Download Baroreflex sensitivity changes with calcium antagonist

Journal of Human Hypertension (1999) 13, 87–95
 1999 Stockton Press. All rights reserved 0950-9240/99 $12.00
http://www.stockton-press.co.uk/jhh
REVIEW
Baroreflex sensitivity changes with
calcium antagonist therapy in elderly
subjects with isolated systolic
hypertension
MA James1, H Rakicka1, RB Panerai2 and JF Potter1
University Departments of 1Medicine for the Elderly, Glenfield General Hospital and 2Medical Physics,
Leicester Royal Infirmary, Leicester, UK
In order to study the effects of calcium-blocking therapy
on cardiovascular homeostasis in elderly subjects with
isolated systolic hypertension, we performed a randomised double-blind placebo-controlled crossover study of
6 weeks therapy with modified-release nifedipine or placebo. Changes with calcium-blocker treatment in clinic
and 24-h blood pressure (BP), heart rate, BP variability,
baroreflex sensitivity (BRS) by three methods (Valsalva
manoeuvre, phenylephrine and sodium nitroprusside
injection), and in baroreflex- and non-baroreflexmediated reflexes (tilt and cold face stimulus) were
studied in 14 elderly subjects (mean age [± SEM] 70 ± 1
years) with sustained isolated systolic hypertension
(clinic BP 179 ± 3/85 ± 1 mm Hg). Clinic systolic BP, but
not diastolic BP, was reduced with treatment (by 14 ± 6
mm Hg, P = 0.03, diastolic BP 4 ± 3 mm Hg, P = 0.16).
Twenty-four hour BP was also reduced by nifedipine
treatment (by 18 ± 3/9 ± 2 mm Hg, both P ⬍ 0.001). Clinic
and 24-h heart rate, and daytime BP variability, were
unchanged with treatment. BRS was significantly
increased during nifedipine therapy by all three
measurement methods (all P ⬍ 0.05). With 60ⴗ tilt during
active treatment, subjects exhibited a greater heart rate
increase (P ⬍ 0.01), and a reduced fall in systolic
(P ⬍ 0.05) and diastolic BP (P ⬍ 0.05). Thus despite the
arteriosclerosis and reductions in large artery compliance described in elderly patients with isolated systolic hypertension, clinically important improvements in
clinic and ambulatory BP and some aspects of cardiovascular homeostasis can be achieved with calciumchannel blocking therapy.
Keywords: elderly; baroreflex; nifedipine; phenylephrine; nitroprusside; Valsalva’s manoeuvre
Introduction
Dihydropyridine calcium antagonists have become
widely used in clinical hypertension practice and
are proven effective antihypertensive agents in the
elderly.1 Nonetheless, it is only recently that evidence has emerged from large-scale clinical trials
regarding their long term efficacy in preventing
adverse cerebrovascular and coronary outcomes.2,3
Furthermore, controversy has recently arisen concerning the safety of short-acting dihydropyridine
calcium antagonists in the treatment of hypertension
and their possible adverse effects on cardiovascular physiology.4,5
The arterial baroreflex is the most important
physiological mechanism for the short-term regulation of blood pressure (BP). An improvement in
the sensitivity of the baroreflex with the treatment
of hypertension has been regarded as a useful secondary goal of therapy, conferring theoretical benefits in terms of improved short-term BP homeostasis
Correspondence: Dr MA James, Royal Devon & Exeter Hospital,
Barrack Road, Exeter EX2 5DW, UK
Received 10 July 1998; revised 5 October 1998; accepted 21 November 1998
and reduced BP variability,6 itself independently
related to target-organ damage.7,8 Several studies
have addressed the issue of the modification of
arterial baroreceptor-cardiac reflex sensitivity (BRS)
with antihypertensive treatment in young and
elderly subjects, predominantly with either angiotensin-converting enzyme inhibitors9–12 or with calcium channel blocking drugs.12–17 The basis for the
observed increases in BRS with treatment, although
not seen in every study,17 is thought to be an
increase in large artery compliance permitting resetting of baroreflexes. On this basis it could be proposed that elderly subjects with isolated systolic
hypertension (ISH), who represent over half of all
elderly hypertensives18 and who have demonstrable
reductions in large artery compliance when compared
to their peers with combined hypertension19–21
(usually attributed to more advanced arteriosclerosis), may not respond with the same alterations in BRS with treatment as have been described
in younger subjects.13,14 This may lead to impaired
cardiovascular homeostasis and practical therapeutic problems such as orthostatic intolerance.22
Conversely, an increase in BRS may lead to
improved cardiovascular reflex responses and
reduced BP variability. The purpose of this study
Baroreflexes and nifedipine in the elderly
MA James et al
88
therefore, was to examine if and to what extent BRS
could be modified by long-acting calcium-channel
blocking therapy in elderly subjects with sustained
ISH.
