertension was associated
with structural changes that partially regressed after declipping. Indirect evidence for slow regression of resistance
vessel structure after declipping was obtained in perfusion
experiments in the hindquarter preparation.15 Slow regression
of heart weight after declipping has also been reported.14 We
therefore decided to examine this question directly in the
resistance vasculature and to test critically the hypothesis that
blood pressure and resistance vessel structure are not necessarily
correlated after an intervention that corrects hypertension. To
address this hypothesis, the current study was performed in
1K-1C rats in which hypertension is pronounced17 and independent of renin.18 After development of a stable high blood
pressure, we removed the clips and studied the time relationship
of the regression of blood pressure, heart and kidney weight, and
resistance artery morphology measured on a myograph from 6
hours to 8 weeks thereafter.
Received July 24, 2002; first decision August 14, 2002; revision accepted December 18, 2002.
From the Department of Pharmacology, University of Aarhus, Denmark.
Correspondence to Dr Stinne Kvist, Department of Pharmacology, Bartholin Building, University of Aarhus, 8000 Aarhus C, Denmark. E-mail
[email protected]
© 2003 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
DOI: 10.1161/01.HYP.0000054977.07679.59
540
Kvist and Mulvany
Blood Pressure, Heart, and Vessels in Declipped Rats
Methods
Materials
541
vessels were bubbled with 5% CO2 in air and allowed to equilibrate
at 37°C for 30 minutes.
Morphometric Measurements
One hundred ninety-nine Male Wistar rats were received (5 weeks
old) from Møllegaard Breeding Center, Lille Skensved, Denmark.
An equilibration period for at least 4 days was allowed before the
start of experimental procedures. The rats had free access to food and
tap water except at the time of blood pressure measurements (see
below). All rats were killed by exposure to CO2 for final studies.
Health status was supervised by the local animal welfare officer,
and all experiments were performed according to Danish legislation.
After equilibration, the myograph was placed on a microscope and
wall structure was measured at 6 different positions by an ocular
micrometer.20 Vessels were then set to normalized diameter, l1, that
is, 0.9 times the internal diameter the vessels would have if fully
relaxed and exposed to a transmural pressure of 100 mm Hg,
calculated on the basis of the Laplace relation.19,21 Mean of media
thickness and internal diameter was expressed as media/lumen ratio.
Protocol for Grouping
Functional Measurements
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The rats were divided into a normotensive, sham-operated group
(sham) of 30 rats and a hypertensive 1K-1C group of 101 rats. All
operations were performed in rats 6 to 7 weeks of age. The sham rats
were subdivided in 2 groups with 15 rats in each, which were studied
at 14 and 18 weeks of age, respectively. The 1K-1C rats were
randomly subdivided into 7 groups: 2 groups with 15 rats in each,
which served as hypertensive controls (control 1K-1C) at 14 and 18
weeks of age, respectively, and 5 groups that were declipped
(declipped 1K-1C) at 14 weeks of age, and the rats were subsequently killed 6 hours (16 rats), 24 hours (14 rats), 1 week (16 rats),
4 weeks (15 rats), and 8 weeks (10 rats) after declipping.
Blood Pressure
Systolic blood pressure was measured by the tail-cuff method with a
plethysmograph (LE5000, Lettica). Before measurements, rats were
preheated for 20 to 30 minutes at 35°C in their cages. Rats were then
moved to a small heated container, where the rats were trained to
stay for periods up to 20 minutes. In each rat, 4 to 6 measurements
were made and mean values were used. The equipment was
calibrated every day by comparison with a mercury column.
Blood pressure measurements in 1K-1C rats were made before
insertion of clips, 2 weeks after and every week hereafter until
systolic blood pressure increased above 160 mm Hg. Afterward,
blood pressure was measured in control 1K-1C rats at the time of
killing, whereas in declipped 1K-1C it was measured just before
declipping and at the time of killing. Blood pressure measurements
in the sham rats took place just before sham operation and at the time
of killing.
