Alterations in Blood Pressure and Heart Rate Variability in
Transgenic Rats With Low Brain Angiotensinogen
Ovidiu Baltatu, Ben J. Janssen, Giampiero Bricca, Ralph Plehm, Jan Monti,
Detlev Ganten, Michael Bader
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Abstract—To study whether the brain renin-angiotensin system plays a role in the long-term and short-term control of blood
pressure and heart rate variability, we examined in transgenic rats [TGR(ASrAOGEN)] with low brain angiotensinogen levels
the 24-hour variation of blood pressure and heart rate. Telemetry recordings were made during basal and hypertensive
conditions induced by a low-dose subcutaneous infusion of angiotensin II for 7 days. Short-term blood pressure and heart rate
variability were evaluated by spectral analysis, and as a measure of baroreflex sensitivity, the average transfer gain between
the pressure and heart rate variations was calculated. During the angiotensin II infusion in control but not TGR(ASrAOGEN)
rats, the 24-hour rhythm of blood pressure was inverted (5.8⫾2 versus ⫺0.4⫾1.8 mm Hg/group of day-night differences of
blood pressure, P⬍0.05, respectively). In both the control and TGR(ASrAOGEN) rats, the 24-hour heart rate rhythms
remained unaltered and paralleled those of locomotor activity. The transfer gain between 0.3 to 0.6 Hz was significantly higher
in TGR(ASrAOGEN) than in control rats during control (0.71⫾0.1 versus 0.35⫾0.06, P⬍0.05) but not during angiotensin
II infusion (0.6⫾0.07 versus 0.4⫾0.1, P⬎0.05). These results demonstrate that the brain renin-angiotensin system plays an
important role in mediating the effects of angiotensin II on the circadian variation of blood pressure. Furthermore, these data
indicate that a permanent deficiency in the brain renin-angiotensin system alters the reflex control of heart rate in rats.
(Hypertension. 2001;37[part 2]:408-413.)
Key Words: renin-angiotensin system 䡲 blood pressure 䡲 baroreflex 䡲 circadian rhythm 䡲 brain
M
oped approaches based on genetically modified animal models offer the opportunity to advance our understanding of the
role that single genes play in the regulation of cardiovascular
rhythms.12–15 The role of the renin-angiotensin system (RAS)
in blood pressure variability (BPV) has been indicated by
studies on transgenic hypertensive TGR(mREN2)27 rats with
an overactive RAS. TGR(mREN2)27 rats manifest an inverted circadian rhythm of BP16 similar to secondary forms of
hypertension in humans (“nondippers”).
Using a transgenic rat model with reduced brain angiotensinogen [TGR(ASrAOGEN)],17 we have recently shown that
the brain RAS modulates the slow pressor response to low
doses of angiotensin (Ang) II.18 These transgenic rats exhibit
up to 90% reduced angiotensinogen levels throughout the
brain, reduced drinking response to intracerebroventricular
renin, hypotension, and low plasma vasopressin levels.17 In
the current study, we evaluated in the same model to which
extent the long-term and short-term BPV is affected by the
brain RAS. Because the pressor response to Ang II may be in
part related to an increased sympathetic tone, which is critical
for the regulation of BPV and HRV,19,20 experiments were
conducted in normotensive as well as hypertensive conditions
induced by an infusion of low-dose Ang II.
ultiple clinical studies have implicated blood pressure
(BP) and heart rate (HR) variability in the diagnosis
and prognosis of arterial hypertension and cardiovascular
diseases.1,2 It has been shown, for instance, that patients with
essential or secondary forms of hypertension can be divided
into 2 groups: “dippers” and “nondippers.”3 In “dippers,”
circadian rhythm of BP is preserved, whereas “nondippers”
lack the characteristic nocturnal fall in BP. Cross-sectional
studies have indicated that target-organ damage is more
pronounced in “nondippers” than in “dipper” patients with
comparable clinical blood pressure.4,5 Furthermore, a circadian pattern becomes obvious in the occurrence of acute
cardiovascular diseases such as ischemia, infarction, stroke,
and sudden death,6 and investigators are using new chronotherapeutic approaches in antihypertensive therapy to exploit
the knowledge of circadian rhythms to reduce these events.7
Furthermore, it has been demonstrated that short-term (beatto-beat) variations of BP and HR contain information about
the activity of the autonomic nervous system,8 and power
spectral analysis of these parameters shows promise for
studying the mechanisms involved in cardiovascular
disease.9,10
There is evidence that in humans, the HR and HR variability (HRV) can be genetically determined.11 Recently devel-
Received October 25, 2000; first decision November 30, 2000; revision accepted December 18, 2000.