Materials and methods
Fourteen untreated elderly (aged ⭓60 years) subjects
with sustained clinic ISH (systolic BP ⭓160 mm Hg
with diastolic BP ⬍90 mm Hg) were studied. Subjects were recruited from among out-patients
attending for assessment of their hypertension at
two large teaching hospitals and through a liaison
with several large local general practices. All subjects were active and living independently in the
community, with a normal physical examination, on
no treatment with cardiovascular or autonomic
effects, and all were in sinus rhythm with a normal
electrocardiogram. No subject had clinical evidence
of secondary hypertension, ischaemic heart disease,
cerebrovascular disease or renal disease, and none
had previously received antihypertensive treatment.
Clinic BP was measured using a standard mercury
sphygmomanometer and a cuff of appropriate size,
after 5 min of supine rest on three separate occasions
at least 2 weeks apart before entry to the study. Subjects’ height, weight and body mass index (BMI;
weight divided by square of height, kg/m2) were
recorded. All subjects gave written informed consent to participate in the study which was approved
by the local ethics committee.
Study design
Following entry to the study, subjects underwent
24 h ambulatory BP monitoring (ABPM) before
returning the following day for the laboratory protocol for assessment of cardiovascular reflexes
(described below). Subjects were then randomised
to receive either nifedipine GITS (‘gastrointestinal
system’; Adalat LA) 30 mg once daily or matching
placebo for the first 6-week period of a double-blind
randomised crossover study design.23 Subjects were
reviewed after 3 weeks of active or placebo treatment at which visit specific enquiry was made
regarding side effects. If target supine systolic BP
had not been achieved (systolic BP ⬍160 mm Hg),
therapy was doubled to nifedipine GITS 60 mg daily
or two matching placebo tablets. Clinic BP (both
supine and after 1 min of standing) were recorded
again after 6 weeks, at which stage subjects
underwent 24-h ABPM and assessment of cardiovascular reflexes using an identical laboratory protocol. Subjects then crossed over to the alternative
treatment for the second 6-week period, with review
of BP and side effects at the halfway stage in a similar manner. At the end of the second period the
study was completed with a repeat 24-h ABPM and
a further visit to the study laboratory for measurement of cardiovascular reflexes and arterial BRS.
24-hour ABPM
Ambulatory BP monitoring was performed using the
SpaceLabs 90207 system (SpaceLabs Inc, Redmond,
WA, USA). The monitor was programmed to take
readings at 15-min intervals between 07.00 and
22.00, and at 30-min intervals between 22.00 and
07.00. This frequency of recording enabled an estimate to be made of daytime BP and heart rate variability in individual subjects.24 When subjects
attended the research clinic to have the monitor fitted, using the large cuff if necessary, the accuracy
of the monitor in each individual subject was verified by sequential same-arm comparison with a standard mercury sphygmomanometer.25 Monitor readings were acceptable if within 5 mm Hg of readings
obtained by the standard method. Subjects were not
given specific advice regarding physical activity
apart from that necessary to preserve the accuracy
of monitor readings. The monitor was removed 24 h
later when subjects attended the cardiovascular laboratory. Data were downloaded to an IBM compatible computer without manual data editing, and
only records with over 90% of possible readings
were regarded as acceptable.
Laboratory cardiovascular studies
An identical protocol for estimation of cardiovascular reflexes and BRS was conducted at entry to the
study (‘baseline’) and at the end of each 6-week
active or placebo treatment period. Subjects
attended the research laboratory for a morning session, having emptied the bladder and following a
light breakfast, and having refrained from smoking,
alcohol and caffeine for at least 12 h. The laboratory
temperature was thermostatically controlled at 20°C.
Subjects rested supine after the insertion of a cannula into a dorsal vein in the right hand, and were
fitted with chest leads for recording of the continuous surface electrocardiogram (model CR7, Cardiac
Recorders Ltd, London, UK). The appropriate-sized
finger cuff of the Finapres 2300 non-invasive beatto-beat BP recording device (Ohmeda Monitoring
Systems, Englewood, CL, USA) was fitted to the
middle finger of the left hand, which rested throughout on an adjustable support at the level of the heart.
