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(Hypertension. 1995;25:384-390.)
© 1995 American Heart Association, Inc.
Articles |
Physiological Determinants of Hyperreactivity to Stress in Borderline Hypertension
From Duke University Medical Center, Department of Psychiatry and Behavioral Sciences (A.S.), Durham, NC, and the University of North Carolina, Departments of Medicine (A.L.H.) and Psychiatry (K.C.L.), Chapel Hill.
Correspondence to Andrew Sherwood, Box 3119, Duke University Medical Center, Durham, NC 27710.
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Abstract Blood pressure hyperreactivity during stress is characteristic of borderline hypertension in white men. The present study evaluated the hemodynamic basis of this hyperreactivity and assessed its physiological basis in terms of sympathetic nervous system function. Cardiovascular adjustments to an aversive reaction time test were compared with those of the forehead cold pressor test, representing stressors that elicit active behavioral responses in contrast to passive tolerance of aversive stimulation. As anticipated, blood pressure increases were greater in 12 borderline hypertensive men compared with 21 age-matched normotensive men during the active reaction time stressor but not during the passive cold pressor test. The pressor hyperreactivity in borderline hypertensives was associated with excessive rises in plasma epinephrine and norepinephrine, leading to greater increases in cardiac output, despite evidence that the cardiac ß-adrenergic receptors in these subjects were downregulated compared with those of normotensive subjects. During the cold pressor test, borderline hypertension was associated with greater increases in systemic vascular resistance, which, in the presence of normal baroreceptor reflex function, led to an attenuation of cardiac output, thus producing no greater net effect on blood pressure than seen in normotensive subjects. Evidence of vascular hypertrophy in the borderline hypertensive subjects was considered to account for their vascular hyperreactivity to cold pressor stimulation. Collectively, the observations in this study further support the view that the early stages of hypertension in white men are characterized by sympathetic nervous system hyperreactivity, but only in association with tasks that elicit active behavioral coping responses. The extent to which these responses are elicited by typical daily events may be an important determinant of whether borderline hypertension matures to its established form, which displays hemodynamic characteristics dominated by vascular structural changes.
Key Words: hypertension, borderline • receptors, adrenergic • stress • blood pressure • cardiac output • vascular resistance • catecholamines
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Introduction |
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Borderline hypertensive patients have been viewed as a population whose study may yield important information about the etiology of essential hypertension.1 Early research on borderline hypertension described a hyperkinetic circulatory state, whereby blood pressure (BP) was elevated as a result of high cardiac output (CO).2 3 4 Longitudinal studies have since documented that this early hemodynamic profile undergoes a progressive transition with time, resulting in a normal or low CO and high total peripheral resistance, the characteristic profile of established essential hypertension.5 A widely acknowledged problem with the study of essential hypertension to address the cause of the disease is that the physiological characteristics observed may themselves be an effect of the elevated BP.6 Therefore, growing interest in the study of borderline hypertension reflects the view that it may yield insight into the physiological mechanisms responsible for the onset of hypertension before their concealment by secondary changes.
