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Baroreflex Sensitivity Modulates Vasodepressor
Response to Nitroprusside
ALEXANDER M. M. SHEPHERD, M.D.,
JOHN L. M C N A Y , M.D.,
P H . D . , MIN-SHUNG LIN,
M.D.,
GARY E. MUSGRAVE, P H . D . , AND T. KENT KEETON, P H . D .
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SUMMARY Baroreflex activity is a determinant of the homeostatic response to alteration in blood
pressure. We examined the factors that determine the magnitude of the vasodepressor response to
sequential incremental intravenous infusions of sodium nitroprusside (NP), 0.05 to 6.4 yug/kg/min, in
eight male patients with essential hypertension. Each infusion level was of 10 minutes' duration.
Change from control values of mean arterial pressure (AMAP), heart rate (AHR) and plasma norepinephrine (ANE) were obtained at the end of each infusion level. Significant correlations were found
between AMAP vs log dose NP, AHR vs AMAP and ANE vs AMAP for each patient (p < 0.05).
However, the slopes of these relationships varied widely between subjects and were significantly
correlated with the control blood pressure of each patient. In addition, the sympathetic responsiveness, as measured by ANE vs AMAP, was inversely correlated with the degree of vasodepressor
response seen. Thus, the magnitude of the vasodepressor response was determined by two major
factors: 1) the predrug blood pressure, possibly reflecting altered vascular geometry with hypertension; 2) the degree of sympathetic response, which probably acts by mediating the degree of reflex
alpha-adrenergic-mediated arteriolar vasoconstriction. (Hypertension 5: 79-85, 1983)
KEY WORDS
* plasma norepinephrine
• hypertension
T
• heart rate • humans
thetic efferent nerves to the heart, and cardiovascular
stress causes alteration in both vagal and sympathetic
nerve activity.10"12 Accordingly, the use of changes in
HR vs changes in blood pressure to measure BRS does
not permit a separate examination of these two neural
components. Third, alteration in the sensitivity of the
cardiac beta-adrenoceptors to norepinephrine (NE)
may contribute to variations in the HR versus blood
pressure relationship. Finally, only the cardiac effects
of alteration in sympathetic nerve activity are measured; therefore, those factors influencing the noradrenergic control of the resistance vessels are not included in this measure of BRS. Since peripheral
vascular tone is affected by the sympathetic but not the
parasympathetic nervous system, the neural regulation
of vascular tone might be better reflected by plasma
NE levels.
HE level of baroreceptor activity, acting by
way of the sympathetic nervous system, is a
major determinant of the homeostatic response to perturbation of blood pressure. Changes in
sensitivity of the baroreflex arc occur in hypertension,1"5 sleep,6 and with a g i n g . 2 3 5
Baroreflex sensitivity (BRS) is usually expressed in
terms of the change in heart rate (HR), or R-R interval,
for each unit of change in blood pressure.' 2 7~9 However, there are practical and theoretical limitations to
this approach. First, in subjects receiving beta-adrenoceptor antagonists, the relationship between HR response and the level of sympathetic activity may
change. Second, HR is controlled by a balance between the level of activity of the vagal and the sympa-
Plasma NE concentration is considered to be a useful quantitative measure of the level of activity of the
sympathetic nervous system, particularly during cardiovascular stress produced by isometric7' 'Oi 13 or dynamic14"16 exercise, tilt,17 change from recumbency to
upright posture,7' "•18 exposure to cold,7'16- "• M induction of hypoglycemia,21 the Valsalva maneuver,16 and
sodium balance.16> u-n
From the Division of Clinical Pharmacology, Departments of
Pharmacology and Medicine, The University of Texas Health Science Center, Audie Murphy Veterans Administration Hospital, San
Antonio, Texas.
Address for reprints: Alexander M.M. Shepherd, M.D., Ph.D.,
Departments of Pharmacology and Medicine, The University of
Texas Health Science Center at San Antonio, 7703 Floyd Curl
Drive, San Antonio, Texas 78284.
Received May 26, 1982; revision accepted July 16, 1982.
79
80
HYPERTENSION
To circumvent the limitations associated with using
change in HR as an index of BRS, we used changes in
the plasma concentration of NE to gauge the sympathetic component of the BRS in supine hypertensive
patients. In addition, we measured the correlation between the level of sympathetic responsiveness as
measured by plasma NE increments and the magnitude
of the vasodepressor response seen after administration of sodium nitroprusside (NP). The baroreflex arc
was activated by sequential stepwise reductions in
blood pressure produced by incremental intravenous
infusion rates of NP. This method provides a graded
series of measurable stimuli for baroreflex activation.
