Download Diminished Baroreflex Sensitivity in High Blood Pressure

Diminished Baroreflex Sensitivity in High
Blood Pressure
By J. DAVID BRISTOW, M.D., A. JOHN HONOUR, D.PHIL.,
GEORGE W. PICKERING, M.D., F.R.S., PETER SLEIGHT, M.D., M.R.C.P.,
AND
HARLEY S. SMYTH, M.D., D.PHIL.
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SUMMARY
Sudden intravenous injections of small amounts of angiotensin or phenylephrine
were given to 30 subjects to produce modest, brief increases in directly measured systemic arterial pressure. A plot of each systolic pressure against the second succeeding
cardiac cycle length produced a linear distribution, the slope of which was expressed
as the millisecond increase in cycle length per mm Hg rise in systolic pressure. The
slope is an index of baroreflex sensitivity and was found to have an average value of
12.8 in 18 subjects without hypertension and 2.8 in 12 others with hypertension. When
all results were pooled, there was an inverse relationship between the resting mean
arterial pressure and slope of the baroreflex regression lines. The findings demonstrate
reduced sensitivity of the baroreflexes in hypertension, with respect to control of heart
rate. A distinction is made between this change in sensitivity and simple resetting of
the reflex.
Additional Indexing Words:
Cardiovascular regulation
Hypertension
Heart rate
Phenylephrine
Angiotensin
Baroreceptor
little new information has become available
in man despite long-standing interest.4 This
paper describes quantitative assessment of one
baroreceptor function, that of heart rate control, in subjects with normal and high arterial
pressures.
IT SEEMS CERTAIN that an alteration of
baroreceptor reflex function is associated
with systemic arterial hypertension. If this
were not so, bradyeardia would be characteristic of most hypertensive syndromes, due
to a continued high level of reflex activity.
The normal heart rate usually found, therefore, reflects either an adaptation of the baroreflex systems to the higher pressure or a
primary dysfunction which could have a
causative role. There is evidence of abnormal baroreceptor activity induced by experimental hypertension in animals,1-3 but
Methods
Observations were made in 30 unsedated subjects who were in the supine or semisupi'e
position. An antecubital vein and a brachial artery were cannulated percutaneously with plastic
tubing. Arterial pressure was measured with a
strain gauge and respiratory phase was detected
by a pneumograph. These signals and lead I
of the electrocardiogram were recorded with' a
direct-writing polygraph. Mean arterial pressure
was found by electrical damping or planimetry.
The characteristics of the recording system have
been described before.5
Multiple injections of 0.25 to 2.0 jig of angiotensin II amide were flushed through the venous
cannula with 5 ml of isotonic saline, producig
modest, transient rises in systemic arterial pressure (BP). Recordings of BP and the other parameters were made at paper speed of 30 or 50
From the Department of the Regius Professor of
Medicine, and the Cardiac Department, Radcliffe
Infirmary, Oxford, England. Work was performed
during Dr. Bristow's tenure of a Special Fellowship,
National Heart Institute, U. S. Public Health Service.
Address for reprints: Dr. J. D. Bristow, Division
of Cardiology, University of Oregon Medical School,
Portland, Oregon.
48
Circulation. Volume XXXIX, January 1969
DIMINISHED BAROREFLEX SENSITIVITY
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mm/sec until the peak of the pressure rise had
passed. In 16 of the subjects 50 to 100-,ug
injections of phenylephrine were also administered, again producing increases of BP in order
to stimulate the baroreflex.6 Both drugs caused
rises in systolic, diastolic, and mean BP, with
little change in pulse pressure.
The records were analyzed by methods which
have been described in detail elsewhere,5' 7 and
which are summarized here. All systolic and
diastolic pressure pulses and R-R intervals (in
milliseconds) were measured from the time of
injection of the pressor agent until just after the
peak of the pressure rise, usually requiring about
35 beats. Each systolic BP was plotted against
the second R-R interval following it, thus allowing
time for reflex activity to occur.8' 9 R-R intervals
during inspiration were not included, in order to
avoid the influence of sinus arrhythmia. Linear
relationships between systolic BP and the R-R
interval were found, and from the set of plotted
values resulting from each angiotensin or phenylephrine injection the correlation coefficient and
the linear regression equation were calculated.10
Results are included in this report if the probability value derived from the correlation coefficient and the sample size was less than 0.05;
this usually was associated with an r value greater
than 0.65.