Evidence that a hyperkinetic circulatory state in borderline
hypertension is due to autonomic imbalance has generated interest in
the role of the sympathetic nervous system (SNS) in the early
pathophysiology of essential hypertension. SNS activation evoked by
behavioral stress can result in an acute hyperkinetic circulatory state
that is strikingly similar to that of borderline
hypertension.7 Thus, the notion that stress may play a key
role in the etiologic picture has gained wide appeal. One prediction
stemming from this viewpoint is that borderline hypertension should be
associated with BP hyperreactivity during mental stress. A
meta-analysis of studies conducted to date confirms that borderline
hypertensive patients indeed show BP hyperreactivity, but only to a
specific class of behavioral stressors—namely, those that elicit
active behavioral coping responses.8 Interestingly, the
so-called active coping stressors typically evoke a fight-flight
pattern of cardiovascular activation, with increases in BP caused by an
increased CO that is mediated primarily by stimulation of cardiac
ß-adrenergic receptors.7 In contrast, borderline
hypertensive patients appear to be no more reactive to stressors such
as the cold pressor test, which require passive tolerance of an
aversive stimulus. The cold pressor test produces an increase in BP by
a vasoconstrictive response that is mediated by vascular 
-adrenergic
activation.9
The putative role of stress in the etiology of essential hypertension
remains a controversial one. For example, it is unclear whether stress
might play a causative role by the long-term effects of repeated SNS
activation in borderline hypertensive patients or whether BP
hyperreactivity to stress in borderline hypertension may simply be an
epiphenomenon of a more generalized SNS dysfunction.10 11
Pickering and Gerin12 emphasized that to address this
question, there is a need for careful evaluation of the physiological
determinants of pressor hyperreactivity in borderline
hypertension.12 The present study responds to this
need by comparing responses in borderline hypertensive patients and
normotensive subjects during exposure to two laboratory-based
behavioral stressors, one designed to elicit an active coping
behavioral response and one requiring passive coping. In addition to
BP, the study is designed to document underlying hemodynamic patterns
of pressor responses. Because the characteristics of borderline
hypertension described above are based on studies that predominantly
tested white men, the present report focuses on the physiological
characteristics of stress reactivity in white borderline hypertensive
men. Compared with their normotensive counterparts, borderline
hypertensive patients were hypothesized to show BP hyperreactivity
caused by excessive increases in CO during the active coping task but
not during passive tolerance of aversive stimulation. Potential SNS
mechanisms of hyperreactivity were assessed in terms of activation,
measured by plasma catecholamine responses, and responsiveness of
cardiac and vascular - and ß-adrenergic receptors. In addition,
baroreceptor reflex gain and an index of vascular hypertrophy were
assessed; both may plausibly contribute to excessive pressor
reactivity.
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Methods |
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Subjects
Thirty-three white male subjects, 18 to 32 years of age, were tested as part of the current study. Recruitment criteria excluded individuals with any history of taking antihypertensive medications. Individuals who were more than 30% above ideal body weight, according to the 1983 Metropolitan Life Insurance tables, were also excluded. All subjects read and signed a consent form approved by the University of North Carolina Medical School Human Rights Committee. At an initial screening session, seated BPs were taken in triplicate by a trained technician using a mercury sphygmomanometer and an occlusion cuff of appropriate size. Subjects were categorized as borderline hypertensive (n=12) if screening (mean of three readings) systolic BP (SBP) fell in the range of 135 to 160 mm Hg and/or diastolic BP (DBP) fell in the range of 85 to 100 mm Hg; blood pressures falling below these ranges led to the designation of normotensive (n=21) BP status. A second set of three seated, resting pressure readings, obtained at least 1 week later, was used to confirm BP status.
These BP criteria were used as screening ranges to classify subjects as borderline hypertensive or normotensive. These criteria do not reflect any standard for the designation of "borderline hypertension," which historically has lacked a universally acknowledged operational definition. However, by its descriptive name, borderline hypertension is widely accepted as describing pressures spanning or fluctuating around the region of the border set by the BP cutoffs defining hypertension. In terms of the most recent criteria set forth by the Joint National Committee on the Detection, Evaluation and Treatment of High Blood Pressure,13 the present study's criteria for borderline hypertension span part of the range formally defining high normal pressure (SBP, 130 to 139 mm Hg; DBP, 85 to 89 mm Hg) and the entire range for stage 1 (mild) hypertension (SBP, 140 to 159 mm Hg; DBP, 90 to 99 mm Hg).
Cardiovascular Measurements
Blood pressure was measured noninvasively with the auscultatory
method. A custom-built device was used to rapidly inflate and slowly
deflate (3 mm Hg/s) an appropriately sized occlusion cuff placed
around the subject's left arm. Korotkoff sounds were recorded with a
piezoelectric microphone positioned over the brachial artery, under the
distal edge of the occlusion cuff. SBP was recorded as the cuff
pressure associated with the onset (phase I) of Korotkoff sounds, and
DBP was associated with the disappearance (phase V) of Korotkoff
sounds. Mean arterial pressure (MAP) was computed as DBP plus one third
of pulse pressure; ie, MAP (mm Hg)= [(SBP-DBP)/3]+DBP.