At each level of blood pressure reduction, HR and
plasma NE and epinephrine (EP) concentrations were
measured and compared with control values.
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Methods
Eight patients (aged 45-55 years, weighing 85-116
kg) with essential hypertension were studied in hospital. All patients were receiving long-term therapy for
their hypertension but antihypertensive medications
except hydrochlorothiazide were stopped at least 6
days prior to the study.
The patients were hospitalized for at least 4 days at
bed rest to permit stabilization of blood pressure. Their
hospital diet contained 137 mEq of sodium per day.
Electrolyte balance was not quantitated; however, no
consistent change of body weight was noted. The patients received nothing by mouth except water, beginning the previous midnight. The patients remained recumbent in bed without smoking throughout the study
period. At 7 a.m., a pediatric scalp vein needle was
placed in a forearm vein for blood sampling. A 5%
solution of dextrose and water (D5W) was slowly infused through a second intravenous needle in the other
arm which was used for NP infusion. Starting at 9
a.m., each patient was given serial incremental infusions of NP, each of 10 minutes' duration, by variable
speed Harvard infusion pump into the side arm of the
D5W infusion run at 0.5 irnVmin. Total fluid volume
given was less than 50 ml over the 80-minute study.
The NP infusion rate was increased over the range of
0.05-6.4 pig/kg/min, or until diastolic pressure was
reduced to the level observed during the outpatient
drug treatment of each individual patient. Blood pressure (Arteriosonde) and HR (EKG) were measured
every 10 minutes for 2 hours before starting the NP
infusion and every 2 minutes during the infusion period. The HR was counted over at least 30 seconds for
each determination.
Venous blood was drawn through the scalp vein
needle during the last 2 minutes of the control period
and during the 9th minute of each infusion period. The
scalp vein needle was kept patent with 0.15 M saline
containing 10 units heparin /ml. Samples were drawn
into 5 ml plastic syringes and immediately transferred
to precooled tubes containing EGTA (60 fig/ml) and
reduced gluthathione (90 fig/ml). Plasma was separated at 4°C and stored at - 70°C until analyzed for NE
and EP by a single isotope radioenzymatic assay.24
VOL 5, No
1, JANUARY-FEBRUARY
1983
Data Analysis
Blood pressure values are expressed as mean arterial
pressure (MAP) calculated as diastolic pressure plus
one-third of pulse pressure. Analysis of variance indicated no significant variation in MAP during the 2
hours prior to NP infusion. Control MAP (CMAP) is
expressed as the average of the 12 values obtained at
10-minute intervals prior to the infusion of NP. A
change in MAP (AMAP) was taken to be the difference
between CMAP and the average of the last three blood
pressure values recorded during each infusion period.
Control HR and the change in HR (AHR) were obtained at the same time intervals. Plasma NE and EP
concentrations were the means of duplicate determinations. Changes in plasma NE (ANE) and EP (AEP)
were the differences between the control values and the
values obtained in the ninth minute of each infusion
period.
Baroreflex sensitivity was calculated as the ratio of
AHR to AMAP, similar to the steady-state method,
which has been shown to be equally reliable with the
ramp method.3
Statistical analysis was performed by the methods
specified in the text. These methods included one-way
analysis of variance, least squares linear regression
analysis, multiple linear stepwise regression analysis
and Z transformation of the correlation coefficient, r.
Statistical significance was taken to be p < 0.05.
Catecholamine Assay
This assay technique has previously been described
in detail.24 Briefly, 100 fiL of plasma was added to a
solution containing buffer, catechol-O-methyltransferase and 3H-S-adenosylmethionine. After the stoichiometric transfer of 3H-methyl groups to the catecholamine by catechol-O-methyltransferase (incubation at
37°C for 60 minutes), the 3H-O-methylated metabolites of NE and EP were separated by a rapid thin layer
chromatographic procedure. This isolation procedure
prior to counting the 3H-O-methylated metabolites permits a high degree of specificity in the differential
assay of NE and EP. The intraassay and interassay
coefficients of variation are 6% and 11% respectively,
for both NE and EP. The limit of detection is 20 pg/ml
for both compounds.