The subject’s right forearm was placed in a thermostatically controlled warmer at 55°C, and after
30 min rest a 10 mL arterialised venous blood sample was drawn without occlusion, centrifuged and
the plasma frozen at −70°C for later catecholamine
analysis.26
Recordings were then made of the variation in RR interval with deep breathing at six breaths/minute
for 1 min, and of the cardiovascular responses to the
Valsalva manoeuvre. After several practices, subjects blew into a modified sphygmomanometer to
maintain a pressure of 40 mm Hg for 15 sec whilst
seated. The manometer contained a small air leak so
that subjects had to maintain a constant respiratory
effort. The manoeuvre was repeated three times with
5 min rest between each.
Measurement of sino-aortic arterial BRS was then
performed from the BP and pulse interval responses
to phenylephrine injection.27,28 An initial bolus dose
of 50 ␮g phenylephrine was progressively increased
in 50 ␮g steps as necessary (up to a maximum of
200 ␮g) to achieve a peak systolic BP rise of 20– 40
Baroreflexes and nifedipine in the elderly
MA James et al
mm Hg, and the effective dose was repeated to
obtain a minimum of three adequate responses.
Bolus injections of 0.9% saline were interspersed at
random between the drug injections and the subject
was blinded to the nature of each injection. BRS was
similarly assessed from the BP and pulse interval
responses to a graded sodium nitroprusside
infusion.29,30 The infusion was commenced at
0.25 ␮g/kg/min and increased (by 0.25 ␮g/kg/min
each minute) until a fall in systolic BP of 20– 40
mm Hg was observed.
The cardiovascular responses to head-up tilt were
then recorded. After familiarising subjects with the
tilting procedure, they were tilted to 60° while
lightly strapped to a hydraulic tilt table fitted with
foot support (Akron Medical Products, Ipswich, UK)
and then held in that position for 3 min. The move
from the supine to the tilted position took about
5 sec. During tilt BP and pulse interval were
recorded from the Finapres, and forearm blood flow
(FBF) in the right arm was measured with a mercury-in-silastic strain guage plethysmograph (QMC
Medical Physics, Nottingham, UK). The hand was
excluded from FBF estimations by the inflation of a
wrist cuff to 40 mm Hg above systolic pressure. FBF
was recorded for 1 min at baseline and then during
the 3 min of tilt. This manoeuvre was repeated a
further two times with at least 5 min in between and
the average of the three responses was taken.
After returning to the supine position and a
further period of supine rest, subjects underwent the
cold face stimulus, where the BP, heart rate and FBF
responses to the application of a refrigerated gel
pack (0– 4°C) to the subject’s forehead for 45 sec
were recorded.31 Subjects wore protective glasses to
avoid the stimulation of the oculo-cardiac reflex.
The average of two responses was taken. A suitable
interval (at least 5 min) was observed between all
the above tests to permit the recovery of stable baseline values for BP and heart rate. During all the
above manoeuvres the hand and forearm attached to
the Finapres was supported on an adjustable shelf to
maintain it at heart level and eliminate hydrostatic
artefacts, and the contralateral arm attached to the
FBF equipment was also raised on an adjustable
support to allow passive venous emptying and to
retain the angle to the horizontal during tilt. The
entire duration of the laboratory protocol was
approximately 3 h.
Data and chemical analyses
The analogue outputs from the Finapres and the
simultaneous ECG were routed to a dedicated personal computer fitted with an analogue-to-digital
converter sampling at 200 Hz per channel. A third
channel recorded pressure from a transducer and
amplifier connected to the sphygmomanometer used
for the Valsalva manoeuvre. Purpose-written
software allowed the recording, calibration and editing of the digitised signal and the derivation for later
off-line analysis of beat-to-beat data for systolic,
mean arterial and diastolic BP, together with the
pulse interval from the Finapres and ECG signals
and the Valsalva pressure. The data from the three
Valsalva manoeuvres were analysed to derive an
index for BRS from Phase 4 of the manoeuvre
according to the method of Smith et al.32 ValsalvaBRS thus described the BRS from the linear
regression of pulse interval on systolic BP for the
overshoot portion of Phase 4 (from the first beat
where systolic BP exceeded that prevailing before
the manoeuvre to the peak value observed several
seconds later).