From Max-Delbrück-Center for Molecular Medicine (MDC), Berlin-Buch, Germany (O.B., R.P., J.M., D.G., M.B.); Cardiovascular Research Institute
Maastricht, University of Maastricht (The Netherlands) (B.J.J.); and INSERM U331, Lyon, France (G.B.).
Correspondence to Ovidiu Baltatu, MD, PhD, Max-Delbrück-Center for Molecular Medicine (MDC), Robert-Rössle-Str 10, Berlin-Buch, D-13092
Germany. E-mail [email protected]
© 2001 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
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Baltatu et al
Cardiovascular Variability and Baroreflex
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Figure 1. Telemetry tracing of systolic BP and
HR in SD and TGR(ASrAOGEN) during basal
conditions and Ang II infusion (averaged values
per group of study). Filled bars on x axis represent dark period (6 PM to 6 AM); open bars
represent light period (6 AM to 6 PM).
Methods
Rat Strains
Adult (aged 5 months) male transgenic rats [TGR(ASrAOGEN)]
(n⫽12) and age-matched Hanover Sprague-Dawley rats (SD, parent
strain used as normal controls) (n⫽11) were obtained from the
animal facilities of the Max Delbrück Center for Molecular Medicine, Berlin, Germany. The rats were housed individually, synchronized to a 12-hour light-dark cycle (light: 6 AM to 6 PM, 200 lux;
dark: 6 PM to 6 AM, ⬍0.1 lux), at ambient temperature 23⫾2°C. A
standard rat diet (ssniff R-ZUCHT) and tap water were supplied ad
libitum. Before starting the experimental protocols, rats underwent
an acclimatization period for at least 10 days.
implanted into the abdominal aorta just below the bifurcation of the
renal arteries, and the sensor itself was fixed to the peritoneum. After
implantation, the rats were allowed to recover from the operation for 13
to 15 days, when the telemetry tracing indicated reestablishment of the
24-hour oscillations of BP and HR. To induce hypertension, Ang II was
infused subcutaneously by osmotic minipump Alzet (model 2001, Alza
Corp) at a rate of 100 nanograms per kilogram per minute for 7 days, as
previously described.18
Experimental Protocols
All experimental protocols were performed in accordance with the
guidelines for the human use of laboratory animals by the Max
Delbrück Center for Molecular Medicine and approved by local
authorities.
The rats underwent chronic implantation of a device that telemetrically monitors BP, HR, and motor activity (Data Sciences). The
telemetry system consists of a radiofrequency transmitter (TA11PAC40), a receiver panel, and an acquisition system (IBM compatible). For
the implantation of the transmitter, rats were anesthetized with 10
mg/100 g body wt ketamine (Ketavet; Parke-Davis) plus 0.02 mg/100 g
body wt xylazine (Rompun; Bayer). The catheter of the transducer was
Figure 2. Acrophases of systolic BP, HR, and locomotor activity
in SD (n⫽ 5) and TGR(ASrAOGEN) (n⫽ 6) in basal conditions
and after 7 days of Ang II infusion. asTGR indicates
TGR(ASrAOGEN) rats. Values are mean⫾SEM. *Significantly different (P⬍0.05) compared with values in basal conditions.
410
Hypertension
February 2001 Part II
The experimental protocols were performed in conscious and unrestrained rats. To study the 24-hour cardiovascular variability, the system
was set to monitor arterial pressure, HR, and locomotor activity at
5-minute intervals. Three-day periods were extracted in basal conditions
and at the end of Ang II infusion. To study the short-term cardiovascular
variability and spontaneous baroreflex function, beat-to-beat values of
BP and HR were extracted from the waveform recordings obtained
between 2 and 4 PM, when locomotor activity is lowest in the rat. Data
were extracted during basal conditions and in the seventh day of Ang II
infusion. Dataquest LabPRO software was used to store and process the
data.
Variability Analysis
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The circadian variability was analyzed as described previously.12 Data
processed by Dataquest LabPRO software were extracted as systolic
arterial pressure, HR, and locomotor activity. Three-day interval data
were further analyzed by fast Fourier curve fitting, by transferring it into
the analysis software developed by Witte et al.21 The following function
was used: f(t)⫽mesor⫹([amplitudei⫻cos(t⫺acrophasei)2(/period
length)i, with the period length fixed at 24 hours.