The brief pressure rise provided a spectrum of
cardiac cycle lengths in relation to a range of
systolic BPs (fig. 1). The degree of cardiac slowing produced was shown by the slope of the
regression line, expressed as milliseconds increase
in cycle length (R-R interval) per mm Hg rise
in systolic BP. The steeper the slope of the distribution, the more sensitive is overall baroreflex
function, with respect to control of heart rate.
Previous studies, as well as this one, found the
slopes of these lines to be independent of the
magnitude of baroreceptor stimulation, that is,
the extent of BP rise, or the dose of drug, once
a detectable increase in BP was produced.5 Multiple injections were given to all subjects and a
total of 159 regression coefficients was calculated.
Systolic BP was chosen as the pressure measurement for these calculations because of the
ease and accuracy of its measurement. We recognize the importance of other components of
the pressure wave as determinants of baroreceptor activity (for example, mean BP each pulse),
but their measurement beat by beat presents
problems not encountered with systolic BP. Since
pulse pressure did not change much with the
pressor response, the correlations that we observed between systolic BP and cycle length no
doubt existed with mean BP as well.
The mean arterial pressure at rest ranged from
72 to 135 mm Hg and presented a continuous seCirculation, Volume XXXIX, January 1969
49
0
RR
r=091
Slope: 27 3
msecl
.
1200[
S
0
0
0
0
.
0
I I
u
SYSTOLIC
A
ILU
PRESSURE
r = 0 73
900-
Slope 1-4
RR
I m sec) -0
700
700
B
0
*
--0'
0
0
w
0
II
170
180
190
SYSTOLIC PRESSURE
200
Figure 1
Relationship between individual systolic arterial pressures (mm Hg) and subsequent pulse intervals (R-R,
in milliseconds) when pressure was transiently increased by the sudden injection of angiotensin. (A)
Results of one injection in a subject with a resting
mean arterial pressure of 74 mm Hg. (B) Results of
one injection in a man with mean pressure of 119 mm
Hg. The diference in slopes of the regression lines is
evident. Abbreviation: r = correlation coefficient.
ries (table 1), Subjects were arbitrarily grouped
as having mean pressure above 110 (hypertension) or below (normal). Eleven of the 12 subjects with the higher pressures were given a
BRISTOW ET AL.
50
Table 1
Age, Control Blood Pressure, and Baroreflex Slope After Injection of Angiotensin and
Phenylephrine
Subject
1
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2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18*
Average
Age
(yr)
23
24
23
24
48
38
39
48
33
24
36
53
30
47
48
28
28
80
37.4
Control mean
arterial pressure
(mm Hg)
Angiotensin
Baroreflex slope
(msec/mm Hg)
Blood pressure less than 110 mm Hg
5.1
72
14.0
73
30.1
74
81
16.7
6.6
88
27.1
89
10.0
89
91
10.4
5.0
91
27.8
92
5.8
93
93
7.5
16.4
100
14.6
100
4.3
100
17.3
104
9.8
108
1.0
108
12.8 i 2.0t
91.4
Blood pressure more than 110 mm Hg
6.4
112
35
19
115
2.8
39
20
2.2
118
21
46
118
3.7
22
55
119
1.8
58
23
120
0.9
24
55
3.3
123
41
25
125
4.3
26
26
0.2
129
55
27*
5.0
131
25
28
2.3
132
43
29
0.1
44
135
30
123.1
2.8 + 0.6t
43.5
Average
* = Postural hypotension
t = Mean + standard error
Subjects are listed in order of increasing control mean blood pressure.
diagnosis of essential hypertension. None had
received diuretic, sedative, or antihypertensive
therapy for several weeks, and most had notbeen treated previously at all. The remaining 18
subjects had lower mean BP ranging from 72
to 108 mm Hg (average, 91), and all were
healthy save one elderly man with postural
hypotension.
Results
The
slopes of the systolic BP-RR interval
Phenylephrine
33.3
18.4
7.3
26.0
10.5
11.4
20.7
12.9
10.7
4.7
15.5
9.4
3.3
14.2
8.0
4.1
3.3
5.1
distributions for each subject were averagzed
and appear in table 1; representative examples are shown in figure 1. With angiotensin injections, individuals with a control
mean BP below 110 mm Hg had an average
slope of 12.8 (SE-+±2.0), compared with 2.8
(SE + 0.6) for those with higher pressures
(P <0.01). Only one hypertensive subject
had a slope greater than 5; 15 of the 18 subjects with lower BP had slopes greater than
Ciscutation, Vo4ume XXXIX,
January
1969
DIMINISHED BAROREFLEX SENSITIVITY
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5. Three patients with hypertension had
virtually no change in heart rate despite the
rise in BP produced by drug injection.