Results
By using infusion rates of NP ranging from 0.05 to
6.4 /xg/kg-min, an average of six (range, five to nine)
stepwise decrements in MAP were elicited in each
patient. The maximal reduction in MAP at the highest
rate of infusion averaged 25 mm Hg and ranged from
14 mm Hg in the least hypertensive patient to 40 mm
Hg in the most hypertensive patient. Linear regression
analysis of data obtained from each patient revealed a
significant log dose-response relationship between
AMAP and the log of the infusion rate of NP (p g
0.005; fig. 1).
The maximal rise in HR during NP-induced vasodepression averaged 26 beats/min (range, 18-38 beats/
min). Within each subject, a significant positive corre-
81
CATECHOLAMINE RESPONSE TO NITROPRUSSIDE/Shepherd et al.
40-
I r-098
I
1 r-092
30X
E
E
Q.
r-096 A
1
/ r-09e
20l/jf
10-
//yCr
r-099
r-093
00.01
0 0 5 O.KD Q20 0 4 0
1.00 2JD0 4.00 8 0 0
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NP Infusion Rate (ng/kg/min)
FIGURE 1. Individual plots of the best-fit calculated regression
lines relating the logarithm of the infusion rate of sodium nitroprusside (NP) to the vasodepressor response seen.
lation (p ^ 0.01) existed between the decrease in
MAP and the resulting increase in HR (fig. 2 a).
The mean plasma NE concentration prior to the administration of NP was 199 pg/ml (range, 162-435 pg/
ml). No relationship was found between the severity of
the hypertension and the baseline levels of either NE (r
= 0.5503) or EP (r = -0.1550) in the plasma. The
stepwise decrements in MAP caused by increasing
doses of NP were accompanied by stepwise increments
in plasma NE concentration in all subjects (fig. 2 b).
Moreover, a correlation existed between the rise in
plasma NE concentration and the corresponding increase in HR at each infusion rate of NP in each patient
(fig. 3). In only one subject was a significant correlation found between rise in EP and AMAP. The maximum rise in plasma EP was small (33 ± 6 pg/ml, mean
± SEM) compared with that of NE (275 ± 84 pg/ml).
Although correlations were noted between AMAP/
log dose NP, AHR/AMAP, ANE7AMAP and AHR/
ANE within the data of each patient, a considerable
amount of interindividual variation was found in the
slopes of these relationships. For example, in some
patients a small fall in MAP was associated with a
(a)
300-
FIGURE 2. Individual plots of the best-fit calculated regression lines relating the vasodepressor
response seen to (a) the rise in heart rate (HR) and
(b) the rise in plasma norepinephrine (NE) concentration.
-= 200-
40-
a.
or
x
LZJ
20-
100-
20
40
20
0
40
AMAP(mmHg)
40-,
FIGURE 3. Individual plots of the best-fit calculated regression lines relating the rise in plasma
norepinephrine (NE) concentration to the rise in
heart rate (HR).
E
a.
.a
cr 20-
100
200
ANE (pg/ml)
300
400
82
HYPERTENSION
large increase in plasma NE concentration, whereas in
other patients, a large decrease in MAP was accompanied by only a small rise in plasma NE levels. The
slopes of the best-fit regression lines for each subject
are shown in table 1.
To determine whether CMAP was related to the
slopes of these relationships, the slopes of the best-fit
regression lines of each of these relationships were
correlated against CMAP for each patient. This method of analysis revealed a positive correlation between
CMAP and the slope of AMAP/log10 NP dose (fig. 4 a):
AMAP/log10 NP dose = - 5 6 . 0 + 0.67 CMAP,
where r = 0.8913, p = 0.0014.
A negative correlation was noted between CMAP and
the slopes of both AHR/AMAP (fig. 4 b) and ANE/
AMAP (fig. 4 c):
VOL 5, No
1, JANUARY-FEBRUARY
1983
TABLE 1. CMAP and the Slopes of the Relationships Between the
Measured Parameters
Subject
1
2
3
4
5
6
7
8
AMAP/
CMAP
log io
(mm Hg) NPdose
98
10.0
107
17.8
108
15.3
15.5
109
13.2
113
37.4
123
131
23.5
46.4
152
AHR/
AMAP
1.85
1.36
1.57
1.40
1.30
0.33
1.20
0.41
ANE/
AMAP
AHR/
ANE
18.6
14.0
30.5
12.1
9.4
0.087
0.070
0.055
0.107
0.080
0.081
0.087
0.140
4.3
13.3
2.37
CMAP = control mean arterial pressure; AMAP = change in
mean arterial pressure from control; NP = nitroprusside; AHR =
change in heart rate; ANE = change in plasma norepinephrine.
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AHR/AMAP = 4.1 - 0.03 CMAP,
where r = 0.8052, p = 0.0128.