Short-term cardiovascular variability was analyzed as previously
described.22 For this analysis, the interbeat interval identified by the
pulse interval (PI) rather than HR was used. The 2-hour beat-to-beat
tracings were divided into segments of 200 seconds each. Because an
equidistant sample rate is required for spectral analysis, relative stationary segments were resampled at 20 Hz by cubic interpolation. After the
resulting time series was linearly detrended and a Hanning window was
applied, spectral power of BP and PI were calculated by fast Fourier
transform algorithm. For each animal, spectral power was then averaged
over sequential data segments in 3 different frequency ranges: (1) a
high-frequency band (HF, 0.6 to 3 Hz), (2) a mid-frequency band (MF,
0.3 to 0.6 Hz), and (3) a low-frequency band (LF, 0.07 to 0.3 Hz). These
bands contain rhythmic oscillations related to (1) the respiratory cycle,
(2) the autonomic nervous system, and (3) peripheral vascular control
mechanisms, respectively.23 As an index of baroreflex sensitivity, the
transfer (TF) gain between BP and PI variations in these frequency
bands was calculated, together with the coherence and phase relation
between the two signals. In rats, the TF gain of the mid-frequency band
is generally taken as the most reliable index of baroreceptor activity
because the linear coupling between BP and PI oscillations is generally
highest in this region, and these oscillations probably result from
resonance phenomena in the baroreceptor reflex.24 Furthermore, by
direct nerve recordings, sympathetic oscillations at this frequency have
been found.25 However, baroreceptor modulation of HR occurs also at
frequencies ⬍0.3 Hz as was found in sinoaortic denervation studies.26
Statistical Analysis
The comparisons for multigroup and multifactorial analyses were
done with a 2-way ANOVA and by Kruskal-Wallis 1-way ANOVA
on ranks for multiple group comparisons. Changes versus control
values (before Ang II infusion) were studied also by statistical
analysis with Student’s paired t test. The criterion for significant
differences between groups of study was P⬍0.05. Data are presented
as mean⫾SEM.
Results
Circadian Variability of BP, HR, and Locomotor
Activity
Figure 1 shows a telemetry tracing for SD and TGR(ASrAOGEN) rats (average values per group of study) and demonstrates the 24-hour rhythms of BP and HR during control
conditions and during the Ang II infusion. The acrophases
and mean day-night differences of the BP and HR diurnal
variations in the TGR(ASrAOGEN) rats in basal conditions
were not significantly different from those of SD rats (Figures
2 and 3). In SD rats, the circadian rhythm of BP was
significantly deviated by the subcutaneous Ang II infusion,
Figure 3. Mean day-night (D-N) differences of systolic BP in SD
(n⫽ 5) and TGR(ASrAOGEN) (n⫽ 6) in basal conditions and after
7 days of Ang II infusion. Values are mean⫾SEM. asTGR indicates TGR(ASrAOGEN) rats. *Significantly different (P⬍0.05)
compared with values in basal condition.
with the acrophase occurring during the daylight period
(Figure 2) and hence inverted mean day-night differences
(Figure 3). Opposite to the SD, the circadian variation of BP
of the TGR(ASrAOGEN) rats was not significantly affected
by the subcutaneous Ang II infusion (Figures 2 and 3).
In contrast to the BP, in both the SD and TGR(ASrAOGEN)
rats, the 24-hour HR rhythms remained unaltered and paralleled
those of locomotor activity during the subcutaneous Ang II
infusion, with acrophases occurring during the night period
(Figures 1 and 2). The mean day-night differences of HR and
locomotor activity remained negative, and the acrophases occurred in the night period (Figures 1 and 2).
Short-Term Variability of BP and PI
The Table shows the averaged values of systolic BP and HR
from data extracted both for circadian (3-day segment) and
short-term (2-hour segment during the lowest locomotor
activity period of the rat) periods. The analysis of the 3-day
period of systolic BP is in agreement with the previously
published observations,18 showing an attenuation in the development of hypertension in the TGR(ASrAOGEN) rats.