Impedance cardiography was used to permit noninvasive monitoring of cardiac performance.14 A Hutcheson Impedance Cardiograph (model HIC-1, University of North Carolina) was used with a tetrapolar band–electrode configuration. The inner two recording electrode bands were positioned around the base of the neck and around the thorax over the xiphisternal junction. The outer two current electrode bands were positioned to encompass the neck and thorax at least 3 cm away from each of the recording electrodes. The electrocardiogram (ECG) was recorded independently with disposable ECG electrodes. The basal thoracic impedance (Zo), the first derivative of the pulsatile impedance (dZ/dt), and the ECG waveforms were processed with specialized ensemble-averaging software (COP, BIT Inc) used to derive stroke volume with the Kubicek et al15 equation, heart rate (HR), CO, pre-ejection period (PEP), and left ventricular ejection time. CO was divided by body surface area to give cardiac index (CI). Total peripheral resistance index (TPRI) of the systemic vasculature was derived on the basis of the concurrently recorded blood pressure and CO measurements with the equation TPRI (dyne · s · cm-5 · m2)=(MAP/CI)x80.
Plasma Catecholamines
Blood was sampled from a cannula inserted into a forearm vein
immediately after noninvasive instrumentation before the stress test
protocol. The cannula was connected by heparin-treated polyethylene
tubing to a blood withdrawal pump (Cormed ML6 continuous blood
withdrawal system, Dakmed Inc). Blood was sampled at a withdrawal rate
of 3 mL/min and collected in EDTA-treated sample tubes. Samples were
immediately cold-centrifuged, and the plasma was pipetted and frozen at
-80°C until the time of assay. Plasma epinephrine and norepinephrine
concentrations were determined with the high-performance liquid
chromatography technique at the University of North Carolina General
Clinical Research Center.
Stress Testing Protocol
Resting Baseline
All test procedures were conducted while subjects were
seated in an electrically shielded, sound-attenuated,
temperature-controlled (24°C) chamber. After instrumentation,
subjects were seated in a comfortable chair and asked to relax as much
as possible for 20 minutes. Resting baseline cardiovascular and plasma
catecholamine measures were taken during the last 3 minutes of this
relaxation period.
Reaction Time Shock Avoidance
This simple reaction time task was described in detail
previously.7 Briefly, the task lasted 3 minutes, with a
loud audible tone presented at varying, unpredictable intervals
(average, 23 seconds). Subjects were told to press a key as fast as
possible on hearing each tone. Subjects were instructed that if, on any
given trial, a reaction time was considered too slow, a "painful but
harmless" electric shock would be delivered immediately by
electrodes previously applied to the leg. In fact, shocks were never
delivered.
Forehead Cold Pressor
A thin plastic bag containing a mixture of crushed ice and water
(0°C to 4°C) was held against the subject's forehead for 3
minutes. The cold pressor is well established as a potent pressor
stimulus, which increases BP almost entirely by vasoconstriction
mediated by -adrenergic receptor activation.9 The
forehead cold pressor elevates BP in the absence of the tachycardia
typical of limb cold pressor tests.16 Hemodynamic response
patterns elicited by the forehead cold pressor have been shown to
distinguish between demographic groups at different risk for the
development of hypertension.17 18 19
ß-Adrenergic Receptor Responsiveness
All receptor responsiveness testing was conducted while subjects
were in a fully reclined posture and at least 6 hours after the last
consumption of caffeine. During adrenergic receptor testing, blood
pressure was measured continuously with the FINAPRES (Ohmeda)
noninvasive BP monitor. This instrument, which uses the vascular
unloading technique to measure SBP, DBP, and MAP on a beat-by-beat
basis, has been validated against intra-arterial measures under various
conditions, including pressor responses to
phenylephrine.20 The standardized isoproterenol
sensitivity test was used to evaluate ß-adrenergic receptor
responsiveness in terms of the chronotropic dose of isoproterenol
required to increase HR by 25 beats per minute (bpm)
(CD25).21 Progressively increasing bolus doses
of isoproterenol (0.125, 0.25, 0.5, 1.0, 2.0, and 4.0 µg) were
injected into an antecubital vein until an increase in HR of at least
25 bpm was observed. HR responses after each dose were computed as the
shortest three successive ECG R-R intervals after drug injection
compared with the shortest three R-R intervals at rest (preinjection).
