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191

Differential Development of Vascular and


Cardiac Hypertrophy in Genetic Hypertension
Relation to Sympathetic Function
Michael A. Adams, Alexander Bobik, and Paul I. Korner
We compared blood pressure, hlndquarter vascular resistance properties, left ventricular weight,
and norepinephrine kinetics, in spontaneously hypertensive rats (SHR) and weight-matched
normotensive Wistar-Kyoto (WKY) rats at 4, 9, 14, 20, 30, and 50 weeks of age- At 4 weeks,
systolic and mean blood pressure measurements were the same in both strains, but the vascular
resistance of the fully dilated hindquarter bed was significantly higher in SHR than in WKY rats,
with a much larger difference during maximum constriction. Plots of resistance at maximum
dilatation and at maximum constriction against body weight suggest that a component of the
increase hi vascular muscle mass in SHR occurred in the neonatal period preceding hypertension
followed by a later component related to the rise in blood pressure. By contrast, left ventricular
hypertrophy was minimal at 4 weeks and most of its development paralleled the rise in blood
pressure. Sympathetic activity, assessed by norepinephrine fractional rate constant, was higher in
SHR than in WKY rats in the left ventricle and kidney through most of the period between 4 and
50 weeks, but was similar in both strains in the muscle bed. This pattern of sympathetic activity
will accentuate hypertension once cardiac and vascular hypertrophy are fully established. In all
regions, norepinephrine tissue concentration was higher in young SHR and could potentiate the
trophic effects of growth factors in early vascular hypertrophy. We suggest that the initial
(primary) component of vascular hypertrophy precedes the rise in blood pressure and may be
critical in the pathogenesis of hypertension. Possible reasons for the short delay in the rise in blood
pressure in young SHR, once the vascular "amplifier" has been established, include high
vascularity, immaturity of smooth muscle, and delay in the development of left ventricular
hypertrophy. (Hypertension 1989; 14:191-202)

olkow1-2 and colleagues were the first to


demonstrate the importance of structural
changes associated with hypertrophy of the
cardiovascular musculature in hypertension. In the
spontaneously hypertensive rat (SHR), they showed
that, as a result of the increase in wall thickness and
narrowing of the lumen, changes in vascular resistance were "amplified" when compared with the
responses of Wistar-Kyoto (WKY) normotensive
rats.3 The concentrically hypertrophied left ventricle also has amplifier properties, which help in the
maintenance of cardiac output against a higher
pressure load.4-5 In chronic secondary hypertension

From the Baker Medical Research Institute, Melbourne,


Australia.
Supported by the National Heart Foundation of Australia, the
National Health and Medical Research Council, and through the
award of a postdoctoral fellowship to M.A.A. by the Canadian
Medical Research Council.
Address for correspondence: Professor P.I. Korner, Baker
Medical Research Institute, Commercial Rd., Prahran, Victoria,
3181, Australia.
Received March 4, 1988; accepted March 6, 1989.

due to renal artery stenosis, the cardiovascular


amplifiers contribute about 70% to the maintenance
of the elevated blood pressure (BP) and this is
probably similar in primary hypertension.6
In secondary hypertension, the hypertrophy is
clearly a consequence of the elevated BP, and it has
generally been assumed that this is also the case in
primary hypertension. There has been speculation
whether, in primary hypertension, the early development of cardiovascular hypertrophy could initiate the rise in BP.7-9 This hypothesis is not readily
testable in humans, because of the difficulty of
performing an adequate longitudinal study. Such a
study is feasible in SHR, where the time course of
the BP changes has been documented in great
detail,10 but the range of ages in previous longitudinal studies on the development of cardiac and
vascular hypertrophy has been too small for an
adequate sequential analysis (see References 1014). For example, we still do not know whether in
SHR the vascular and cardiac hypertrophy develop
over the same age span.

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192

Hypertension

Vol 14, No 2, August 1989

Present evidence suggests that sympathetic nervous system is important in the development of
hypertension in SHR.2-15-19 Folkow et al15 showed
that immunosympathectomy in very young rats
attenuated the development of hypertension.
Recently Lee et al,20 using an improved ablation
technique, found that hypertension could be prevented completely. One way in which increased
sympathetic neural activity in SHR could elevate
BP is through a net increase in vasoconstrictor tone
associated with a low threshold of the "defense"
reaction,1'2-16'17 so that the hypertrophy will occur
as a direct consequence of the rise in BP. An
alternative hypothesis is that the sympathetic nervous system exerts a local trophic role in the
development of cardiovascular hypertrophy.7-18-19
Such a role presupposes elevation of regional norepinephrine tissue concentration [NE] and high
turnover at the time of development of cardiovascular hypertrophy. However, there has been only
one detailed longitudinal study by Patel et al,21 who
determined the fractional rate constant of norepinephrine, but did not relate it to the development of
cardiovascular hypertrophy.
In the present experiments, we examined the
time course of development of cardiac and vascular
hypertrophy and how this related 1) to the development of hypertension and 2) to the various measures of regional sympathetic function. Accordingly, we compared the vascular properties of the
hindquarters in SHR and WKY rats and measured
the left ventricular and right ventricular weights at
six time points over an age span of 4-50 weeks of
age. Indexes of regional sympathetic function were
obtained in a parallel study in skeletal muscle
vessels, heart, and kidney.
Materials and Methods