The analysis of the 2-hour segment of systolic BP shows a
lower (but not statistically significant) systolic BP in
TGR(ASrAOGEN) than in SD rats. The HR was not different
Averaged Values of Systolic BP and HR
3-d Average
Treatment
Group
Systolic BP
2-h Average
HR
Systolic BP
HR
SD
Basal
⫹Ang II
128⫾1.4
324.4⫾5.6
120.4⫾1.8
320.9⫾5.9
168.2⫾0.9†
310.1⫾6.1
156.3⫾8.8†
311.7⫾13.6
TGR(ASrAOGEN)
Basal
122.0⫾1.6
325.7⫾8.0
115.3⫾0.8
297.1⫾4.3
⫹Ang II
152.0⫾3.5*†
325.9⫾8.5
142.5⫾10.5†
294.9⫾8.2
*Significantly different (P⬍0.05) in comparison to values in SD rats;
†Significantly different (P⬍0.05) in comparison to values in basal conditions.
Baltatu et al
Cardiovascular Variability and Baroreflex
411
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Figure 4. Comparison of average spectral powers of systolic BP and PI between SD (n⫽ 6) and TGR(ASrAOGEN) (n⫽ 6) rats during
basal conditions and Ang II infusion. Average frequency-dependent changes in coherence are given in lower plots. Values are means
per group of study. LF (0.07 to 0.3 Hz), MF (0.3 to 0.6 Hz), and HF (0.6 to 3 Hz) band values are shown. *Significantly different (P⬍0.05)
between TGR(ASrAOGEN) and SD rats. asTGR indicates TGR(ASrAOGEN) rats.
between SD and TGR(ASrAOGEN) and was not affected by
Ang II treatment. The short-term variation of BP and PI
analysis and results are summarized in Figure 4. During
baseline conditions as well as during Ang II infusion, power
spectra of BP were not different between SD and
TGR(ASrAOGEN). In contrast, PI power spectra were different between TGR(ASrAOGEN) and SD rats. Mid- and
low-frequency power of PI was significantly higher in
TGR(ASrAOGEN) than in SD rats in both baseline
(3.05⫾0.69 ms2 versus 1.03⫾0.25 ms2) and hypertensive
conditions (2.36⫾0.44 ms2 versus 1.1⫾0.24 ms2). In control
conditions, the coupling between the oscillations of BP and
PI, as indicated by the average coherence, was highest in the
mid-frequency band (0.4 Hz) both in SD and TGR(ASrAOGEN) (Figure 4). During the Ang II infusion, the average
coherence between BP and PI in this band was still significant
but less pronounced. In control conditions, the average TF
gain between BP and PI was significantly higher in
TGR(ASrAOGEN) than in SD rats (Figure 5) in MF bands.
During Ang II infusion, such differences in TF gain remained
statistically significant in the very low-frequency band (0.02
to 0.07 Hz) and LF band but not in the MF band.
412
Hypertension
February 2001 Part II
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Figure 5. TF gain (ms/mm Hg) at different frequency ranges
(index of baroreceptor activity). Values are mean⫾SEM; 0.02 to
0.07 Hz is very-low-frequency band; 0.07 to 0.3 Hz, lowfrequency band; 0.3 to 0.6 Hz, mid-frequency band; and 0.6 to
3 Hz, high-frequency band. *Significantly different (P⬍0.05)
between TGR(ASrAOGEN) (n⫽ 6) and SD (n⫽ 6).
Discussion
The main new findings of this study are (1) Ang II inverts
day-night rhythm of BP but not of HR or locomotion in SD rats.
(2) The fact that this is not observed in TGR(ASrAOGEN) rats
points to a central role of the brain RAS in this process. (3)
Short-term HRV but not BPV is elevated in TGR(ASrAOGEN)
rats and hence the TF gain between these two, as an index of
baroreflex sensitivity, is also higher. This indicates that a
permanent deficiency in brain RAS can alter the reflex control of
HR. Peripheral Ang II infusion did not generally alter this
pattern. (4) Neither long-term nor short-term BPV is altered
under basal conditions in TGR(ASrAOGEN).
The SD rats infused with a slow pressor dose of Ang II (this
study) and the transgenic hypertensive rats TGR(mREN2)27
with overactive RAS16 develop an inverted 24-hour rhythm of
BP and are therefore reliable study models for human secondary
hypertension, in which the same phenomenon is observed.27 We
previously observed that a normal activity of the brain RAS is
necessary for the development of hypertension induced by
subcutaneous infusion of a slow pressor dose of Ang II.18 In the
actual study, the fact that this treatment inverts day-night rhythm
of BP in SD but not TGR(ASrAOGEN) rats indicates that brain
RAS is also a crucial factor that determines 24-hour BP rhythm.