Preparation of Sham and 1K-1C Rats
Rats were anesthetized with 7 mg/kg IP methohexital, and, if
necessary, supplemented with small doses of methohexital directly to
the abdominal cavity during the operation. The fur was shaved off
the abdomen and the operation was performed through a 4-cm
longitudinal incision as described by Stacy and Prewitt.16 The left
renal artery was dissected free of fat and connective tissue, and in
animals chosen to be hypertensive, a U-shaped silver clip, 230- to
250-␮m internal diameter, was placed around the renal artery as far
from the kidney as possible. Afterward, the right kidney was
removed and the incision was closed by suturing the muscular layer
and by attaching wound clips to the skin. Sham rats were prepared by
the same procedure as the 1K-1C rats apart from the application of
a clip. In declipped rats, the clips were gently removed from 1K-1C
rats after cleaning for adhesive tissue in an operation through the
initial incision.
In Vitro Protocols
Dissection
After killing with exposure to CO2, the rat was weighed and heart,
kidney, and a piece of the mesenteric vascular bed were cut out and
placed in ice-cold physiological salt solution (PSS, see below for
composition). The atria of the heart were cut away and the heart was
wiped with paper and weighed. The kidney was cleaned from fat and
connective tissue, wiped with paper, and weighed. From the mesenteric vascular bed, 2 segments of vessels from the third branch, 2 mm
long and with an internal diameter of ⬇230 ␮m, were dissected free
from fat and mounted in a wire myograph.19 In the myograph,
After normalization, vessels were exposed to PSS with potassium
(K-PSS, see below for composition) for 2 minutes as a measure of
contractile capacity. A concentration response curve to acetylcholine
(10⫺8–10⫺5 mol/L) was performed on top of a precontraction with 3
␮mol/L noradrenaline by adding the drug in half-logarithmic concentrations to the bath every second minute.
Exclusion Criteria
Rats were excluded from the study if (1) systolic blood pressure in
rats with clips was below 165 mm Hg after 8 weeks; (2) systolic
blood pressure in sham rats was above 140 mm Hg; (3) internal
diameter of the vessels in the myograph was below 150 ␮m or above
350 ␮m; (4) active pressure response of the vessels [active wall
tension/(l1/2)]21 to K-PSS for 2 minutes was below 13 kPa; (5) if
renal scars caused by renal infarction were present at the time of
killing.
Solutions and Drugs
Physiological salt solution consisted of (mmol/L): 119 NaCl, 4.7
KCl, 1.17 MgSO4,7H2O, 25 NaHCO3, 1.18 KH2PO4, 0.0026 EDTA,
5.5 glucose, and 1.6 CaCl2. In K-PSS, NaCl was replaced with
equimolar KCl.
Drugs used were methohexital (Brietal7, Lilly), (⫺)noradrenaline
hydrochloride (Sigma Chemicals Co), and acetylcholine (Fluka AG).
Data Analysis
Analysis was based on the mean of the 2 vessels taken from each
animal. All values are given as mean⫾SEM. One-way ANOVA was
used for comparisons between groups. If ANOVA showed a significant difference, data were analyzed by the Student 2-tailed, unpaired
t test and linear regression for specified groups. A value of P⬍0.05
was considered significant.
Results
Basal Characteristics
After the application of the clips or sham operation at age 6
to 7 weeks old, 68 rats (34%) were lost as the result of
uremia/malignant hypertension (n⫽46), rupture of the renal
artery when declipping (n⫽8), anesthesia (n⫽6), infarction of
the kidney (n⫽1), unknown reason (n⫽7), or exclusion
according to the above exclusion criteria.15 This left 131 rats
for investigation.
Before application of clips, the average weight of the rats
was 163⫾3 g, and the average systolic blood pressure and
heart rate were 116⫾1 mm Hg and 409⫾4 beats/min, respectively. There were no differences in the parameters between
the groups.
Blood Pressure
The blood pressure of the 1K-1C rats was increased 2 weeks
after application of clips and increased further until 6 weeks
after application of clips. Afterward, the blood pressure
remained stable. After declipping, there was an immediate
542
Hypertension
March 2003
Figure 1. Time relationship of blood pressure after application
of clips and after declipping. 䡬, 1K-1C rats before and after
declipping; F, sham rats; f, control 1K-1C rats. Results are
mean⫾SEM. ***P⬍0.001 vs age-matched control 1K-1C rats.
Downloaded from http://hyper.ahajournals.org/ by guest on June 16, 2017
fall in blood pressure to the control level within 6 hours. The
blood pressure decreased further and reached the level of the
sham rats 1 week after declipping. The blood pressure then
remained stable until the end of follow-up at 22 weeks of age,
8 weeks after declipping. The blood pressure in the sham rats
gradually increased between 6 and 7 weeks and 18 weeks of
age (Figure 1). There were no differences in heart rate
between any of the groups (data not shown). Mean heart rate
for all groups was 409⫾4 beats/min.