Animals and Blood Pressure Measurements


Male SHR and WKY rats (Animal Resources
Centre, Perth, Western Australia) were housed in
groups of three rats to a cage in a room with a
12-hour light/dark cycle and an ambient temperature of 22-24 C, with food and water provided ad
libitum. We had intended to take special care to
weight-match pairs of SHR and WKY rats at the
different ages (see below). However, no special
selection procedure turned out to be necessary, and
in all experiments the difference in body weight was
less than 5%. The rats came originally from the
National Institutes of Health in the United States
and the strain of WKY rats that we used was that in
which the age-body weight relation was similar to
that of SHR.22
Systolic BP and heart rate were measured in
conscious rats with an automated multichannel system (IITC Life Science Instruments, Woodland
Hills, California, 24 channel) that used tail cuffs and
photoelectric sensors to detect the tail pulses. A
test chamber maintained at 27-28 C was used to

place rats in holders appropriate for their body


weight. Over the last 2 weeks of each time period,
there was a minimum of four BP recording sessions:
the first two were regarded as training sessions and
the data was discarded; the systolic BP was taken
as the mean of the last two sessions (4-6 sets of
measurements) recorded over the last 2-3 days. In
addition, mean arterial pressure was measured
directly in a separate series of 4-week-old SHR and
WKY rats which were anesthetized with methohexitone anesthesia (Brietal, Eli Lilly, Indianapolis,
Indiana, 30 mg/kg i.p.) and were cannulated with
aortic catheters 4-7 days before recording, as
described by Head and McCarty.23 In these rats
pressure was recorded for a period of 3-4 hours on
the day of the study.
Hindquarter Preparation
Hindquarter perfusions were carried out in pairs
of age- and weight-matched SHR and WKY rats by
using a slight modification of the method of Folkow
et al.24 The system included a common reservoir for
both rats, an injection port and bubble trap/mixing
chamber in line with a peristaltic pump (Minipuls 2,
Gilson Medical Elec, Inc., Middleton, Wisconsin).
The perfusate consisted of 1.5% dextran T-40 (Pharmacia, Upsala, Sweden) in Tyrode's solution, which
was aerated with 95% O2 and 5% CO2. The composition (mM) of the Tyrode's solution was: KC1 20,
CaCl2 2H2O 32.3, MgCl2 6H2O 5.1, NaH2PO4 2H2O
6.2, NaHCO3 100, glucose 100, and NaCl 800 mg/
100 ml fluid. The perfusate in the reservoir was
warmed, and we used a heating pad to maintain
rectal temperature at 36-38 C.
The rats were anesthetized with sodium pentobarbital (60 mg/kg i.p.) and the lower abdominal
aorta was exposed at the iliac bifurcation through a
midline abdominal incision. After heparinization
(1,000 IU/kg), the aorta was cannulated with a 19or 23-gauge needle, with the tip immediately proximal to the iliac bifurcation. The middle caudal and
the caudal mesenteric arteries, which are close to
the bifurcation, were ligated and not perfused. Flow
of perfusate was started immediately after transection of the spinal cord and vena cava adjacent to the
cannula entrance. The heart and other tissues were
rapidly removed for catecholamine assays (see
below). About 5 minutes after the start of perfusion,
when the vasculature had been flushed clear of
blood, papaverine HC1 (12 mg/ml) was given as a
bolus (1.5 mg/100 g body wt) and the perfusion
pressure at maximum vasodilatation (PPmudii)
remained constant over a 20-minute washout period,
indicating that edema was minimal. Subsequently,
we obtained cumulative concentration-vascular
resistance (=PP) response curves to the ar
adrenergic receptor agonist methoxamine (0.4-300
/tg/ml, Burroughs Wellcome, Research Triangle
Park, North Carolina) by stepwise increases in the
infusion rate (0.66-66 fiVmin i.v.) from a syringe
pump (Perfusor IV, Braun, Munich, FRG) contain-

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Adams et al Vascular and Cardiac Hypertrophy

193

TABLE 1. Linear Regression Equations in Spontaneously Hypertensive Rats and Wlstar-Kyolo Rats
Age

Group
BW-HQW relation
SHR+WKY
PP-flow relation
SHR

(wk)

4-40

23

WKY

8*
1*
6'

SHR

14

WKY

14

8*

SHR

27

4'

WKY

27

4'

SE b

HQW=24.97+0.031 BW

0.0023

0.95

P P ^ do=10.07+0.72 HQQ
PPm. <ffl=6.83+0.72 HQQ
PPmrc.do'-13.45 + 1.48 HQQ
PPmdii=9.84+1.48HQQ
PP mtdi =12.89+1.43HQQ
PPo-x ,8=8.70+1.43 HQQ

0.088
0.047
0.181
0.144
0.387
0.543

0.85
0.94
0.91
0.90
0.95
0.91

PPn*<ffl=13.34+0.046 BW
PPIOT<ffl=11.33+0.034BW
PPmDcc=225+0.319BW
PPmcc=159+0.274BW

0.0039
0.0039
0.32
0.27

0.91
0.85
0.89
0.85

Regression equation

PP-BW relation
SHR
WKY
SHR
WKY

40-50
40-50
40-50
40-50

31
32
31
32

n, number of rats; SEt,, standard error of regression coefficient; r, correlation coefficient; BW, body weight (g);
HQW, hindquarter weight (% of BW); SHR, spontaneously hypertensive rats; WKY, Wistar-Kyoto rats; PP,
perfusion pressure; max dil, maximum dilatation; HQQ, hindquarter flow (ml/min/100 g HQW); max con, maximum
constriction.
'For PP-flow curves, number of data points were, in order, spontaneously hypertensive rats, Wistar-Kyoto rats:
4 weeks, 32 and 28; 14 weeks, 17 and 24; 27 weeks, 12 and 12.

ing methoxamine. The concentration of methoxamine was related to the body weight of the rats, so
that in each experiment we used similar drug concentrations and increments. For each dose a perfusion pressure plateau was reached before giving the
next dose, up to a dose of methoxamine where there
was no further elevation in perfusion pressure. After
this we tested whether this corresponded to perfusion pressure at maximum constriction (PP^cd)*
which was obtained by means of a bolus of angiotensin II (Ang II, 50/x.g) or of BaCl2 (100-200 ^g)The rats were perfused at a constant flow of 4
ml/min/100 g body wt, which in adult rats corresponds to a flow of 10 ml/mih/100 g hindquarter
wt.24 The relation between hindquarter weight and
body weight was closely similar in SHR and WKY
rats, but differed at different stages of growth (Table
1). Thus, in low body weight (young) rats of each
strain, the hindquarter weight was a lower fraction
of the total body weight than in adult rats. For
example, in a 50-g rat, hindquarter weight was
26.50.4% body wt, whereas in a 450-g rat, hindquarter weight averaged 38.80.6% body wt, which
was close to the value of 40% that Folkow et al24
reported in adult rats. Thus, at constant perfusion
per unit body weight, young rats will receive a
higher flow per gram hindquarter weight than adult
rats, so that the vascular resistance at P P ^ m will
be overestimated. The body weight-hindquarter
weight relation accounted for about 90% of the
variance, and we used it to correct P P ^ ^ to the
value corresponding to a standard perfusion rate of
10 ml/min/100 g hindquarter wt. This was done from
perfusion pressure-flow lines obtained in a separate