BRS was derived from the phenylephrine ‘ramp’
technique by the method of Smyth et al,27 but
including both inspiratory and expiratory beats. A
value for phenylephrine-BRS for each individual
was obtained from the average of the (minimum
three) effective phenylephrine responses. Nitroprusside-BRS was derived from the sodium nitroprusside depressor response by the same ‘ramp’ method.
FBF was expressed as ml/min/100 mls of forearm
tissue, and the ratio of FBF to the mean arterial
pressure prevailing during that cycle (taken from the
simultaneous Finapres recording) was calculated
and expressed in arbitrary units representing forearm vascular resistance (FVR). Baseline values for
FBF prior to tilting and the cold face stimulus were
obtained from the mean of the four curves in the
minute immediately before the stimulus. FBF and
FVR values at 15, 30, 60, 90, 120 and 180 seconds
following tilt were considered. The mean of the
three values obtained in each subject for each of
those time points was taken as the final value. Similarly the two values were averaged for 15, 30, and
45 sec following application of the cold face stimulus.
Plasma adrenaline and noradrenaline samples
were stored at −70°C and duplicate samples were
analysed using high pressure liquid chromatography
with electrochemical detection. The coefficient of
variation of this technique has previously been
shown to be 8% for noradrenaline and 13% for adrenaline.26
Statistical analysis
Data are presented as mean ± SEM or as median
(interquartile range). After testing for period effects
and treatment-period interactions,33 analysis of
treatment effects was performed by comparison of
changes from baseline after the treatment and placebo phases of the study. Paired t-tests were used
after confirmation of normality using the ShapiroFrancia W-test, but for the BRS and catecholamine
data non-parametric tests were used (Wilcoxon rank
sum test). For the tilt and cold face stimulus data,
statistical analysis was performed using two-way
repeated measures analysis of variance, with group
(nifedipine or placebo) and time point as factors.
Summary statistics (systolic and diastolic BP and
heart rate change, and time to maximum change)
were also examined for the tilt and cold face stimulus tests. A probability of ⬍0.05 was regarded as
indicating statistical significance.
Results
Thirteen subjects successfully completed the study,
one subject having withdrawn within the first
89
Baroreflexes and nifedipine in the elderly
MA James et al
90
period because of side effects on placebo. Other side
effects during the active treatment period were
minor and consisted of slight ankle swelling in three
patients and mild headache on initiating therapy in
two subjects. None required dose adjustment or
stopping therapy. Seven women and six men of
mean age 70 ± 1 years (range 60–77 years), weight
75.9 ± 2.5 kg and BMI 27.2 ± 0.7 kg/m2 completed
the study. Group mean supine clinic systolic BP at
entry to the study was 179 ± 3 mm Hg, range 161–
197; diastolic BP was 86 ± 1 mm Hg, range 75–89.
After 6 weeks of nifedipine therapy, clinic supine
systolic BP was significantly lower by 14 ± 6 mm Hg
compared to the corresponding placebo period
(P = 0.028; Figure 1 and Table 1). Clinic supine diastolic BP was not significantly affected by nifedipine
treatment, being reduced by only 4 ± 3 mm Hg compared to placebo (P = 0.16). Similarly, clinic heart
rate was not affected by treatment (difference nifedipine vs placebo −2.5 ± 2.0 bpm, P = 0.26, Table 1).
Active treatment did not affect the changes in BP
or heart rate after 1 min of standing in the clinic. At
baseline, the change in BP on standing was
−6 ± 3/+9 ± 2 mm Hg. After 6 weeks’ nifedipine therapy, the clinic BP change at 1 min of standing was
−6 ± 3/+4 ± 2 mm Hg; similarly after 6 weeks of placebo the clinic BP change on standing was
−9 ± 4/+7 ± 2 mm Hg (P = 0.39 for systolic BP,
P = 0.20 for diastolic BP). The heart rate response to
active standing was similarly unaltered by active
treatment (Table 1).
Data were available for 24-h ABPM recordings at
Table 1 Clinic and ambulatory BP and heart rate at baseline and
after 6 weeks’ active (nifedipine) or placebo therapy
Figure 1 Clinic and 24-h blood pressure and heart rate at baseline
(entry to the study; BL) and after 6 weeks therapy with placebo
(P) or nifedipine (N). BPM: beats per minute.
Figure 2 24-h ambulatory blood pressure and heart rate at baseline (BL; solid lines) and after 6 weeks therapy with placebo
(dotted lines) or nifedipine (dashed lines).