ANE/AMAP = 51.1 - 0.32 CMAP,
where r = 0.6347, p = 0.0935.
Last, a positive correlation existed between CMAP
and the slope of the AHR/ANE relationships (fig. 4 d):
AHR/ANE = - 0 . 0 3 3 + 0.001 CMAP,
where r = 0.6925, p = 0.0565.
60-,
80
The last two relationships failed to reach statistical
significance.
To determine whether the slopes of the individual
dose response relationships were influenced by BRS or
by the reactivity of the sympathetic nervous system,
the slopes of the dose response curves were regressed
against AHR/AMAP (fig. 5 a) and against ANE/
3.0-1,
160
80
CMAP (mmHg)
l60
120
160
FIGURE 4. Individual data, with calculated best-fit regression lines relating the baseline arterial blood pressure
(CMAP) to the slopes of the relationships: (a) vasodepressor response vs logarithm of sodium nitroprusside (NP)
infusion rate; (b) rise in heart rate (HR) vs vasodepressor response; (c) rise in plasma norepinephrine (NE)
concentration vs vasodepressor response; (d) rise in HR vs rise in plasma NE concentration.
CATECHOLAMINE RESPONSE TO NlTROPRUSSIDE/S/iep/imf et al.
AMAP (fig. 5 b). The following regression equations
were obtained:
AMAP/logl0
AMAP/log10 NP dose
where r = 0.9468, p
AMAP/log10NP dose
where r = 0.6870, p
where r = 0.9714, p < 0.0001.
=
<
=
=
49.2 - 22.7 AHR/AMAP,
0.0001;
35.5 - 1.00 ANE/AMAP,
0.0590.
Since the parameters CMAP, AHR/AMAP and ANE/
AMAP were likely to covary, multiple linear stepwise
regression analysis was undertaken with AMAP/
log]0NP dose as the dependent variable and CMAP,
AHR/AMAP, ANE/AMAP as independent variables.
The following regression equation was obtained:
NP dose = 8.57 + 0.27
- 15.64 AHR/AMAP,
83
CMAP
This indicates that both CMAP and AHR/AMAP were
independent determinants of the slope of the dose response curve.
To determine if CMAP or BRS (expressed as AHR/
AMAP) was related to the extrapolated threshold values of the regression lines, AMAP vs log dose NP,
AHR vs AMAP, and ANE vs AMAP, the threshold
values were correlated against CMAP for each patient.
No significant correlations could be found between
CMAP and the relationships; AMAP vs log dose NP (p
= 0.40); AHR vs AMAP (p = 0.60); ANE vs AMAP
(p = 0.50).
(a)
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40-
20-
•a
CO
10
o
20
30
AHR/AMAP
60-i
(b)
40-
20-
10
20
30
ANE/AMAP
FIGURE 5. Individual data, with calculated best-fit regression
lines for the group, relating (a) the slope of the relationship
A///?/AMAP and (b) the slope of the relationship ANE/AAMP,
to the slope of the dose/response relationship (hMAPIlogio NP
infusion rate).
Discussion
In the present study we have shown a positive correlation between slope of the NP vs blood pressure dose
response curves and the predrug blood pressure. Similar relationships have been found for other vasodilators
including diazoxide23 and minoxidil26 and for diuretics.27"29 We could not detect any interrelationship between the threshold dose of nitroprusside required and
the baseline blood pressure. This supports the work of
Sivertsson,30 who found no evidence of supersensitivity in the hand resistance vessels of hypertensive patients. Increased vascular sensitivity might be expected to be reflected in a shift of the threshold dose of
vasodilator required to cause fall in pressure.
Despite the potential limitations, already discussed,
to using change in HR as a measure of baroreflex
sensitivity, we were able to demonstrate good relationships between the slope of the dose-response relationship and both AHR/AMAP and baseline blood pressure. A relationship between baroreflex sensitivity and
baseline blood pressure has been previously demonstrated.31 However, the relationship between baroreflex sensitivity and vasodepressor responsiveness has
not been previously demonstrated. It indicates an association between this measure of baroreflex sensitivity
and the degree of homeostatic responsiveness to reduction in blood pressure.
The sympathetic nervous system is known to play an
important role in the control of the circulation. However, it is difficult to assess the basal level of activity of
the sympathetic nervous system in clinical studies.