series of 4-, 14-, and 27-week-old SHR and WKY


rats (see Table 1 and Results). The correction was
applied as shown in Figure 1, where P P ^ ^ is
plotted against both flow/unit body weight and
flow/unit hindquarter weight. In rats of this body
weight, perfusion at 4 ml/min/100 g body wt corresponds to perfusion of 14.6 ml/min/100 g hindquarter wt; PPmaxdj at this flow was 24.1 mm Hg while,
at a flow of 10 ml/min/100 g hindquarter wt, it was
20.4 mm Hg, so that the first value requires a
correction of -3.7 mm Hg. We have assumed that
the perfusion pressure-flow relation at 9 weeks was
halfway between that at 4 and 14 weeks (Table 1).
The average corrections applied to normalize the
PPmx dii values to perfusion at 10 ml/100 g hindquarter wt at 4, 9, 14, 20, 30, and 50 weeks were as
follows: in SHR -3.7, - 3 . 1 , - 2 . 3 , -1.5, -0.8, and
-0.2 mm Hg; in WKY rats -3.0, - 2 . 3 , -1.6, -1.2,
-0.8, and -0.2 mm Hg. For the PP^a,,,, a similar
correction is not required, since the muscle "yields"
instead of developing more tension.3
Tissue Norepinephrine
The rats were anesthetized with sodium pentobarbital (60 mg/kg i.p.) and killed by exsanguination.25 The left ventricle plus septum, the kidneys, and the forelimb muscle (caput longum of
triceps brachii) were quickly dissected from the
other tissues, weighed, rapidly frozen in liquid
nitrogen, and then stored at 80 C until analysis.
Norepinephrine was extracted from the tissue by a
slight modification of a procedure described previously.26 Briefly, the tissues were homogenized (Porytron PT 20) in ice-cold 0.4 M perchloric acid (4.0 ml,

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194

Hypertension

Vol 14, No 2, August 1989

0.4 M) containing 3,4-dihydroxybenzylamine


(DHBA). After the homogenate was centrifuged to
pellet-precipitated proteins, the pH of the supernatant was adjusted to pH 8.6 with 1 M Tris buffer 8.6
containing ethylenediaminetetraacetate (EDTA, 10
mg%). Norepinephrine was then extracted from this
solution onto 300 mg alumina (active/neutral form,
Merck Sharp & Dohme, West Point, Pennsylvania),
which was washed twice with water. Norepinephrine
was eluted with 0.4 M perchloric acid.
Quantitation of norepinephrine was carried out
by high-performance liquid chromatography
(HPLC), using either fluorometric (Schoeffel, FS970) or electrochemical (LC-4A controller, Bioanalytical Sys., Inc., West Lafayette, Indiana)
detection.26-27 Fluorescence of catecholamines was
measured through a Corning (Corning Glass Works,
Corning, New York) 7-60 glass filter (band pass
250-400 nm) on excitation at 200 nm. For electrochemical estimation of the catecholamines, an electrochemical cell with a glassy carbon electrode
(TL-8A, Bioanalytical Sys., Inc.) was used, with
the potential set at 0.8 V against a Ag/AgCl reference electrode. The use of 0.8 V was validated by
comparison of redox curves (detector response vs.
oxidation potential) for norepinephrine and for alumina eluates containing norepinephrine extracted
from heart, kidney, and muscle tissue. Signals from
these detection systems were recorded on a Shimadzu data system (C-R3A Chromatopac, Shimadzu Sci. Instrs., Columbia, Maryland), and norepinephrine was quantified by using peak area ratios
relative to the internal standard (DHBA). The liquid
chromatographic system consisted of a Varian 5000
Pump equipped with a refrigerated autosampler
(AS-48, Bio-Rad Labs., Richmond, California) and
an Altex Ultrasphere-ODS column (3 /Am; 46x7.5
cm). When fluorescence detection was used, the
mobile phase consisted of 10 mM perchloric acid
(pH 2). Since with electrochemical detection sensitivity is relatively poor at this pH, the mobile phase
for this system consisted of dihydrogen phosphate
(0.05 M), sodium citrate (0.05 M), EDTA (2 mM),
and octyl sodium sulfate (100 mg%), dissolved in
methanol/water (3%/10% vol/vol). The pH of the
prepared solution was adjusted to 4.5. Quantitatively the two systems provided identical estimates
of norepinephrine in the three tissues.
Norepinephrine Turnover
The rate of norepinephrine synthesis (turnover)
can be expressed as .KxfNE], where K (the fractional rate constant) is the fraction of norepinephrine lost in unit time after suppression of norepinephrine biosynthesis by inhibition of the enzyme
tyrosine hydroxylase by a-methyl-DL-/?-tyrosine
methyl ester HC1 (AMPT) and [NE] is the steadystate tissue norepinephrine concentration. K is
closely related to sympathetic nerve impulse
traffic21 29-30 and was calculated from the rate of
decline of the tissue [NE] according to the equation