Clinic
Supine
SBP
DBP
HR
Standing SBP
DBP
HR
Ambulatory*
24-h
SBP
DBP
HR
Daytime SBP var
DBP var
HR var
Baseline
Placebo
Nifedipine
P
179 ± 3
86 ± 1
66 ± 2
173 ± 3
94 ± 3
70 ± 3
172 ± 6
80 ± 3
66 ± 3
162 ± 6
87 ± 3
71 ± 3
157 ± 5
75 ± 3
64 ± 2
152 ± 6
80 ± 3
69 ± 2
0.028
0.16
0.26
0.12
0.047
0.19
151 ± 2
151 ± 3
133 ± 2
83 ± 3
84 ± 2
75 ± 2
72 ± 2
70 ± 2
70 ± 2
13.5 ± 0.5 13.1 ± 1.0 13.4 ± 0.9
10.7 ± 0.6 9.7 ± 0.9 9.4 ± 0.7
9.3 ± 1.2 9.0 ± 1.0 9.6 ± 0.9
0.0002
0.0009
0.88
0.71
0.63
0.50
*n = 11. Data are given as mean ± SEM. Daytime: 07.00 to 22.00.
Var: variability.
the end of both the nifedipine and placebo periods
in 11 subjects. Both 24-h systolic and diastolic BP
were significantly lower after nifedipine treatment
(by 18 ± 3/9 ± 2 mm Hg; Table 1 and Figure 1) with
24-h heart rate unaffected by therapy (Figure 2).
Daytime BP and heart rate variability were calculated from the standard deviation of all daytime
reading taken at 15-min intervals between 07.00 and
22.00 for each individual.24 The ‘longer-term’ variability of BP and heart rate was unchanged from baseline after both the nifedipine and placebo treatment
periods (Table 1).
Baroreflexes and nifedipine in the elderly
MA James et al
Figure 3 The systolic blood pressure and pulse interval
responses to bolus phenylephrine injections in a typical study
subject.
The systolic BP and pulse interval responses to
bolus phenylephrine injections in a typical study
subject are shown in Figure 3. The results of cardiovascular reflex and arterial BRS testing for the laboratory visits at baseline and at the end of the nifedipine and placebo periods in all 13 subjects are
shown in Table 2. Heart rate variability with regular
deep breathing was unaffected by nifedipine treatment. By the Valsalva method, 12 subjects demonstrated an increase in their BRS with 6 weeks’ active
treatment and one a decrease compared to placebo.
After nifedipine treatment, Valsalva-BRS was a
median 1.6 msec/mm Hg higher (95% confidence
interval (CI) 0.10–3.20) than after placebo. By the
phenylephrine pressor method, 11 subjects showed
an increase in BRS following the nifedipine phase,
and two a decrease compared to placebo. Phenylephrine-BRS was a median 1.8 msec/mm Hg higher
with treatment (95% CI 0.30–3.20) compared to after
the corresponding placebo period. With the sodium
nitroprusside depressor method, again 11 subjects
manifested an increase in nitroprusside-BRS with
active treatment, and two a decrease. NitroprussideBRS was higher by a median 2.3 msec/mm Hg after
nifedipine therapy (95% CI 0.23– 4.35) compared to
after placebo. Overall eight subjects demonstrated
an increase relative to placebo in all measures of
BRS with active treatment and although the absolute
treatment effects on BRS were small, these represented relative increases with nifedipine of 46%,
78% and 190% in Valsalva, phenylephrine and
sodium nitroprusside measures of BRS respectively.
Changes in BRS after 6 weeks placebo or nifedipine
therapy are indicated in Figure 4. There were no significant differences between the different methods
for the assessment of BRS (Valsalva, phenylephrine
or nitroprusside) at baseline or during either the
nifedipine or placebo periods.
Changes in plasma adrenaline and noradrenaline
levels, and baseline FBF and FVR were no different
between the nifedipine and placebo phases of the
study (Table 2). In examining the overall response
of FBF and FVR to tilt, there was no significant difference in the proportional fall in FBF between
nifedipine and placebo (Figure 5; effect of group:
F = 2.91, P = 0.09; effect of time: F = 0.55, P = 0.74).
Similarly, the overall increase in FVR with tilt was
not different between nifedipine and placebo
(Figure 5; effect of group: F = 1.26, P = 0.26; effect of
time: F = 0.37, P = 0.86). The maximum BP and heart
rate responses to tilt and the cold face stimulus at
baseline and after each of the study phases are given
in Table 3. The maximum heart rate increase with
Figure 4 Individual changes in baroreceptor sensitivity by the
three methods with placebo (P) and nifedipine (N) treatment.