After each dose, the next higher dose was not injected for at least 5
minutes, or until cardiovascular activity had returned to resting
levels, usually within 5 to l0 minutes. The linear regression model of
log-dose/HR response for each subject was used to determine
CD25 exactly by interpolation. The CD25 measure
provides an index of cardiac ß1- and
ß2-receptor responsiveness. A vascular
ß2-receptor responsiveness index was also derived by
determining the vasodilatory dose of isoproterenol required to decrease
TPRI by 40% (VD40) by use of log-dose/TPRI response
interpolation. Both the CD25 and VD40 indexes
are inversely related to receptor responsiveness.
1-Adrenergic Receptor Responsiveness
The procedure used to assess 1-receptor
responsiveness was analogous to the ß-receptor responsiveness test
described above but with bolus doses of the 1-agonist
phenylephrine to stimulate vascular 1-receptors.
Previous studies using this technique have defined -adrenergic
responsiveness in terms of the dose required to raise either SBP by 20
mm Hg22 or MAP by 20%.23 In the present
study, the criterion response was defined as the dose of phenylephrine
required to increase MAP by 25 mm Hg (PD25). An initial
dose of 25 µg phenylephrine was used, with successive doses doubled
until the 25 mm Hg response was exceeded or until a maximum dose of
800 µg was reached. Again, at least 5 minutes or longer if required
for recovery of cardiovascular activity to resting levels preceded
administration of successive doses. The linear log-dose/MAP response
curve was used to determine the exact PD25 dose. The
PD25 index is inversely related to vascular
1-receptor responsiveness.
Baroreceptor Reflex Sensitivity
Baroreceptor gain (milliseconds per millimeter of mercury) was
measured during 1-receptor responsiveness testing as the
reflex increase in ECG R-R interval associated with the peak SBP that
occurred after administration of the phenylephrine dose that raised MAP
to 25 mm Hg or higher. The assessment of concurrent changes in SBP and
R-R interval to phenylephrine has become a standard approach to
evaluating baroreceptor reflex sensitivity under resting
conditions.22
Minimal Forearm Vascular Resistance
Minimal forearm vascular resistance (MFVR) was measured
according to the technique described by Egan and
colleagues.24 In brief, forearm blood flow was measured in
milliliters per minute per 100 milliliters with strain-gauge
plethysmography (EC-4 Plethysmograph, Hokanson Instruments) after the
forearm had been made temporarily ischemic (10-minute occlusion). MFVR
(peripheral resistance units) was derived by dividing MAP by forearm
blood flow. MFVR is an index of peripheral vascular structure that is
considered to reflect hypertrophy and/or decreased numbers of
resistance vessels.
Statistical Analyses
Unpaired Student's t tests were used to compare
borderline hypertensive and normotensive subjects for demographic and
resting physiological characteristics. We used 2x2 repeated-measure
ANOVA and ANCOVA tests to evaluate the effects of BP status (borderline
hypertensive versus normotensive) on cardiovascular and catecholamine
responses during reaction time and cold pressor testing.
SAS software (SAS) was used to perform the t
tests, ANOVAs, and ANCOVAs, with the multiple-contrasts procedure used
to evaluate ANOVA and ANCOVA interaction effects.
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Results |
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Screening BPs and General Characteristics
Table 1 presents average screening BPs for borderline hypertensive and normotensive subjects and other demographic characteristics. Table 1 also summarizes the t tests, which confirm greater SBP and DBP in borderline hypertensive compared with normotensive subjects and show that borderline hypertensive subjects were heavier and had greater body mass indexes (BMI) compared with normotensive subjects, although the groups were similar in age, height, and body surface area.
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Resting Baseline Hemodynamic Characteristics
Table 2 gives the cardiovascular measures taken
after 20 minutes of quiet relaxation in a darkened room. As the summary
of t tests comparing borderline hypertensive with
normotensive subjects shows, SBP and DBP were somewhat lower than at
screening but remained significantly higher in borderline hypertensive
than in normotensive subjects. Resting HR was also significantly higher
in borderline hypertensive than in normotensive subjects, whereas CI,
systemic vascular resistance index, and PEP showed no group
differences. Resting plasma catecholamine levels were not significantly
different for borderline hypertensive compared with normotensive
subjects.