K=(ln [NEJ-ln [NEt.0])/t


where [NE,_o] and [NE,] are the norepinephrine
concentrations at zero time and after 4 or 8 hours of
inhibition of synthesis with 300 mg/kg AMPT i.p.
every 4 hours, in a solution of 60 mg/ml in 0.9%
NaCl, which is known to inhibit tyrosine hydroxylase.29-30 For determination of K, we used all data
points in three subgroups of rats killed at 0, 4, or 8
hours after administration of AMPT, using the slope
of the In [NEJ-time regression equation. Norepinephrine turnover is the amount of norepinephrine
released per gram of tissue per unit time, and is
calculated from the product of K times the endogenous steady-state tissue [NE]. An individual K
was estimated in each rat, based on the rate of
decline from the animals' own zero time concentration to the average [NE] of the group, after 4 or 8
hours inhibition of synthesis. This method provides
a reasonable estimate of the standard error of the
mean of the group's norepinephrine turnover rate,
and makes allowance for the errors associated with
the determination of both K and [NE].
Data Analysis
We found that a logistic function curve described
the relation between methoxamine concentration
and change in perfusion pressure; a computer program was used to fit the data points using the
algorithm of Marquardt.31 Each curve was characterized by the following parameters: 1) PPnumdai 2)
tn
ECJOJ e concentration of methoxamine to reach
50% of the pressure range of the curve between
minimum and maximum pressures with methoxamine, 3) the maximum slope of the concentrationresponse curve with methoxamine, and 4) the range
between P P ^ & and P P ^ with methoxamine or
Ang II. The slope of the logistic curve depends in
part on the range between the two plateaus (i.e.,
PPmMcoo-PPmix<ni) and we therefore also calculated
the range-independent (normalized) slope of the
logistic function, where the range is regarded as
100% under all conditions.32
The various age and strain differences were compared by one-way analysis of variance and
covariance. 33 Individual comparisons between
strains at particular ages were done using an unpaired
Student's t test and, where appropriate, the MannWhitney test. A /?<0.05 was taken to indicate
statistical significance.
Results
Age Relation to Body Weight, Blood Pressure,
and Heart Rate
The relation between age and body weight was
closely similar in SHR and WKY rats (Figure 2).
The rate of body weight gain was about 25 g/wk
over the period 4-14 weeks, compared with the
average increase of about 4 g/wk over the subsequent 36 weeks. The similar body weights in the
paired perfusion experiments ensured that, at any

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Adams et al Vascular and Cardiac Hypertrophy


40

Q/100g BVV,

g 30
E
I
_j

Q 20
X
wk

g-10
2

ml/mln/100g BW
4
6
8
10

15 20
0
5
10
FLOW- ml/min/100a HQW

15

20

FIGURE 1. Left panel, relation ofperfusion pressure at


maximum dilatation (PPmaxdii) to flow (Q) in isolated
hindquarters of 4-week-old spontaneously hypertensive
rats (SHR) (n=8), plotted as ml/min/100 g body wt (BW)
(left line) and ml/min/100g hindquarter wt (HQW). In rats
of 75.5 g, PPmcx m corresponds to flows of 4 ml/min/100 g
BWandto 14.6 ml/min/100 g HQW. PP^ m, at a flow of
10 ml/min/100 g HQW lies at the tip of the arrowhead.
Right panel, relation of PPn^du to flow (ml/min/100 g
HQW) in 4-week-old SHR (lower solid line and symbols;
n=8) and Wistar-Kyoto (WKY) rats (lower interrupted
line and symbols; n=7) and in corresponding pooled data
in 14- and 27-week-old SHR (n=10) and WKY rats
(n=12). Points are expected means from the regression
lines SEM.

given age, strain differences in vascular resistance


properties did not depend on differences in body
size.
The difference in systolic BP between the two
strains increased progressively during the period of

195

rapid growth between 4 and 14 weeks (Figure 2).


The difference was minimal and not significant at 4
weeks (n=5 in each strain). We also performed
direct measurements of mean arterial pressure in
4-week-old SHR and WKY rats, which was 1135
and 110 6 mm Hg, respectively (n=7 and 6; A
N.S.), in agreement with the systolic BP findings
when using tail-cuff measurements. At all times
after and including 9 weeks, the systolic BP was
higher in SHR than in WKY rats (/XO.OOOI). In
WKY rats the "adult" BP value was reached by
about 9 weeks of age, whereas the corresponding
value in SHR was reached by about 14 weeks
(Figure 2). There was a progressive increase in the
difference in systolic BP throughout the period of
rapid growth, to a stable difference in the adult of
about 75 mm Hg.
In both SHR and WKY rats, heart rate declined
with increasing age at a rate of 1-2 beats/min/wk.
The rate of decline was similar in both strains, but
at all ages the heart rate was higher in SHR than
in WKY rats. The average heart rate over all
time intervals was 371 38.9 beats/min in SHR
and 34940.3 beats/min in WKY rats (A=22;
F(1,264)=23.2,/J<0.001).

Heart Weight
The left ventricle plus septum weight/body weight
ratio and the ratio of right ventricular weight/body
weight declined in both SHR and WKY rats from
4 weeks to reach stable values at about 14-20
weeks (Figure 2). At 4 weeks the left ventricle plus
septum weight/body weight ratio was only 8%
higher in SHR than in WKY rats (p=0.05), rising
to =*25% at 14 weeks and to a final value of =*40%

400
i

FIGURE 2. Relation between age (weeks)


and 1) (top left) body weight (g) in spontaneously hypertensive rats (SHR) (n=126)
and Wistar-Kyoto (WKY) rats (n=131); 2)
(lower left) tail-cuff systolic blood pressure
in the same SHR and WKY rats; 3) (upper
right) left ventricle plus septum (LVS)
weight/body weight ratio (g/kg), with asterisks representing significant strain differences; 4) (lower right) average values of
LVS and right ventricle (RV) weight/body
weight ratio, expressed as percentages of
corresponding values in WKY rats at each
age. In 3 and 4, number of SHR and WKY
rats were: 4 weeks (5,5); 9 weeks (6,5); 14
weeks (6,6); 20 weeks (5,5); 30 weeks (4,6);
and 50 weeks (4,6).

300
/

1f
1
1

* 200
a
o

"

IOO

?240
E
E
'.200
oc
Q.

B160

/r-*-n

J120

T^

, ^.

' ^

WKY

0)

80

9 14 20
30
40
AGE - weeks

60

0 14 20
30
40
AGE - weeks

60

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196

Hypertension

Vol 14, No 2, August 1989


FIGURE 3.