*P ⬍ 0.05; **P ⬍ 0.01 for treatment effect. Horizontal bars represent group medians.
Table 2 Cardiovascular reflexes, forearm blood flow and plasma catecholamines at baseline and after 6 weeks’ active (nifedipine) or
placebo therapy
Heart rate variability (bpm)
BRS Valsalva
PE
SNP
Forearm blood flow (ml/min/100 ml)
Forearm vascular resistance (units)
Plasma noradrenaline (nmol/L)
Plasma adrenaline (pmol/L)
Baseline
Placebo
Nifedipine
P (treatment effect)
8.8 ± 1.0
4.3 (2.5–6.4)
3.5 (1.2–6.1)
1.8 (0.9– 4.6)
2.3 ± 0.2
51.4 ± 5.8
1.29 (1.02–2.69)
165 (92–307)
10.4 ± 1.4
3.5 (2.2– 4.7)
2.3 (1.4 –6.0)
1.2 (0.4 –4.3)
2.3 ± 0.3
54.2 ± 6.0
1.03 (0.49–1.43)
121 (82–150)
9.1 ± 0.8
4.6 (3.9–7.6)
3.7 (2.5–8.5)
3.5 (2.4 –5.8)
2.7 ± 0.4
42.7 ± 5.7
1.28 (0.44 –2.05)
123 (75–218)
0.48
0.019
0.006
0.03
0.34
0.17
0.55
0.39
Data are given as mean ± SEM or median (interquartile range). Bpm: beats per minute; BRS: baroreflex sensitivity; PE: phenylephrine;
SNP: sodium nitroprusside. All baroreflex sensitivities given in msec/mmHg.
91
Baroreflexes and nifedipine in the elderly
MA James et al
92
Figure 5 Changes in forearm blood flow and vascular resistance
with 60° passive tilt at baseline (entry to the study; solid line,
open circles) and after 6 weeks therapy with placebo (dotted line,
closed circles) or nifedipine (dashed line, open circles). FBF: forearm blood flow; FVR: forearm vascular resistance; some error bars
omitted for clarity.
tilt was significantly greater (P = 0.039), and the
maximum falls in systolic and diastolic BP were significantly less (P = 0.03 and P = 0.047 respectively),
following the nifedipine phase of the study,
although when the entire response was examined
the overall heart rate and systolic BP responses to
tilt were not different between nifedipine and placebo (for heart rate; effect of group: F = 3.27,
P = 0.07; effect of time: F = 0.73, P = 0.63. For systolic BP; effect of group: F = 0.02, P = 0.89; effect of
time: F = 0.84, P = 0.53, Figure 6).
In general there was a fall of approximately 20%
in FBF with a rise in FVR of about 25% following
Figure 6 Changes in heart rate and systolic blood pressure with
60° passive tilt at baseline (entry to the study; solid line, open
circles) and after 6 weeks therapy with placebo (dotted line,
closed circles) or nifedipine (dashed line, open circles). BPM:
beats per minute; some error bars omitted for clarity.
application of the cold face stimulus. However, the
changes in both FBF and FVR with the cold face
stimulus were not different between the nifedipine
and placebo phases of the study (For FBF; effect of
group: F = 3.19, P = 0.08; effect of time: F = 0.04,
P = 0.97. For FVR; effect of group: F = 1.49, P = 0.28;
effect of time: F = 0.04, P = 0.97). Similarly, although
systolic BP rose by on average 10–25 mm Hg with
the cold face stimulus, the changes in systolic and
diastolic BP and heart rate were not significantly different between the two phases of the study (Table 3).
Table 3 Maximum observed changes in blood pressure and heart rate in response to 60° passive tilt and the cold face stimulus at
baseline and after 6 weeks active (nifedipine) or placebo therapy
Baseline
Placebo
Nifedipine
Time 0
Maximum/
minimum
Change
Time 0
Maximum/
minimum
Change
Time 0
Maximum/
minimum
Change
Tilt
SBP
DBP
HR
169 ± 7
77 ± 3
61 ± 2
121 ± 8
59 ± 4
77 ± 3
48 ± 6
18 ± 2
16 ± 2
170 ± 8
79 ± 4
62 ± 3
124 ± 6
64 ± 3
76 ± 3
46 ± 6
16 ± 3
14 ± 2
154 ± 5
72 ± 3
61 ± 2
124 ± 4
62 ± 2
82 ± 3
30 ± 4*
10 ± 2*
21 ± 2**
Cold face
stimulus
SBP
DBP
HR
163 ± 8
77 ± 3
61 ± 3
182 ± 7
84 ± 4
63 ± 3
18 ± 4
7±2
2±1
166 ± 7
79 ± 3
62 ± 2
185 ± 11
89 ± 6
63 ± 2
19 ± 4
10 ± 3
1±1
156 ± 6
73 ± 3
63 ± 2
169 ± 7
79 ± 3
67 ± 3
14 ± 3
6±1
5±2
Data are given as mean ± SEM. SBP: systolic blood pressure; DBP: diastolic blood pressure (both in mm Hg); HR: heart rate (beats per
minute). *P ⬍ 0.05, **P ⬍ 0.01.