As mentioned earlier, the magnitude of
rise of BP appears to be independent of the
slopes we have described. Nonetheless, in
order to be certain that the experimental
manipulations were similar in these two
groups of subjects the amount of change of
pressure produced by the drug was evaluated.
Angiotensin injections increased systolic BP
an average of 21 mm Hg in those with
lower control BP and 32 mm Hg in those
with hypertension. When expressed as a percentage of the control level, those with lower
BP had an average rise of 17% compared with
20% for the hypertensives. The degree of baroreceptor stimulation thus seemed comparable.
Not all subjects received phenylephrine,
but the results were similar to those with
angiotensin. The average slope with phenylephrine for 13 subjects with lower pressures
was 14.2; the average for the three hypertensives was 5.1.
The angiotensin results from both groups
were then pooled and each subject's mean
BP in the control state was plotted against
the slope of the systolic BP-RR interval
line, as presented in figure 2. A significant
negative correlation resulted (r =-0.62, P
<0.001), demonstrating progressively less influence of systolic BP on heart rate at higher
control mean pressure.
An attempt was made to determine whether
the spontaneous variations in BP during normal breathing were associated with different
degrees of variation in heart rate in the two
groups. The measurements were made before
any drug effects. During the respiratory cycle,
the hypertensives demonstrated an average
variation of systolic BP of 13 mm Hg, or 8% of
the lowest systolic level observed at the time.
Those with lower BP varied 9 mm Hg, or 7% of
the lowest systolic value. However, the spontaneous variation of the R-R interval during
the respiratory cycle was different in the two
groups, being 72 msec in the hypertensives
and 128 msec in the others (P < 0.05). Although the normal group was weighted by
Circulation, Volume XXXIX, January 1969
51
.
.
0
r =-0O62
p=<0 001
0
.
0
cn
E
E
0
Cn
-3
-le
cn
S
0
0
0
0
0
0
80
110
CONTROL MEAN B.P.
140
mm Hg)
Figure 2
The results from all subjects are presented. There is
an inverse relationship between resting mean arterial
pressure and the slope of the regression lines produced
by angiotensin injections, indicative of progressively
less influence of systolic pressure on heart rate at
higher resting mean pressure.
one person with considerable variation in
heart rate, it is suggested, nonetheless, that
hypertensives have less variation in heart rate
than normotensives, yet have slightly more
variation in pressure.
Discussion
The results contrast the influence of the
baroreflexes on heart rate at normal and
chronically high levels of BP. The control
heart rates were similar in the low and high
pressure groups (68 and 71 beats per minute,
respectively), but in the hypertensives they
changed little with further elevations of BP.
We believe that the gross differences in slope
BRISTOW ET AL.
52
testing herein employed appraises overall reflex function and allows no firm conclusions
!n
about a locus of altered sensitivity. Thus, an
It
influence on heart rate which overrides
baroreceptor activity would be interpreted
Re-set
Sensit ivity
as an influence on the sensitivity of the reflex
.p..
in our studies.
There was an apparent, inverse relation160
200
120
160
120
200
between age and the slope of the baroship
BLOOD PRESSURE
reflex
lines (r =-0.53, P < 0.01), but the
Figure 3
average age of those with high pressures was
Two hypotheses for an alteration of baroreflex function
about 6 years greater than that of those with
in hypertension. (Left) Resetting of the reflex without
normal pressures. Thus, our data do not proa change in sensitivity. The slope of the relationship
vide unequivocal evidence that there is a
between blood pressure and pulse interval is not
changed. (Right) In addition to resetting of the reflex,
strong, specific effect of age on the barowith the line moved to the right, there is a diminution
reflexes. Fairly steep slopes were found
in sensitivity. Our results support the latter hypothesis.
around age 50 years in the absence of hypertension,
and some subjects with lower slope
of the regression lines at low and high convalues
were
in their twenties or thirties.
trol pressures demonstrate a decrease in the
Nonetheless,
some
decrease in sensitivity of
sensitivity of the baroreceptor reflexes in esthe
reflex
with
advancing
years cannot be
sential hypertension, at least with respect to
completely
denied.
control of heart rate. This is quite different
The relative unresponsiveness of the reflex
from "resetting" of the reflex at a higher level
be accounted for in several ways.
might
of BP in hypertensives, but with unchanged
Alexander
and DeCuir2 have described resensitivity, as shown in figure 3. Resetting
sults
analogous
to ours in renal hypertension
without a change in sensitivity (slope of
in
With
rabbits.
development of raised BP
line) has been produced by alterations in
the
animals
lost
the ability to produce
blood gas composition in normal subjects,,"
in
bradycardia
response to further elevation
but this adaptation does not appear to be
of pressure produced by injections of angiocharacteristic of chronic hypertension.
tensin.