400

SHR

WKY

E
I 300
^
ir
3
to

SO

_ 20
i
g

UJ

tr 200
-4
O 100
CO
3

60

above the corresponding values in WKY rats after


20 weeks (/?<0.001; Figure 2). At no time period
was there a significant difference in right ventricular weight/body weight ratio between SHR and
WKY rats (Figure 2).
Hindquarter Vascular Resistance Properties
Perfusion pressure-flow relation. We obtained
perfusion pressure-flow curves in the fully dilated
vascular bed of 4-, 14-, and 27-week-old SHR and
WKY rats (see Table 1 for numbers). In 4-week-old
rats of both strains, the relation between PPmaxdii
and flow was linear up to flow rates of about 25
ml/min/100 g hindquarter wt (Figure 1 and Table 1).
From analysis of covariance of the regression lines
in SHR (n=8) and in WKY rats (n=7), there was no
significant strain difference in regression coefficients, but there was a significant difference in
intercepts (Table l,p<0.001); P P ^ ^ was on average 3.2 mm Hg higher in SHR than in WKY rats.
The pressure-flow curves in 14- and 27-week-old
rats were linear up to flow rates of about 15 ml/
mm/100 g hindquarter wt. Over this range, the
relation was virtually the same at the two time
periods, so that we pooled the results from both
groups (Figure 1). Again, there were no significant
differences in regression coefficients but the intercepts differed, with PP,* ^ on average 3.7 mm Hg
higher in SHR than in WKY rats (Table l,p<0.001).
The slopes of the 14- and 27-week-old SHR and
WKY rats were about twice as steep as those of the
4-week-old rats, indicating a greater resistance to
flow in the older animals (Table 1 and Figure 1). At
a flow of 10 ml/min/100 g hindquarter wt, P P ^ da in
the young and older SHR averaged 17.3 and 27.8
mm Hg, respectively, with the corresponding figures in WKY rats 13.6 and 24.1 mm Hg (both
p<0.01). Thus, there was a similar age-related
increase in vascular resistance in both strains.

9n

r/

T
J

100
1
METHOXAMINE - jjfl/ml

30
_,.
" '

10

14
9

100

Methoxamine con-

centration perfusion pressure


response curves of hindquarters,
with values adjusted to constant
flow per unit hindquarter weight
(see Materials and Methods).
Each curve was reconstructed
from average values of the curve
parameters obtained in spontaneously hypertensive rats (SHR)
(right panel) and Wistar-Kyoto
(WKY) rats (left panel) at 4, 9,
14, 20, 30, and 50 weeks, as
marked on the right of each
curve, n at each age were, in
order, SHR and WKY: 4 weeks
(5,5); 9 weeks (6,5); 14 weeks
(6,6); 20 weeks (5,5); 30 weeks
(5,6); and 50 weeks (4,6).

In 4-week-old SHR, increasing flow beyond the


linear part of the pressure-flow curve resulted in a
plateau value of P P ^ ^ of =37 mm Hg at high
flows greater than 35-40 ml/min/100 g hindquarter
wt. In WKY rats, the slope of the perfusion pressureflow curve at these high flows was significantly less
than in the more physiological range, but there was
no definite plateau at flows as high as 50 ml/min/100
g hindquarter wt. The difference between SHR and
WKY rats suggests that the hindquarter bed was
less distensible in young SHR. In the older SHR,
we did not study flows greater than 20-25 ml/
min/100 g hindquarter wt and the perfusion pressureflow curves were of similar appearance in both
strains.
Responses to methoxamine. In other SHR and
WKY rats, we obtained dose-response curves to
methoxamine at different ages adjusted to constant
flow perfusion of 10 ml/100 g hindquarter wt (see
Materials and Methods) (Figure 3). When the hindquarters were maximally dilated with papaverine,
PPmdii was higher at all ages in SHR than in WKY
rats (p<0.01 except at 4 weeks, Figure 4). The
relation between age and PP,,** da was curvilinear in
each strain (Figure 4). The (PP^du in SHR)/
(PPmo dii in WKY rats) ratio was similar at all ages
and averaged 1.26.
Similarly, at every age PP^c*, was higher in
SHR than in WKY rats (Figures 3 and 4). One
finding common to both strains was that in 4- and
9-week-old rats, the maximum methoxamineinduced constrictor response was below the maximum constriction induced by Ang II or BaCl2 (Table
2). But in rats at or older than 14 weeks, a r
adrenergic receptor stimulation elicited the same
maximum constrictor responses as supramaximal
doses of Ang II or BaCl2. The (PP^co,, in SHR)/
(PPmocon in WKY rats) ratio (produced by either
methoxamine or Ang II) was similar at all time
periods and averaged 1.35.

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Adams et al

Vascular and Cardiac Hypertrophy

197

FIGURE 4. MeanSEM ofparameters of


methoxamine-perfusion pressure (PP)
response curves of spontaneously hypertensive rats (SHR) and Wistar-Kyoto
(WKY) rats at different ages. "Significant
difference between strains p<0.05. Parameters were 1) PP^M at maximum dilatation; 2) PPmaxcan at maximum constriction
(see Materials and Methods); and 3) ECX
dose of methoxamine at PP halfway
between PPmiu M and PP^ c^

100

9 14 20
30
AQE -

4 9 14 20
30
AQE - *

In both SHR and WKY rats, we determined the


relation between body weight on the one hand and
PPm^xdj and P P ^ e c on the other (Figure 5 and
Table 1). Analysis of covariance showed that, with
PPmx dii, the slopes of the regression lines diverged
significantly (p<0.05), and the slope in SHR was
about 35% steeper than in WKY rats. Thus, in a
60-g rat the P P ^ ^ averaged 16.1 0.9 in SHR and
13.40.9 mm Hg in WKY rats (A=2.7 mm Hg;
p=0.05); at the end of the rapid growth phase (400-g
rat), PPn^da in SHR was 31.80.7 mm Hg compared with 25.10.6 mm Hg in WKY rats (A=6.7
mm Hg; p<0.001). By contrast, the slopes of the
lines relating body weight to P P ^ ^ were only 16%
steeper in SHR than in WKY rats (N.S., Table 1
and Figure 5), with the perfusion pressure in 60-g
rats 69 mm Hg higher in SHR than in WKY rats, as
compared with an only slightly greater difference in
400-g rats of 85 mm Hg (p<0.001 for both sets).
In both SHR and WKY rats, EQo decreased
progressively after the age of 9 weeks, with the
values in the two strains virtually identical after
about 14 weeks (Figure 4). Between 4 and 14 weeks,
EQo was significantly less in SHR than in WKY
rats, so that only about 50% of the concentration of
methoxamine was required to elicit the same constrictor response (p=0.02).
The maximum slope of the sigmoid curve was
significantly greater in SHR than in WKY rats, and
in both strains there was a linear increase with age,
with the two lines approximately parallel (Figure 4).
The slope parameter is related to the perfusion
pressure range between PPn^da and P P ^ a * (see
Data Analysis under Materials and Methods), so
that overall the greater maximum slope in SHR