Heart, Kidney, and Body Weight
The weights of the kidney and the body of the 1K-1C rats
were reduced compared with that in the sham rats at 14 weeks
of age, but the differences had disappeared at 18 weeks of
age, 4 weeks after declipping (Table 1). Kidney weight as a
fraction of body weight was similar for all groups. The
heart/body weight ratio was increased in 1K-1C rats at 14
weeks of age compared with sham rats. Between 14 and 18
weeks, there were no changes in the heart/body weight ratio
in either the sham rats or in the control 1K-1C rats. In
declipped 1K-1C rats, the heart/body ratio declined gradually
and was significantly reduced after 1 week and not significantly different from sham rats within 4 weeks (Figure 2).
Morphometric Characteristics of the Vessel Wall
The morphometric data are shown in Table 2 and Figure 3.
When rats were 14 weeks old, 8 weeks after the application of
Figure 2. Time relationship of heart/body weight ratio after
declipping. 䡬, Declipped 1K-1C rats; F, sham rats; f, control
1K-1C rats. Results are mean⫾SEM. ***P⬍0.001 vs agematched control 1K-1C rats.
clips, the media/lumen ratio of mesenteric resistance arteries
was increased in the 1K-1C rats compared with the agematched sham rats. There was no further increment in
media/lumen ratio between 14 and 18 weeks of age, either for
sham rats or control 1K-1C rats. Declipping did not induce
regression of media/lumen ratio of mesenteric resistance
arteries (ANOVA for declipped 1K-1C groups: P⫽0.11).
Linear regression of media/lumen ratio of resistance arteries
from declipped 1K-1C rats showed a tendency for regression
(P⫽0.07).
Media area and media thickness of the mesenteric resistance arteries were increased in the control 1K-1C rats
compared with the sham rats at 14 and 18 weeks of age. There
was no regression of media area and media thickness after
declipping. There were no significant differences in internal
diameter of arteries from sham rats, control 1K-1C rats, or
declipped 1K-1C rats.
Functional Measurements
No functional differences were found (Table 3). Thus, there
were no differences in maximal effect of acetylcholine
between the sham, control 1K-1C, or declipped 1K-1C
groups. The vessels relaxed by ⬇65% of the noradrenaline
preconstriction when exposed to acetylcholine in all groups.
The acetylcholine concentration for half-maximal relaxation
was similar in all groups (compared with 0.1 ␮mol/L, data
TABLE 1. Weight of Body, Left Kidney, and Heart in SHAM, Control 1K-1C, and
Declipped 1K-1C Rats
BW, g
KW, g
KW/BW⫻10⫺3
HW, g
HW/BW⫻10⫺3
14 wk
304⫾11*
1.6⫾0.06**
5.2⫾0.2
1.2⫾0.05**
4.0⫾0.2**
18 wk
395⫾8
1.9⫾0.06
4.9⫾0.1
1.2⫾0.07
3.1⫾0.2
14 wk
361⫾5
1.9⫾0.10
5.3⫾0.3
0.9⫾0.03
2.5⫾0.1
18 wk
405⫾8
1.9⫾0.08
4.8⫾0.2
1.0⫾0.07
2.6⫾0.2
14 wk
315⫾12*
1.5⫾0.05**
4.9⫾0.2
1.3⫾0.05**
4.1⫾0.2**
18 wk
374⫾18
1.9⫾0.09
5.1⫾0.2
1.3⫾0.08*
3.6⫾0.2**
Rat Type
Declipped 1K-1C rats
SHAM rats
Control 1K-1C rats
BW indicates body weight; KW, kidney weight; and HW, heart weight.
*:P⬍0.05 compared with age-matched SHAM rats; **:P⬍0.01 compared with age-matched SHAM
rats.