Baroreflexes and nifedipine in the elderly
MA James et al
No significant period effects or treatment-period
interactions were found in the analysis of clinic or
ambulatory BP, or arterial BRS.
Discussion
This study of the effect of 6 weeks of therapy with
a long-acting calcium-channel blocking agent in elderly subjects with isolated systolic hypertension has
demonstrated a significant reduction in both clinic
and ambulatory systolic BP with a smaller fall in 24h ambulatory diastolic BP and no change in heart
rate. The study has also shown a modest but statistically significant increase in baroreceptor-cardiac
reflex sensitivity when measured by three comparable methods,34 which appears to translate into an
improved reflex response to orthostatic stress with
a greater increase in maximum heart rate and a
consequent smaller fall in systolic and diastolic BP
with passive tilt. Notably, both the vagal efferent
function and the sympathetically-mediated cold
face stimulus were unaffected by nifedipine treatment. The reliability of the Finapres beat-to-beat BP
monitoring device in cardiovascular studies of this
kind has previously been established during pressor
and depressor drug injection, Valsalva manoeuvre
and vasomotor stimuli.35–37
Previous studies have provided us with varying
evidence of the effects of antihypertensive treatment
in general, and calcium-channel blocking therapy in
particular, on the function of the arterial baroreflex
in human hypertension.17 Few of these studies have
gone on to include an assessment of the implications
of changes in the baroreflex on the physiological
response to orthostatic stress. No published studies
have looked at the specific case of elderly subjects
with isolated systolic hypertension, despite the
prevalence of this condition and the different pathophysiology that characterises it.20,21,34,38,39 This
study is thus the first to indicate that some of the
adverse pathophysiology of ISH can be reversed by
treatment with calcium-blocker therapy with few
problems in terms of tolerability.
The mechanism by which these beneficial effects
are seen cannot be asserted with certainty from this
study. In particular, the study does not permit the
assertion that the observed effects are independent
of the BP reduction achieved with active treatment,
or specific to calcium-channel blocking drugs. However, the study protocol enables some scrutiny of the
various components of cardiovascular reflex homeostasis. The heart rate variation with controlled deep
breathing acts as a test of the vagal reflex loop,40 and
this was unchanged during the active leg of the
study, suggesting that the alterations seen in BRS
with nifedipine therapy were not mediated either
through a direct effect on the vagus or through any
effect on the sinus node producing alterations in
heart rate, which was unchanged with chronic dosing. This would also suggest that the increase in BRS
occurred through either an increase in the sensitivity of the baroreceptors themselves, or through an
effect on the central integration of baroreflex control.
The unchanged plasma catecholamine levels with
the chronic administration of nifedipine also miti-
gate against any prolonged state of sympathetic activation with active treatment with the sustainedrelease preparation used for this study, although
such plasma levels have their limitations as indicators of sympathetic activity.