Also noticeably, the Ang II–induced shift on BP circadian
rhythm in SD rats was not associated with alterations in 24-hour
rhythmicity of HR, contributing to the concept that the circadian
variability in BP and HR are differentially regulated.12,20 We and
others have previously shown that the central nervous system is
importantly involved in the circadian cardiovascular rhythmicity
because the ablation of the suprachiasmatic nucleus (SCN)
abolished the cardiovascular circadian rhythmicity.28,29 It is well
known that the SCN contains a high concentration of Ang II
receptors30 that may influence its neuronal activity.31 In the
present study, the alterations in BP rhythm were not associated
with disturbances in HR and locomotor 24-hour variability. This
might indicate that the effect of Ang II does not occur in the
SCN, because lesions of the SCN also alter HR and locomotor
activity.28 Although it has been shown that Ang II can induce
differential effects in different neuronal populations within the
SCN, there is no evidence for specific sites in this nucleus to
regulate BP and HR. Where in the brain Ang II causes its effects
is not known.
HRV but not BPV is enhanced in TGR(ASrAOGEN). Hence,
it is not surprising that the TF gain is also enhanced. Ang II does
not considerably affect these parameters in TGR(ASrAOGEN)
or SD rats. The reasons for that are not clear. If Ang II would
increase sympathetic tone, then probably steady-state HR would
have been higher and the 0.4-Hz BPV would have been
enhanced because the 0.4-Hz BP rhythm in rats is directly
coupled to sympathetic tone.25 The 0.4-Hz rhythm in HR is
coupled both to sympathetic tone and vagal tone and sensitive to
both atropine and ␤-blockers.32 Thus, this suggests that in
TGR(ASrAOGEN), the vagal tone is higher because the HR
during the time period tested was lower.
Pharmacological approaches have indicated a role of the brain
RAS in fast adaptive changes of BP. For instance, the components of the RAS are present in cardiovascular-regulatory brain
areas,33 and pharmacological manipulations of the system in
these regions affect BP and the sensitivity of the baroreceptor
reflex.34 Importantly, as indicated by the TF gain, the
TGR(ASrAOGEN) rats have an exaggerated spontaneous
baroreflex sensitivity in comparison to the SD rats, indicating
that a lifetime deficiency in brain angiotensinogen production
can affect baroreflex. These results confirm the inhibitory role of
the brain RAS in the modulation of the baroreflex,34 –37 and it can
be concluded that a properly operating RAS inside the bloodbrain barrier is necessary to maintain the baroreflex function.
Moreover, the difference in TF gain between the two strains is
maintained during the induction of hypertension, indicating that
peripheral administration of Ang II does not reverse the alterations observed in the TGR(ASrAOGEN) rats during basal
conditions. The fact that the induction of hypertension in both rat
strains did not significantly alter TF gain correlates with previous observations regarding the ability of the brain angiotensin
peptides to change the sensitivity of the baroreceptor reflex in a
pressure-independent manner.34,38
It has been proposed that cardiac hypertrophy can be one of
the causes of reduced baroreflex sensitivity in hypertension.39
Interestingly, however, despite the cardiac hypertrophy induced
by the slow pressor dose of Ang II,18 the baroreflex sensitivity
was only slightly attenuated without reaching statistical significance, as it has been observed in a similar study in rabbits.40
Summary
The results obtained from this study indicate that normal
activity of the brain RAS importantly contributes to the
short-term cardiovascular variability and spontaneous baroreflex activity and to the modulation of the circadian rhythm of
BP. These results have potentially interesting implications for
developing diagnosis and treatment strategies. For instance,
the penetrability through the blood-brain barrier of a drug
affecting the RAS may be an important parameter to consider
in therapeutic regimens.
Baltatu et al
Acknowledgments
This study was supported in part by Deutsche Forschungsgemeinschaft (grant no BA1374/5–1). We thank Marion Somnitz for
excellent technical assistance.
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Alterations in Blood Pressure and Heart Rate Variability in Transgenic Rats With Low
Brain Angiotensinogen
Ovidiu Baltatu, Ben J. Janssen, Giampiero Bricca, Ralph Plehm, Jan Monti, Detlev Ganten and
Michael Bader
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Hypertension. 2001;37:408-413
doi: 10.1161/01.HYP.37.2.408
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