Kvist and Mulvany
Blood Pressure, Heart, and Vessels in Declipped Rats
TABLE 2. Morphometric Measurements in Rat Mesenteric
Resistance Vessels
Internal
Diameter,
␮m
Media
Thickness,
␮m
Media
Area,
␮m2⫻103
6 h (14 wk)
233⫾10
17.37⫾0.81
12.96⫾0.96
24 h
207⫾10
17.21⫾1.15
11.51⫾1.13
1 wk
227⫾8
15.80⫾1.16
11.39⫾1.02
4 wk (18 wk)
244⫾10
16.85⫾0.74
8 wk
223⫾6
14 wk
18 wk
Rat Type
543
TABLE 3. Maximal Responses of Mesenteric Resistance
Arteries to Acetylcholine (Relaxation) and to K-PSS and
Noradrenaline (Contraction)
Acetylcholine,
% of Precontraction
K-PSS,
mN/mm
Noradrenaline,
mN/mm
6 h (14 wk)
74⫾4
2.53⫾0.19
2.14⫾0.22
24 h
59⫾9
2.74⫾0.25
2.26⫾0.22
1 wk
41⫾7
3.05⫾0.28
3.73⫾0.35
13.02⫾0.90
4 wk (18 wk)
70⫾6
3.26⫾0.27
3.56⫾0.37
14.62⫾0.70
10.11⫾0.45
8 wk
67⫾7
2.83⫾0.11
3.17⫾0.17
233⫾9
12.53⫾0.39
9.07⫾0.57
14 wk
60⫾7
2.26⫾0.18
2.33⫾0.22
244⫾9
13.01⫾0.60
9.76⫾0.60
18 wk
75⫾6
2.79⫾0.21
2.69⫾0.23
Declipped 1K-1C rats
Rat Type
Declipped 1K-1C rats
SHAM rats
SHAM rats
Control 1K-1C rats
Control 1K-1C rats
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14 wk
229⫾10
18.25⫾1.60**
13.92⫾2.09*
14 wk
72⫾6
2.79⫾0.26
2.66⫾0.33
18 wk
228⫾8
17.60⫾1.13**
12.98⫾1.22*
18 wk
62⫾7
2.55⫾0.22
2.82⫾0.24
*:P⬍0.05 compared with age-matched SHAM rats; **:P⬍0.01 compared
with age-matched SHAM rats.
not shown). There were no differences in contractile responses to noradrenaline and K-PSS between the groups.
Discussion
The main finding of this study was that while declipping
caused a rapid normalization of blood pressure, heart weight
and resistance vessel morphology regressed either slowly or
not at all.
Given the strong association between blood pressure and
vascular structure, as discussed in the Introduction, it was
surprising that the structure of the small arteries was not
significantly regressed 8 weeks after declipping, despite
normal pressure for almost the whole of this time. This is in
apparent contrast to the relation seen in SHR. Here, for
example, treatment of established hypertension with different
vasodilator antihypertensive drugs for 8 to 12 weeks results in
a gradual reduction of blood pressure and regression of
cardiac hypertrophy22,23 and regression of abnormal structure
of small resistance vessels.23,24 Similarly, in humans, successful treatment of essential hypertension with vasodilators
causes regression of heart weight and resistance vessel
Figure 3. Time relationship of media/lumen ratio after declipping. 䡬, Declipped 1K-1C rats; F, sham rats; f, control 1K-1C
rats. Results are mean⫾SEM. ***P⬍0.001 vs age-matched control 1K-1C rats. **P⬍0.01 vs age-matched declipped 1K-1C
rats.
There were no differences between any of the groups.
structure, at least after 1 year.7,25,26 As described in the
Introduction, the retarded regression of the hypertrophy of the
heart despite fast normalization of blood pressure in renovascular hypertensive rats was also observed by Friberg and
Nordborg14 and Lundgren,15 and similar findings were observed in the arterioles of the rat cremaster muscle by Stacy
and Prewitt16 and indirectly in the hindquarter perfusion
preparation by Lundgren.15 These indications of fast normalization of blood pressure and the retarded or absent regression
of heart weight and resistance vessel structure in declipped
renovascular hypertensive rats are now strongly supported by
the direct investigations of the structure of the vessels in our
experiments. It appears therefore to be a general finding in
these animals that hypertrophy of vessels and heart are not
able to keep blood pressure high, and any hypertensive action
of the hypertrophy is eliminated either by removal of a
vasoconstrictor agent or by activation of a vasodilator agent.