compared with WKY rats at a given age was partly


due to the greater perfusion pressure range in SHR
at a given age. However, there was also a "true"
increase in responsiveness in SHR between 4 and
20 weeks, since their range-independent slope parameter was significantly greater than in WKY rats
(Table 3). At 30 and 50 weeks, however, the rangeindependent slope was similar in both strains (Table
3), so that during this period the absolute value of
40
SHR

30
Q
X
20
0.
Q.

10
400

300

2 200

a.
a.
100L0
100

200
300
BODY WEIGHT - g

400

FIGURE 5. Relation between body weight and perfusion


pressures at maximum dilatation (PPmm &J and maximum
constriction (PP^a*) in 31 spontaneously hypertensive
rats (SHR) () and 32 Wistar-Kyoto (WKY) rats (o) aged
4-50 weeks.

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198

Hypertension

Vol 14, No 2, August 1989

TABLE 2. Differences Between Perfuskm Pressure at Maximum Constriction Produced by Methoxamine and by
Angiotensin II
SHR

Age (wk)
4
9
14-50t

Methoxamine
176.54.19
287.35.53
347.05.00

WKY

Angiotensin II
231.54.82*
314.87.15*
347.05.00

Methoxamine
130.215.09
210.0+9.51
264.3+3.90

Angiotensin II
161.8+19.39*
231.210.36*
264.3+3.90

Values for differences in perfusion pressure (mm Hg) are meanSEM. SHR, spontaneously hypertensive rats;
WKY, Wistar-Kyoto rats.
*p for difference <0.05.
tValues for methoxamine and angiotensin II responses between 14 and 50 weeks were similar at all times.

the slope of the SHR was higher only because of


elevation of the perfusion pressure range.
Regional Sympathetic Function
In the left ventricle plus septum there is a substantial sympathetic innervation of the myocardium. However, in skeletal muscle and kidney most
of the innervation goes to blood vessels.34-35
In the left ventricle plus septum, [NE] was nearly
twice as great in SHR as in WKY rats from 4 to 14
weeks of age (Figure 6, /?<0.01). However, at 20
weeks and older the [NE] was closely similar in
both strains. The left ventricle plus septum fractional rate constant K tended to be higher in SHR
than in WKY rats at most times between 4 and 50
weeks, but the variability was large, so that, at the
individual time intervals, only the strain differences
at 9 and 50 weeks were statistically significant. The
average norepinephrine turnover (i.e., A"x[NE])
was also higher at most ages in SHR than in WKY
rats, but again because of the variability the difference was statistically significant only at 4 and 9
weeks.
Forelimb muscle [NE] was about 40% higher in
SHR than in WKY rats during the rapid growth
period from 4 to 14 weeks (/><0.01) (Figure 6), but
after that period the difference in tissue concentration was much smaller and not significant. In contrast to the findings in heart and kidney, K was
virtually identical in SHR and WKY rats between 4
and 30 weeks, but at 50 weeks K in SHR was about
40% below the value observed in WKY rats. Norepinephrine turnover tended to be higher at 4 and 9

weeks in SHR than in WKY rats, but the difference


was significant only at 4 weeks (/?<0.01).
In the kidney, [NE], K, and norepinephrine turnover were all higher in SHR than in WKY rats at most
time periods (Figure 6). The only exception was at 20
weeks when K and norepinephrine turnover were the
same as in WKY rats. On average, K and norepinephrine turnover in SHR were, respectively, 1.66 and
1.92 times the corresponding values in WKY rats.
Discussion
The present study provides the most detailed
analysis to date of the time course of cardiovascular
hypertrophy and sympathetic function in SHR during the first year of life. We found that: 1) a higher
vascular resistance in SHR compared with WKY
rats was already established at 4 weeks, suggesting
that vascular hypertrophy was present at a time
when there was no difference in BP between the
two strains; 2) left ventricular hypertrophy lagged
behind the development of vascular hypertrophy
and occurred in parallel with the rise in BP; 3) in
both strains a^-adrenergic receptor stimulation with
methoxamine did not elicit maximum hindquarter
bed vasoconstriction until after 14 weeks of age;
between 4-14 weeks the resistance vessels of SHR
were relatively hyperresponsive compared with
those of WKY rats, as assessed by the differences
in EQo and in range-independent slope; and 4) [NE]
and turnover was increased in the heart, kidney,
and skeletal muscle vessels of young SHR; in the
skeletal muscle bed these changes were indepen-

TABLE 3. Comparison of Range-Independent and Maximum Slopes in Spontaneously Hypertensive Rats and
WIstar-Kyoto Rats of Methoxamine/ConcentratJon-Response Curves
Range-independent slope
(normalized units)
Age (wk)
4
9
14
20
30
50

Maximum slope (pressure/unit dose)

SHR

WKY

SHR

WKY

11916.9
904.6
12211.8
127+11.8
1303.6
18112.8

9714.5
717.3*
95 4.7*
976.2
1234.8
18625.8

19026.4
23415.3
36636.3
39740.8
42111.3
61643.0

12328.5
13315.2*
21414.2'
24219.9*
28419.5*
45247.7*

*p for difference <0.05.


Values are meanSEM. SHR, spontaneously hypertensive rats; WKY, Wistar-Kyoto rats.