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Adrenergic Receptor, Baroreceptor, and Vascular Structure
Measures
As Table 3 shows, both cardiac (CD25)
and vascular (VD40) ß-adrenergic receptor responsiveness
was significantly lower in borderline hypertensive compared with
normotensive subjects, whereas no differences were found for vascular
1-adrenergic receptor responsiveness. Baroreceptor
reflex sensitivity was comparable for borderline hypertensive and
normotensive subjects. However, borderline hypertensive subjects were
found to have significantly higher MFVRs than normotensive subjects,
suggesting vascular hypertrophy of the forearm resistance vessels in
borderline hypertensive subjects.
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Hemodynamic Responses During Reaction Time and Cold Pressor
Tests
The Figure shows the responses for each
cardiovascular measure, defined as change from resting baseline to the
average levels observed during the reaction time and cold pressor
tests.
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BP Responses
SBP increased from resting baseline levels in response to both the
reaction time and cold pressor tests (P<.001). ANOVA of SBP
responses yielded a significant BP status by test condition interaction
effect (P<.001), which was associated with a significantly
greater increase (P<.05) in SBP during the reaction time
task in borderline hypertensive compared with normotensive subjects.
The two groups did not differ in their SBP responses to a cold pressor.
DBP also increased in response to both experimental stressors
(P<.001). For DBP, there was a nonsignificant trend toward
a greater increase during the reaction time task in borderline
hypertensive compared with normotensive subjects (P<.07).
DBP increases during the cold pressor test were of similar magnitude
for the two groups.
CO and Vascular Resistance Responses
During the reaction time test, there was a significant increase in
CI only in the borderline hypertensive group (P<.01), and
during cold pressor tests, there was a significant decrease in CI only
in the borderline hypertensive group. ANOVA for the CI response yielded
a significant BP status by test condition interaction
(P<.02). This interaction was associated with a greater
increase (P<.05) in CI during the reaction time test in
borderline hypertensive compared with normotensive subjects (the
Figure), but there was no significant response difference to the cold
pressor test. There was also a significant BP status by test condition
interaction for the systemic vascular resistance (TPRI) response
measure (P<.05). As the Figure shows, the pattern of
responses associated with this effect are quite different from that for
CI. During reaction time tests, neither borderline hypertensive nor
normotensive subjects showed a significant TPRI change from baseline.
However, during the cold pressor test, both groups showed an increase
in TPRI (P<.001), but this increase was greater
(P<.05) for borderline hypertensive subjects than for
normotensive subjects.
Chronotropic and Inotropic Responses
HR increased in both groups during the reaction time test
(P<.01) but not during the cold pressor test (the Figure).
There was a significant BP status by test condition interaction for HR
response (P<.02) caused by a greater increase in HR for
borderline hypertensive compared with normotensive subjects during the
reaction time task (P<.02). Shortening of PEP, a myocardial
contractility index, was evident during the reaction time test for
borderline hypertensive subjects (P<.001) but not for
normotensive subjects, and there was no significant change in PEP
during cold pressor for either group (the Figure). ANOVA yielded a
significant BP status by test condition interaction for PEP response
(P<.01). This interaction was due to the greater decrease
in PEP during the reaction time test in borderline hypertensive
compared with normotensive subjects (P<.005), but there was
no group difference during cold pressor tests.
Plasma Catecholamine Responses During Reaction Time and Cold
Pressor
The Figure also shows plasma norepinephrine and epinephrine
responses (task levels minus baseline levels) during the reaction time
and cold pressor stressors. During the reaction time task, borderline
hypertensive subjects exhibited significant increases in both plasma
norepinephrine (P<.001) and epinephrine
(P<.005). Normotensive subjects showed only nonsignificant
tendencies for norepinephrine and epinephrine to rise during the
reaction time task (P>.05). During the cold pressor test,
plasma norepinephrine increased significantly in normotensive subjects
(P<.01) and showed a nonsignificant tendency to increase in
borderline hypertensive subjects (P<.1). Plasma epinephrine
showed no significant change in either group during the cold pressor
test. Consistent with these observations, ANOVAs yielded a significant
BP status by test condition interaction for epinephrine, F(1,31)=4.41,
P<.05), and a strong trend toward a similar interaction for
norepinephrine (P<.07), both reflecting the stronger
catecholamine response in borderline hypertensive subjects during the
active reaction time task.