The existence of such an agent has also been proposed by
Muirhead et al,27 who provided evidence for an antihypertensive neutral renomedullary lipid, medullipin, suggested to be
released from the declipped kidney.27,28
The divergence in the rates of normalization in blood
pressure and cardiovascular structure seen in this study
confirms other situations in which blood pressure and cardiovascular structure are not always tightly associated. Thus,
although this tight association is normally seen in most forms
of hypertension, as discussed above, specific interventions
may interrupt this association. For example, treatment of
SHR29 or of patients with essential hypertension patients with
␤-blockers30,31 causes blood pressure reduction without affecting small-artery structure. As another example, withdrawal of treatment, both in humans32 and in SHR,26 induces
a rise in blood pressure that is not time-related to changes in
resistance artery structure, and the data emphasize that
abnormal vascular structure is not in itself sufficient to
maintain a high blood pressure. As regards normalization of
blood pressure, normalization of resistance vessel structure
may not therefore be important. However, it cannot be
544
Hypertension
March 2003
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excluded that abnormal structure may have other consequences, such as reduced vascular reserve33; further studies
are, however, needed to establish this.
The role of the endothelium in hypertension has been
investigated intensively, and the results in normotensive rats
and hypertensive rats of different kinds are conflicting.
However, as regards renovascular hypertensive rats, there has
been general agreement that the response to acetylcholine is
reduced (in 1K-1C as well as in 2K-1C rats) compared with
normotensive rats.34 –38 This is in contrast to our results that
showed no differences in response to acetylcholine. We found
no obvious reason for the conflicting results because the
conditions we have used are in general similar, such that
some subtle difference in our protocol probably accounts for
the discrepancy.
It was of some concern that approximately one third of the
animals did not survive the consequences of the operation,
which we ascribed to the crucial importance of the clip
aperture: Variations of ⬇30 ␮m were found to span the
difference between no hypertensive effects and induction of
uremia.17 However, our finding that for the survivors after
placement of the clip, blood pressure was elevated after 2
weeks and remained stable after 6 weeks is in agreement with
the findings of Stacy and Prewitt.16 The hypertrophy of the
heart and increased media/lumen ratio and media area of the
resistance arteries is also in agreement with previous findings,39 as is the normalization of the weight of the clipped
kidney after an initial weight reduction.17 The rapid fall in
blood pressure within a few hours after declipping is also
similar to that previously reported,40,41 although it took more
than 1 day to normalize. The model thus appears to have been
satisfactory.
Perspectives
This study has provided clear evidence that rapid reduction of
blood pressure, achieved in this study by declipping of 1K-1C
rats, is not necessarily accompanied by a corresponding
normalization of resistance vessel structure over a period of 8
weeks, although heart weight was normalized after 4 weeks.
This thus provides definitive evidence that an abnormal
resistance vessel structure is not in itself sufficient to maintain a high blood pressure. Conversely, reduction of blood
pressure does not in itself necessarily result in a rapid
normalization of resistance vessel structure. As indicated,
treatment of genetic hypertension does in some cases result in
normalization of resistance vessel structure, but it is not
known how quickly this occurs. Furthermore, some treatments of genetic hypertension do not normalize resistance
vessel structure even after 1 year or more. Taken together
with the results of the present study, this indicates a need for
a better understanding of the mechanisms that allow normalization of resistance vessel structure in the treatment of
hypertension. The results of this study also underline the need
for understanding the degree to which an abnormal resistance
vessel structure should be a target for antihypertensive
therapy.
Acknowledgments
This study was supported by the Danish Heart Foundation, the
Danish Society of Rheumatic Patients, the Danish Society of
Nephrologic Patients, and the Danish Society of Hypertension.
Michael Mulvany is supported by the Danish Medical Research
Council. The authors are grateful for the technical assistance of Lotte
Paaby.
References
1. Lundgren Y, Hallback M, Weiss L, Folkow B. Rate and extent of
adaptive cardiovascular changes in rats during experimental renal hypertension. Acta Physiol Scand. 1974;91:103–115.
2. Li JS, Schiffrin EL. Effect of calcium channel blockade or angiotensinconverting enzyme inhibition on structure of coronary, renal, and other
small arteries in spontaneously hypertensive rats. J Cardiovasc
Pharmacol. 1996;28:68 –74.
3. 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.
4. Muiesan ML, Rizzoni D, Salvetti M, Porteri E, Monteduro C, Guelfi D,
Castellano M, Garavelli G, Agabiti-Rosei E. Structural changes in small
resistance arteries and left ventricular geometry in patients with primary
and secondary hypertension. J Hypertens. 2002;20:1439 –1444.