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Adams et al
FORELIMB MUSCLES

KIDNEY

Vascular and Cardiac Hypertrophy

LEFT VENTRICLE & SEPTUM

300

tNE]
ng/g

200
100
0
0.2

SHR

Rata

0.1
Constant
WKY

NE

20

Turnover
10
(ng/g)/h

9 14 20

30

60

7S
50
25
0
4 9 14 20
30
AQE - weeks

199

50

dent of increased neural activity, as assessed from


the fractional rate constant.
Vascular and Cardiac Changes
In our colony there were no significant differences at 4 weeks between SHR and WKY rats, in
either systolic or mean arterial BP. However, by 6
weeks in the same colony, there was a definite rise
in mean arterial pressure, which increased in subsequent weeks in a manner similar to our systolic
pressure findings.36 Gray's review37 of blood pressure changes in young SHR suggests that BP may
already be raised in SHR during the neonatal period,
but, in our experiments, there was no evidence of
this at 4 weeks. Thus, our findings indicate that in
SHR there already was considerable vascular hypertrophy by 4 weeks, preceding the rise in BP. Later,
there was a further increase in vascular hypertrophy, suggesting that there also was a component
associated with the rise in BP. But at 4 weeks, left
ventricle plus septum weight in SHR was only 8%
above that in WKY rats. Thus, before the rise in
BP, left ventricular hypertrophy was slight, and
over 90% of the rise in left ventricular weight
followed the rise in BP.
We have assumed that the greater vascular resistance at full dilatation and during maximum constriction in SHR is due to the greater muscle mass in
the media of their resistance vessels. Medial hypertrophy in SHR is the main determinant of the
increased wall/lumen ratio of individual resistance
vessels, which, by causing narrowing of the vessel
compared with the lumen of WKY rats, is responsible for the greater values of the vascular resistances at full dilatation and at maximum constriction
and for the greater slope of the stimulus-response
curve. 1Aii^8 There is controversy concerning to
what extent anatomic "rarefaction" (i.e., reduction
in vascular density of resistance vessels per unit
tissue volume) contributes to the strain differences in
resistance properties. 3 9 - 4 0 Experimentally,
microsphere-induced anatomic rarefaction in the hind-

4 9 14 20

30

FIGURE 6. Relation between


age and tissue norepinephrine
concentration [NE], fractional
NE rate constant and NE turnover in forelimb muscles, kidney, and left ventricle and septum. 'Significant differences
between strains, n of spontaneously hypertensive rats (SHR)
and Wistar-Kyoto (WKY) rats,
respectively: 4 weeks (5,5); 9
weeks (6,6); 14 weeks (6,6); 20
weeks (5,5); 30 weeks (5,5); and
50 weeks (7,5).

SO

quarter bed causes elevation of P P ^ &, but leaves


unaltered P P ^ ^ and slope.41 By contrast, an
increased wall/lumen ratio and associated vascular
narrowing increases all three parameters of the doseresponse curve, both in individual small arteries42
and in the whole vascular bed.41
From the perfusion pressure-flow curves, the
differences in PP,,^ ^ between SHR and WKY rats
were similar at 4, 14, and 27 weeks (Figure 1).
However, the main study, which encompasses a
wider age and body weight range, suggests that the
difference between the strains widened progressively and that at 4 weeks, the difference was about
hah0 that observed in adult rats (Figure 5). The two
series included a substantial number of rats, thus
providing strong evidence that, by 4 weeks, a considerable amount of vascular hypertrophy had developed. However, the strain difference in PPnuxcco a t 4
weeks was only =20% below the value in adults
(Figure 5). One reason why PP,^, in SHR was
closer to the final adult value than P P ^ ^ is that the
amplification is accentuated during constriction,
since resistance increases in proportion to the fourth
power of the radius. In addition, the stiffer vessels
in the young SHR compared with the WKY rats
may accentuate the degree of luminal encroachment
during maximum constriction.
We did not determine vascular resistance before
the age of 4 weeks and extrapolation from the body
weight-PPn^ da and body weight-PP,^ relation in
Figure 5 is somewhat hazardous. Had we extrapolated the body weight-PP^ ^ relation to a lower
body weight value, we would have concluded that
the amount of vascular hypertrophy soon after birth
was small or absent. However, the body weightPPmx con relation is consistent with some degree of
hypertrophy at, or soon after, birth. The anatomic
literature on this point is conflicting.43-44 To date,
only the structure of large arteries has been examined in these very young animals, with evidence of
hypertrophy in one study,43 but not in another.44

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200

Hypertension

Vol 14, No 2, August 1989

Although the rise in P P ^ dn for a given increase


in body weight was somewhat steeper in SHR than
in WKY rats, in each strain there was a substantial
increase in this parameter with increasing body
weight and age (Figures 4 and 5). With increasing
body weight, most of the narrowing in average
cross-sectional area per unit tissue of the hindquarter bed was similar in SHR and WKY rats (e.g.,
Figure 1). We do not know the mechanisms involved
in these body weight-related and age-related vascular resistance rises, but each of the following could
play a role: 1) reduction in the rats' metabolic rate
during the early postnatal period,45 which may be
associated with a reduced density of resistance
vessels and a rise in resistance as the rat gets older;
2) growth-related increases in the length of resistance vessels; 3) changes in the proportion of skeletal muscle to fat in the hindquarters at different
stages of development; 4) changes in collagen and
elastin composition of the fibrous matrix of the
vessel, which affect wall distensibility2-3; and 5)
changes in proportion of different isoforms of vascular smooth muscle actin, reflecting alterations in
the proportion of the various phenotypes of smooth
muscle in the vasculature.46
In the absence of autonomic support, the development of vascular hypertrophy ahead of left ventricular hypertrophy in SHR will result in some
degree of mismatching of the intrinsic properties of
the vascular amplifier and the cardiac pumping
capacity.5 This occurs with normal left ventricular
myocardial function per gram of myocardium, as
indicated in studies performed under highly controlled conditions in renal hypertensive dogs5 and in
SHR.4 The development of additional myocardial
elements in left ventricular hypertrophy allows the
heart to maintain a given stroke volume and cardiac
output against a higher BP than is possible without
hypertrophy.5 In the event, there is enhanced left
ventricular neural activity at an early age (Figure 6,
rate constant data), which could provide sufficient
inotropic support to raise BP. Possibly, the reason
why the pressure does not rise to higher values than
in WKY rats is that renal sympathetic activity is
also elevated at the time, so that there is still some
degree of mismatch.
Sympathetic Innervation
At most periods there was elevation in heart rate
and in regional sympathetic activity (assessed from
the fractional norepinephrine rate constants) in heart
and kidney, but sympathetic regional activity in the
muscle was normal (Figure 6). Such a pattern
resembles the defense reaction.2'16-17 The elevation
of cardiac sympathetic activity in young SHR will
help to compensate for any inadequacy in intrinsic
pumping capacity (see above) and later on, will
provide enhanced cardiac pumping once left ventricular hypertrophy has fully developed. In the
hypertrophied vessels of the hindlimb bed, the
amplifier properties will ensure that resting vascular