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Discussion |
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The results of the present study are consistent with the collective evidence from previous reports that in white men, borderline hypertension is characterized by excessive increases in SBP during exposure to mental stressors that provide an effective means of coping by active behavioral response.8 Also consistent with existing evidence, we found that white borderline hypertensive men do not show exaggerated BP responses during stressors that require passive tolerance of an aversive stimulus. This replication of previous observations was a prerequisite to identification of mechanisms associated with BP hyperresponsivity in white borderline hypertensive men.
During the active coping stressor (aversive reaction time task), BP increases were due to augmented CO, with little or no change in vascular resistance, independent of BP status. However, the greater BP response of borderline hypertensive subjects was due to a more marked augmentation of CO than observed in normotensive subjects. These hemodynamic observations are consistent with those of two previous studies that evaluated cardiac and vascular contributions to the pressor responses of individuals with borderline BP elevations.25 26 In terms of mechanisms, the HR and PEP data show that both chronotropic and inotropic influences on the heart were greater during the active coping stressor in borderline hypertensive subjects. These effects are consistent with greater SNS stimulation of the heart, along with synergistically reduced vagal influences. The inference concerning sympathetic influences is supported empirically by the greater plasma concentrations of epinephrine and norepinephrine during the task in borderline hypertensive subjects. No specific indexes of vagal activity were recorded in the present study, although previous observations of vagal tone, indexed by HR variability, are consistent with the possibility that parasympathetic contributions may also account for the greater cardiac responses of borderline hypertensive subjects.27
The finding that cardiac ß-adrenergic receptor responsiveness, assessed by isoproterenol challenge, was reduced in borderline hypertensive compared with normotensive subjects supports a growing body of evidence that ß-receptors are blunted in the early pathogenesis of hypertension.28 29 Progressive downregulation of ß-receptors has been postulated as one mechanism that may account for the hemodynamic alterations occurring with the progression of hypertensive disease. Reduced responsiveness of cardiac ß-receptors should reduce CO, while similar changes in peripheral vascular ß2-receptor function should increase vascular resistance. Thus, with progressive ß-receptor downregulation, BP should become increasingly supported by vascular resistance in the presence of a diminishing CO. This is the transition widely understood to be the characteristic hemodynamic shift during the decades over which hypertension matures.1 5
Studies incorporating ß-adrenergic blockade demonstrated that it is ß-receptor activation that primarily mediates the fight-flight cardiovascular activation pattern.7 30 Thus, the reduced ß-receptor responsiveness appears inconsistent with the more pronounced fight-flight response pattern seen in borderline hypertensive subjects. Indeed, this observation underscores the impact of the excessive sympathetic activation reflected in the greater plasma catecholamine increases in borderline hypertensive subjects. Moreover, the observations are consistent with an etiological model of hypertension whereby ß-receptor downregulation is a consequence of excessive stimulation during repeated episodes of stress-induced SNS arousal.11
The passive stress of the painful forehead cold pressor test led to a
very different hemodynamic pattern underlying the pressor response. In
this case, BP increased entirely because of a rise in vascular
resistance, with CO tending to fall. The pressor response was
independent of BP status, whereas the fall in CO was significant only
in borderline hypertensive subjects, who commensurately showed a
greater rise in vascular resistance than the normotensive subjects.
Consistent with previous evidence that the cold pressor response is
mediated predominantly by activation of vascular
1-adrenergic receptors,9 the task was
associated with a significant rise in plasma norepinephrine and no
significant change in epinephrine. Norepinephrine responses were not
significantly different for borderline hypertensive compared with
normotensive subjects. In contrast, borderline hypertensive subjects
did show significantly greater MFVR values than normotensive subjects,
suggesting the presence of vascular hypertrophy in the borderline
hypertensive group. Speculatively, these observations support the
possibility that the presence of vascular hypertrophy in borderline
hypertensive subjects may have manifested itself in a greater degree of
vasoconstriction to a given level of activation of arteriolar
-adrenergic receptors. Consistent with this possibility, the mean
PD25 value for borderline hypertensive subjects was
directionally (though nonsignificantly) lower than in normotensive
subjects, reflecting a trend toward greater vasoconstriction for a
given dose of phenylephrine in borderline hypertensive subjects.