5. Devereux RB, Palmieri V, Sharpe N, De Quattro V, Bella JN, de Simone
G, Walker JF, Hahn RT, Dahlof B. Effects of once-daily angiotensinconverting enzyme inhibition and calcium channel blockade-based antihypertensive treatment regimens on left ventricular hypertrophy and diastolic filling in hypertension: the prospective randomized enalapril study
evaluating regression of ventricular enlargement (preserve) trial. Circulation. 2001;104:1248 –1254.
6. Rizzoni D, Porteri E, Castellano M, Bettoni G, Muiesan ML, Muiesan P,
Giulini SM, Agabiti-Rosei E. Vascular hypertrophy and remodeling in
secondary hypertension. Hypertension. 1996;28:785–790.
7. Schiffrin EL. Vascular changes in hypertension in response to drug
treatment: effects of angiotensin receptor blockers. Can J Cardiol. 2002;
18(suppl A):15A-18A.
8. Folkow B. Physiological aspects of primary hypertension. Physiol Rev.
1982;62:347–504.
9. Korner PI, Bobik A. Cardiovascular development after enalapril in spontaneously hypertensive and Wistar-Kyoto rats. Hypertension. 1995;25:
610 – 619.
10. Mulvany MJ. Resistance vessel growth and remodelling: cause or consequence in cardiovascular disease. J Hum Hypertension. 1995;9:
479 – 485.
11. Heagerty AM, Izzard AS. Small-artery changes in hypertension.
J Hypertens. 1995;13:1560 –1565.
12. Russell GI, Brice JM, Bing RF, Swales JD, Thurston H. Haemodynamic
changes after surgical reversal of chronic two-kidney, one-clip hypertension in the rat. Clin Sci. 1981;61(suppl 7):117s–119s.
13. Brown AJ, Casals-Stenzel J, Gofford S, Lever AF, Morton JJ. Comparison of fast and slow pressor effects of angiotensin II in the conscious
rat. Am J Physiol. 1981;241:H381–H388.
14. Friberg P, Nordborg C. Functional, morphological and metabolic characteristics of isolated hearts from normotensive and spontaneously hypertensive rats before, during and after renal hypertension. Acta Physiol
Scand. 1986;126:161–171.
15. Lundgren Y. Regression of structural cardiovascular changes after
reversal of experimental renal hypertension in rats. Acta Physiol Scand.
1974;91:275–285.
16. Stacy DL, Prewitt RL. Effects of chronic hypertension and its reversal on
arteries and arterioles. Circ Res. 1989;65:869 – 879.
17. Murphy WR, Coleman TG, Smith TL, Stanek KA. Effects of graded renal
artery constriction on blood pressure, renal artery pressure, and plasma
renin activity in Goldblatt hypertension. Hypertension. 1984;6:68 –74.
18. Skeggs LT, Kahn JR, Levine M, Dorer FE, Lentz KE. Chronic onekidney hypertension in rabbits. I. treatment with kidney extracts. Circ
Res. 1975;37:715–724.
19. Mulvany MJ, Halpern W. Contractile properties of small arterial
resistance vessels in spontaneously hypertensive and normotensive rats.
Circ Res. 1977;41:19 –26.
20. Mulvany MJ, Hansen OK, Aalkjaer C. Direct evidence that the greater
contractility of resistance vessels in spontaneously hypertensive rats is
associated with a narrowed lumen, a thickened media, and an increased
number of smooth muscle cell layers. Circ Res. 1978;43:854 – 864.
21. Buus NH, VanBavel E, Mulvany MJ. Differences in sensitivity of rat
mesenteric small arteries to agonists when studied as ring preparations or
as cannulated preparations. Br J Pharmacol. 1994;112:579 –587.
Kvist and Mulvany
Blood Pressure, Heart, and Vessels in Declipped Rats
Downloaded from http://hyper.ahajournals.org/ by guest on June 16, 2017
22. Levy BI, Duriez M, Samuel JL. Coronary microvasculature alteration in
hypertensive rats: effect of treatment with a diuretic and an ACE inhibitor. Am J Hypertens. 2001;14:7–13.