resistance is elevated, even at normal levels of


sympathetic activity. Assuming the early development of the renal vasculature is similar to that of the
hindlimb, the rise of resting renal vascular resistance in SHR will tend to be relatively greater than
in the hindlimb. We cannot say from the available
data how the defense pattern of sympathetic activity will affect the mismatch between vascular amplifier and cardiac pump before left ventricular hypertrophy has fully developed. However, at the latter
time, the elevated neural activity (fractional rate
constant) will accentuate the elevation of BP.
Tissue [NE] was raised in all three regions up to
14 weeks of age, and in the kidney for most of the 50
weeks. Chronic increases in sympathetic activity
have been shown to increase steady-state concentrations of the enzymes tyrosine hydroxylase and
dopamine ^hydroxylase, thereby increasing tissue
[NE].47 In SHR, higher levels of both enzymes have
been reported in the mesenteric vessels, compared
with those in WKY rats.48 The effect of modulation
of transmitter release on [NE] by, for example,
increased reuptake42 are difficult to predict. However, another mechanism capable of increasing tissue [NE] independently of neural activity (as in the
case in the muscle bed in our experiments) may be
an increased innervation density in the vasculature
of young SHR, as recently demonstrated by Head
and colleagues.49-50 Thus, both a chronic increase in
neural activity and an increased innervation could
alter postjunctional properties and contribute to the
lower ECJO (and threshold) and to the higher rangeindependent slope observed in 4-14-week-old SHR
during methoxamine stimulation (Figure 4, Table
3). Neuromuscular coupling between vascular ar
adrenergic receptors and the contractile machinery
of the smooth muscle cell develops slowly in both
SHR and WKY rats, as judged by the inability to
develop maximum constriction with methoxamine
until they are above 14 weeks of age, as has also
been observed in rabbits.51 Below this age both
strains have a lower response for a given level of
a r adrenergic receptor stimulation than the corresponding group of older rats (Figures 3 and 4), but
the lower threshold and increased slope of young
SHR will tend to enhance the resistance vessel
responses, compared with those of young WKY
rats.
Recent studies by Lee et al20 have shown that
hypertension and hypertrophy are completely prevented by sympathetic ablation (see above), but we
do not know how this comes about. The observed
pattern of sympathetic activity will elevate BP
through enhanced constrictor and inotropic
responses once cardiovascular hypertrophy has
developed, but it may have an additional trophic
growth-promoting role at an earlier stage, which is
independent of the level of neural activity.52 In
normal rabbits in vivo, trophic effects of the sympathetic innervation have been found to contribute
to the development of the smooth muscle of the ear

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Adams et at Vascular and Cardiac Hypertrophy


artery18 and to the development of medial hypertrophy of cerebral vessels in SHR.53 In tissue culture,
catecholamines stimulate growth through adrenergic receptor-mediated mechanisms,19-54 but the process is complex and appears to involve interactions
with numerous growth factors.7'55
In the hindlimb bed, in contrast to the other
regions, elevation of [NE] and turnover occurs at
normal levels of sympathetic activity.47 From the
time course of P P ^ da, hypertrophy develops in the
immediate postnatal period and any trophic role of
the sympathetic activity should be apparent by the
age of 4-6 weeks. In the light of tissue culture
studies,19-53 our findings of high [NE] at 4 weeks in
the skeletal muscle bed provide a pointer of a
possible trophic role of the sympathetic in early
vascular hypertrophy. We may hypothesize that the
transiently increased density of sympathetic vascular innervation49-50 elevate the amount of norepinephrine released in the tissue, where it can interact
with local growth factors released by immature
vascular smooth muscle.54-55 A more definitive
answer must await further experiments.
Is There Primary Cardiovascular Hypertrophy?
Our findings suggest that a significant component
of vascular hypertrophy precedes the elevation of
hypertension, while the rest occurs pari passu with
the rise in BP. The first can be regarded as the
primary component that is critical to the development of hypertension, while the additional later
hypertrophy occurs as the conventional adaptive
response associated with the pressure rise. By
contrast, there is little, if any, primary left ventricular hypertrophy and this process appears to be
predominantly adaptive.
A priori we would expect that the simultaneous
establishment of cardiovascular hypertrophy will
produce an almost immediate elevation of BP, due
to the properties of the vascular amplifier. However, though the latter was well established by 4
weeks, we observed no rise in BP at this time,
though hypertension developed soon afterwards
(e.g., Reference 37). We do not know either the
reason for the small delay, despite the defense
pattern of sympathetic activity, or why it took
14-20 weeks before the adult BP level was reached
in SHR. Factors discussed earlier, such as the
metabolically related high vascularity in the young
rat, slow development of adrenergic receptor coupling to the contractile apparatus of the smooth
muscle cell, and mismatch between left ventricular
pumping capacity and vascular impedance may all
play a role in delaying the manifestation of the
vascular amplifier on the BP of SHR.
Acknowledgments
We are grateful to Susan Timmins for her able
technical assistance and to Judith Segal, Frances
Cribbin, and Tessa Morton for their help in preparing the manuscript.

201

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KEY WORDS primary hypertension hypertrophy


vascular resistance norepinephrine spontaneously
hypertensive rats

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Differential development of vascular and cardiac hypertrophy in genetic hypertension.


Relation to sympathetic function.
M A Adams, A Bobik and P I Korner
Hypertension. 1989;14:191-202
doi: 10.1161/01.HYP.14.2.191
Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 1989 American Heart Association, Inc. All rights reserved.
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