A direct effect of nifedipine on the afferent baroreflex is suggested by the findings of other studies in
human and experimental hypertension. Lowering of
extracellular calcium has been observed to reduce
the threshold and increase the sensitivity of baroreceptors in a feline model,41 and nifedipine has been
shown to enhance baroreceptor sensitivity in the
isolated canine carotid sinus.42 A direct action in
relaxing the smooth muscle in the region of the baroreceptors themselves and reducing the ‘splinting’
effect may be responsible for any enhancement of
sensitivity, although traditionally the diminished
BRS observed in ISH has been attributed to arteriosclerosis and arterial rigidity not readily reversed by
short-term antihypertensive therapy, rather than any
modifiable functional alteration in the vessel wall.19
Recent work has shown a direct relation between
baroreceptor-sympathetic nerve activity and arterial
compliance in patients with congestive heart failure,43 but no similar data is available to confirm this
relation in systolic hypertension. We have made no
study of the independent effect of calcium-blocker
therapy on arterial compliance in the region of the
aortic arch and carotid sinus in the present study,
although other studies of older hypertensives have
not identified an independent effect of nifedipine on
large artery compliance.12 A recent study using the
dihydropyridine calcium antagonist lacidipine in
younger mild-to-moderate combined hypertensives
observed resetting of the arterial baroreflex independent of alterations in the elastic properties of the
arterial wall induced by acute dosing.44 Significantly, the present study would suggest that when
BP is lowered with chronic calcium-channel blocking therapy, at least in elderly patients with isolated
systolic hypertension, BRS resetting is not the principal outcome, but rather increases in baroreceptorcardiac and possibly also baroreceptor-mediated
vascular reflex responses. Were this to lead to
increased background sympathetic activation this
might be regarded as an unfavourable consequence
of the baroreflex alterations, but this is not supported by the unchanged FVR and plasma catecholamines with nifedipine treatment, although
these measures alone give only a limited assessment
of longer-term sympathetic changes.
The study has not examined other possible influences that may be partly responsible for the
observed alterations in BRS. We have not measured
left ventricular mass, which is known in animal
studies to modify cardiac baroreflexes.45 Although it
is unlikely that left ventricular mass would be altered to any great extent by 6 weeks of antihypertensive treatment, previous studies in younger subjects
with moderate combined hypertension have found
left ventricular mass to be significantly reduced after
only 16 weeks of nifedipine therapy, so some alteration cannot be entirely discounted.13 The tilt test
examines the integrated response of the cardiovascular system to orthostatic stress and does not
93
Baroreflexes and nifedipine in the elderly
MA James et al
94
discriminate between arterial high-pressure baroreflex responses and those evoked by the cardiopulmonary low-pressure receptors that are stimulated by pooling of blood in the lower limbs.
Although the two responses can be separated to an
extent by use of low and high-level lower body negative pressure,46 passive tilt has the advantage of
simulating the stresses to which the cardiovascular
system is subjected during normal activities and
when the drug is used in clinical practice. The
present study does not however offer proof that the
described changes on the arterial side of the baroreflex are exclusively responsible for the alterations
seen in the response to tilt with nifedipine treatment. Nonetheless studies in younger normotensive
and hypertensive subjects have not demonstrated a
significant effect of dihydropyridine calcium antagonists on cardiopulmonary baroreflex function.46,47
Active standing in the clinic did not demonstrate
any adverse effect of nifedipine therapy on the BP
and heart rate responses under those circumstances,
when some clinicians might caution against antihypertensive treatment because of the recognised
association between ISH and orthostatic hypotension in the elderly.48
We have not shown in the present study that the
observed increase in arterial BRS with short-term
chronic dosing with a long-acting nifedipine preparation leads to reductions in BP variability measured by 24-h ABPM. The estimation of BP and heart
rate variability with intermittent ambulatory
recorders does have its limitations24 and provides
only an incomplete assessment of overall short-and
long-term variability, with additional information
being available in recent studies using new techniques such as wide-band power spectral analysis49
which have not been used in the current study. BP
variability from ambulatory recorders has been independently related to adverse outcomes,7,8 and theoretically improvements in baroreflex homeostatic
mechanisms should translate into reduced BP variability and increased heart rate variability. However,
other workers have similarly not found that
increases in BRS with the treatment of hypertension
necessarily lead to reduced longer-term BP variability.50 Whether this mitigates some of the apparent
benefits of antihypertensive treatment in such cases
is not known.
The results of the present study would indicate
that far from simply reflecting a rigid and irreversibly damaged arterial tree, some of the adverse pathophysiology of ISH is potentially reversible with simple antihypertensive treatment that is well tolerated.
Furthermore, the present study has indicated that
the lowering of BP and increased BRS seen with sustained-release nifedipine treatment leads to
improved orthostatic tolerance. Thus the study we
report here has shown that despite the observed
reductions in large artery compliance and reported
arteriosclerosis in elderly patients with ISH, modest
but clinically significant improvements in some
aspects of cardiovascular reflex homeostasis can be
achieved with calcium antagonist therapy that may
relate to improved management and even outcomes
in this important group of elderly hypertensive
patients.
Acknowledgements
MAJ was supported by a project grant from the Sir
Jules Thorn Trust. The authors acknowledge the
support provided by Bayer UK for this study. The
authors are also grateful to Professor Ian MacDonald
for the catecholamine measurements made in the
study.
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