Although the plasma concentration of NE is generally
regarded as a useful measurement of the level of stimulation of the sympathetic nervous system, the resting
levels of plasma NE do not necessarily reflect sympathetic nervous system activity. This is probably in part
due to the levels of NE in the blood, which are not
determined solely by the rate of spillover from peripheral sympathetic nerves into the circulation. Additional factors influencing the plasma NE levels include
variation in distribution and rate of metabolism, which
84
HYPERTENSION
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is seen in normal subjects,32 hypertensive patients,
autonomic insufficiency, and following drug interventions.33 It may be for this reason that there is dispute as
to the interrelationship between baseline plasma NE
levels and the presence and extent of hypertension.22' 3K 34~36 However, plasma NE levels are considered to be representative of sympathetic nerve activity. ' 3 -" The failure of plasma EP to rise significantly
indicates that adrenal medullary secretion is probably
not a major source of the plasma catecholamines measured in this study.
It is recognized that NP infusion results in increased
plasma NE concentration.38 The slope of the relationship of ANE/AMAP may be regarded as reflecting the
degree of stimulation of the sympathetic nervous system for each decrement in blood pressure induced by
NP. As expected, therefore, the slope of ANE/AMAP
was proportional to both baseline blood pressure (fig. 4
c) and the slope of the dose response curve (fig. 5 b).
Multiple linear stepwise regression analysis indicated that control blood pressure and slope of the AHR/
AMAP relationship were independent correlates of the
slope of the dose-response relationship. Accordingly,
baseline blood pressure appeared to determine the
slope of the dose-response relationship by an alternative or additional mechanism to its effect on baroreflex
sensitivity. This additional mechanism may be the
structural differences in vascular geometry caused by
hypertension as demonstrated by Folkow.39 The
dependence of the slope of the dose-response curve on
the degree of tachycardia induced, rather than on the
degree of sympathetic stimulation, may be because
mechanisms other than sympathetic stimulation will
contribute to the homeostatic response seen. Man in'T
Veld et al.12 have shown that reduction of vagal tone is
the principal mechanism for increase in HR and cardiac output seen when blood pressure is decreased with
diazoxide. The degree of sympathetic stimulation will
determine the reflexly mediated peripheral vasoconstriction that will oppose the vasodepression induced
by NP. When Mancia et al.40 decreased transmural
pressure in the carotid sinus by changing the pressure
in a chamber placed around the neck, they found that
peripheral vasoconstriction, presumably resulting
from increased NE release and alpha-adrenoreceptor
activation, was the only mechanism accounting for the
pressor response. Thus, the mechanisms contributing
to the homeostatic response seen following vasodilation may be complex and have not yet been fully
elucidated.
While our experiments do not rigorously define
cause and effect, we propose that NE secretion relative
to arterial pressure reduction provides an estimate of
adrenergically mediated vasoconstriction. The latter
effect would nonspecifically antagonize the vasodepressor effect of NP. Data from several animal studies support the conclusion that baroreflex activation of
the sympathetic nervous system antagonizes the vasodepressor effect of NP. Flacke et al.41 have shown that
the veratrum alkaloid, cryptenamine, which acts on
baroreceptors, potentiates the vasodepressor effect of
VOL 5, No
1, JANUARY-FEBRUARY
1983
NP. Greenway and Innes42 found that carotid reflex
mechanisms reduced the vasodepressor response of
anesthetized vagotomized cats to intravenous NP by
approximately two-thirds. The principal mechanism of
this physiological antagonism was defined as an increase in peripheral resistance. A reflex increase in
iliac resistance during NP infusion in conscious dogs
has been clearly demonstrated by Pagani et al.43 Accordingly, activation of vascular alpha-adrenoceptors
may be a major mechanism by which autonomic reflexes modulate the vasodepressor response to vasodilator drugs. By contrast, the hemodynamic effects of
altered autonomic control of heart rate and contractility
may be relatively minor, since combined pretreatment
with atropine and propranolol does not potentiate the
vasodepressor response of supine hypertensive patients to intravenous bolus doses of diazoxide.12
In conclusion, we have demonstrated associations
between the degree of vasodepressor response seen
with graded infusions of NP and both the baroreflex
sensitivity and baseline blood pressure. The latter association possibly reflects structural vascular changes
related to the degree of hypertension. In addition, the
data are consistent with the conclusion that adrenergically mediated vasoconstriction antagonizes the hypotensive response to nitroprusside in supine hypertensive patients.
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A M Shepherd, M S Lin, J L McNay, G E Musgrave and T K Keeton
Hypertension. 1983;5:79-85
doi: 10.1161/01.HYP.5.1.79
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