The borderline hypertensive subjects tested in the present study were significantly heavier, with higher BMIs than the normotensive subjects. By some criteria, the borderline hypertensive subjects could be considered obese, whereas the normotensive subjects were within the range of normal body weight. The observation that the borderline hypertensive subjects were overweight compared with the normotensive subjects is consistent with the findings from the Tecumseh population study in which borderline hypertensive subjects averaged 30% above ideal body weight.31 In the present study, our recruitment criteria required volunteers to be within 30% of ideal body weight and may therefore, if anything, have led to a bias toward normal weight in our borderline hypertensive sample. Nonetheless, one possible confounder with our observations of physiological hyperreactivity associated with borderline hypertension is that the effects may have been due to obesity rather than BP. To examine this possibility, the ANOVA tests of physiological response to stress were also performed with BMI as a covariate. All the significant group differences in physiological response (summarized in the Figure) remained significant after controlling for the effects of BMI, suggesting that the physiological hyperreactivity to stress was related primarily to the elevated BP rather than to obesity in the borderline hypertensive subjects.
A growing body of evidence indicates that hemodynamic response patterns
exhibited during stress are individual difference characteristics that
are stable over time and across stressors, supporting the notion of a
causal role for the stress response in the development of
hypertension.32 However, a review of the available
evidence suggests that the very characteristic (SNS hyperreactivity)
that has been postulated to play an initiating role in the
pathophysiology of hypertension is either no longer evident or far less
robust after the hypertension has become established.11 12
Julius33 proposed a pathophysiological model of
hypertension that may explain this seemingly paradoxical phenomenon. In
brief, this model postulates that the central nervous system possesses
BP-seeking properties, which include negative feedback loops that can
modulate sympathetic outflow to maintain a target pressure. As vascular
hypertrophy develops with the progression of hypertensive
disease6 and ß-adrenergic receptors become
downregulated,28 29 there is a resulting amplification of
the pressor response produced by sympathetic vasoconstrictor
(-adrenergic) effects on the arterioles. This model postulates the
existence of a central nervous system directive to maintain BP within a
target range, which is achieved by a compensatory reduction in
sympathetic tone as hypertension becomes predominantly controlled by
vascular structural changes. This conceptual framework provides a
plausible explanation for why sympathetic hyperreactivity may be
important in the pathogenesis of hypertension but may play a lesser
role in the later stages of this disease.
Ethnicity and sex have been associated with specific hemodynamic
response patterns during exposure to stressors that activate the SNS. A
consistent observation across several independent studies is that
African American men tend to exhibit greater vascular contributions to
their pressor responses than white men.18 19 30 34 Recent
preliminary evidence indicates that heightened vascular responses in
African American men may be due in part to increased responsiveness of
vascular 1-adrenergic receptors.35
Interestingly, in the same study, no evidence of reduced ß-adrenergic
receptor responsiveness was observed in borderline hypertensive African
Americans, whereas ß-blunting was observed in the white borderline
hypertensive subjects. Women also tend to exhibit a characteristic
hemodynamic pattern during stress, this time typically displaying
greater vasodilation and thus a more marked contribution from CO to
their pressor responses.34 36 37 In light of these
observations, it seems likely that the emerging picture of the
pathogenesis and progression of hypertension based on the study of
white men may be far from representative of all demographic
groups.
The present findings indicate that relative to normotensive subjects, young borderline hypertensive white men show (1) greater pressor responses to an active coping task, owing to greater increases in CO associated with greater plasma epinephrine and norepinephrine levels, and (2) greater vascular resistance increases to a passive coping task, which is related to evidence of vascular hypertrophy. These observations are consistent with the view that early dysregulation of BP in borderline hypertensive white men is associated with SNS hyperreactivity reflected by greater circulating levels of catecholamines owing to enhanced adrenal release and/or increased spillover from adrenergic nerve terminals.38 The compensatory blunting of ß-adrenergic receptor responsiveness fails to normalize the excessive pressor response associated with challenges that elicit attempts at active control. Frequent episodes of BP hyperreactivity may partially account for the early development of vascular hypertrophy, which we found to be evident in borderline hypertension. In the broad biopsychosocial context, SNS hyperreactivity in borderline hypertension may provide the pathway by which job demands and psychosocial factors affect the development of hypertensive disease.
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Acknowledgments |
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This work was supported by grants HL-38950, HL-49427, HL-31533, and RR00046 from the National Institutes of Health.
Received August 29, 1994; first decision October 17, 1994; accepted November 28, 1994.
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References |
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