23. Sharifi AM, Li JS, Endemann D, Schiffrin EL. Effects of enalapril and
amlodipine on small-artery structure and composition, and on endothelial
dysfunction in spontaneously hypertensive rats. J Hypertens. 1998;16:
457– 466.
24. Gillies LK, Lee RM. Effects of chronic blockade of angiotensin II
receptor on the maintenance of hypertension and vascular changes in
spontaneously hypertensive rats. Can J Physiol Pharmacol. 1996;74:
1061–1069.
25. Sihm I, Thygesen K, Krusell LR, Lederballe O. Long-term renal and
cardiovascular effects of antihypertensive treatment regimens based upon
isradipine, perindopril and thiazide. Blood Press. 2000;9:346 –354.
26. Thybo NK, Korsgaard N, Eriksen S, Christensen KL, Mulvany MJ.
Dose-dependent effects of perindopril on blood pressure and small-artery
structure. Hypertension. 1994;23:659 – 666.
27. Muirhead EE, Pitcock JA, Nasjletti A, Brown P, Brooks B. The antihypertensive function of the kidney: its elucidation by captopril plus
unclipping. Hypertension. 1985;7(suppl I):I-127–I-135.
28. Thomas CJ, Woods RL, Evans RG, Alcorn D, Christy IJ, Anderson WP.
Evidence for a renomedullary vasodepressor hormone. Clin Exp
Pharmacol Physiol. 1996;23:777–785.
29. Christensen KL, Jespersen LT, Mulvany MJ. Development of blood
pressure in spontaneously hypertensive rats after withdrawal of long-term
treatment related to vascular structure. J Hypertens. 1989;7:83–90.
30. Schiffrin EL, Deng LY, Larochelle P. Effects of a beta-blocker or a
converting enzyme inhibitor on resistance arteries in essential hypertension. Hypertension. 1994;23:83–91.
31. Thybo N, Stephens N, Cooper A, Aalkjaer C, Heagerty AM, Mulvany
MJ. Effect of antihypertensive treatment on small arteries of patients with
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
545
previously untreated essential hypertension. Hypertension. 1995;25:
474 – 481.
Korner PI, Bobik A, Jennings GL, Angus JA, Anderson WP. Significance
of cardiovascular hypertrophy in the development and maintenance of
hypertension. J Cardiovasc Pharmacol. 1991;17(suppl 2):S25–S32.
Strauer BE, Schwartzkopff B. Left ventricular hypertrophy and coronary
microcirculation in hypertensive heart disease. Blood Press. 1997;
2(suppl):6 –12.
Bennett MA, Thurston H. Effect of angiotensin-converting enzyme inhibitors on resistance artery structure and endothelium-dependent
relaxation in two-kidney, one-clip Goldblatt hypertensive and shamoperated rats. Clin Sci (Colch). 1996;90:21–29.
Lee BH, Shin HS. Interaction of nitric oxide and the renin angiotensin
system in renal hypertensive rats. Jpn J Pharmacol. 1997;74:83–90.
Nakamura T, Prewitt RL. Alteration of endothelial function in arterioles
of renal hypertensive rats at two levels of vascular tone. J Hypertens.
1992;10:621– 627.
Ortenberg JM, Cook AK, Inscho EW, Carmines PK. Attenuated afferent
arteriolar response to acetylcholine in Goldblatt hypertension. Hypertension. 1992;19:785–789.
Angus JA, Dyke AC, Jennings GL, Korner PI, Sudhir K, Ward JE, Wright
CE. Release of endothelium-derived relaxing factor from resistance
arteries in hypertension. Kidney Int. 1992;41(suppl 37):S73–S78.
Korsgaard N, Mulvany MJ. Cellular hypertrophy in mesenteric resistance
vessels from renal hypertensive rats. Hypertension. 1988;12:162–167.
Byrom FB, Dodson LF. The mechanism of the vicious circle in chronic
hypertension. Clin Sci. 1949;8:1–10.
ten Berg R, de Jong W. Time course of the enhanced blood pressure
response to reinduction of renal artery stenosis in unclipped renal hypertensive rats. Pflugers Arch. 1979;380:133–137.
Contrasting Regression of Blood Pressure and Cardiovascular Structure in Declipped
Renovascular Hypertensive Rats
Stinne Kvist and Michael J. Mulvany
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Hypertension. 2003;41:540-545; originally published online February 10, 2003;
doi: 10.1161/01.HYP.0000054977.07679.59
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