The mechanism responsible for this
Differences in responsiveness to angiois not known, but the findings
adaptation
tensin or phenylephrine are not factors to
are
consistent
with the well-known earlier
account for the differences in slope, as the
studies
of
McCubbin
and associates,' who
magnitude of rise in BP produced by the
showed
a
decrease
in
baroreceptor afferent
drugs was similar in proportion to the connerve
impulse
frequency
associated with renal
trol level and, if anything, was weighted to
in
hypertension
dogs.
It
is clear, therefore,
provide greater stimulation of the reflex in the
that
adaptation
of
baroreflex
control of heart
high pressure group. Direct effects of the drugs
rate
to
hypertension
can
and
does occur in
on heart rate have been evaluated previously
animals.
and do not explain our results.5 12-15
In man, such diminished sensitivity might
The relationship of heart rate to blood
result
from decreased compliance of the arpressure during ordinary breathing, without
terial
walls
in baroreceptor regions, allowing
drug effects, further supports the idea of abless
stretch
of receptors per unit rise of
normal baroreflex function in hypertension.
and
thus
BP,
producing the damped response
In those with bigh BP, slightly greater swings
we
found.
Medial
hypertrophy of arteries or
in a systolic BP were associated with less
arteriosclerosis would diminish arterial comvariation in heart rate than is seen in
pliance, as might an alteration in the water
normotensives.
It must be emphasized that the baroreflex
and electrolyte composition of arterial walls.16
Normal
Re -set
C=
Normal
i
I
I
I
-cc
cr-
I
I
I
LU
I
LAJ
It
*0
-j
C36
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Circulation, Volume XXXIX, January 1969
53
DIMINISHED BAROREFLEX SENSITIVITY
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In this regard, the findings of Biglieri and
McIlroy17 are of special interest. Their patients with primary aldosteronism demonstrated qualitative abnormalities of baroreflex
function which were associated with deranged
potassium, sodium, and water relationships.
Degeneration of receptors in the carotid
sinuses of patients who died with hypertension has been described.'8 19 This is compatible with our results, but it still remains to
be shown whether these anatomic findings
are a result of high blood pressure or a cause.
As Koch20 showed, the sensitivity of the
baroreflex is linear over only a part of its
range; at the highest pressures it levels off.
Moreover, in acute experiments the baroreflex adapts quickly to a given increase in
pressure. Thus less reflex effect might be anticipated at higher pressure.2' 23 However,
when a moderate, acute rise in BP is induced
in man by alterations in blood gases, the
sensitivity of the baroreflex is not significantly
diminished.11
Finally, there remains the possibility that
baroreflex dysfunction can cause human arterial hypertension. Support for this view is
not strong, yet a fault anywhere from receptor
cells via central nervous system to end-organ
could conceivably establish hypertension. Our
demonstration of reduced baroreflex sensitivity
in hypertension certainly does not exclude the
possibility.
The baroreceptors are concemed with several aspects of circulatory regulation.24-26
The reflexes influence venous capacitance,
systemic vascular resistance, and myocardial
contractility, in addition to the heart rate.
Final conclusions about the role of altered
baroreflex performance in producing or maintaining hypertension will depend in part upon
evaluation of these other functions. Two such
studies concluded that the carotid sinuses
were functioning in hypertension, because
an increase in blood pressure or vascular
resistance followed neural blockade of the
sinuses by local anesthesia in hypertensive
patients.27 28 In experimental hypertension,
Alexander and DeCuir2 demonstrated their
animals' ability to buffer the increased BP
Circulation, Volume XXXIX, January 1969
produced by angiotensin injections, despite
the loss of cardiac slowing, mentioned earlier.
These studies do not allow one to conclude,
however, that baroreflex dysfunction is innocent of any etiological or permissive responsibility in clinical hypertension. Our results
suggest a fault in cardiovascular regulation
in essential hypertension, and whether eventually shown to be a primary disorder or
secondary to the hypertensive process, it may
have significance in the maintenance of raised
arterial pressure.
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Circulation, Volume XXXIX,
January
1969
Diminished Baroreflex Sensitivity in High Blood Pressure
J. DAVID BRISTOW, A. JOHN HONOUR, GEORGE W. PICKERING, PETER
SLEIGHT and HARLEY S. SMYTH
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Circulation. 1969;39:48-54
doi: 10.1161/01.CIR.39.1.48
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
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