www.elsevier.com/locate/autneu
Autonomic Neuroscience: Basic and
Effects of long-term angiotensin converting enzyme inhibition on
cardiovascular variability in aging rats
Valdo Jose Dias da Silva a, Nicola Montano b, Helio Cesar Salgado c, Rubens Fazan Junior c,*
a Department of Biological Sciences, School of Medicine of Triangulo Mineiro, Uberaba, MG Brazilb Department of Clinical Sciences, Internal Medicine II, L. Sacco Hospital, University of Milan, Milano, Italy
c Department of Physiology, School of Medicine of Ribeirao Preto, Av. Bandeirantes 3900, 14049-900, Ribeirao Preto, SP, Brazil
Received 20 July 2005; received in revised form 28 November 2005; accepted 28 November 2005
Abstract
We studied the effects of chronic (4 weeks) angiotensin converting enzyme inhibition with captopril on arterial pressure (AP) and heart rate
(HR) variability, as well as on cardiac baroreflex sensitivity (BRS), in aged (20 months) rats. Series of basal RR interval (RRi) and systolic AP
(SAP) were studied by autoregressive spectral analysis with oscillations quantified in low (LF: 0.2–0.8 Hz) and high frequency (HF: 0.8–
2.5Hz). BRSwasmeasured by linear regression betweenHR andMAP changes. Captopril did not affect the spectra of RRi or SAP in young rats.
Aged rats presented a reduction in variance (time domain) and in LF and HF oscillations of RRi and SAP. Captopril induced, in aged rats, a
decrease in absolute and normalized LF oscillations and in LF/HF ratio of RRi. Captopril also reduced the variance, without changing its LF or
HF components of SAP. Reflex tachycardia was reduced in aged as compared to young rats (�1.1T0.2 versus �3.4T0.5 bpm/mm Hg) and
captopril did not affect it. Reflex bradycardia was also reduced in aged rats (�0.7T0.5 versus�2.0T0.4 bpm/mm Hg), but captopril prevented
this attenuation in aged rats (�2.3T0.3 versus�0.7T0.5 bpm/mm Hg). These data indicate that there is a reduction in HR and SAP variability
during aging, suggesting impairment of cardiovascular autonomic control. Captopril was able to change the power of oscillatory components of
RRi, suggesting a shift in cardiac sympatho/vagal balance toward parasympathetic predominance. In addition, blockage of ACE improved the
reflex bradycardia, but not the reflex tachycardia in aged rats.
D 2005 Elsevier B.V. All rights reserved.
Keywords: Aging; Heart rate variability; Baroreceptor; ACE inhibitor; Rats
1. Introduction
Aging is associated with an impairment of arterial
pressure regulation which is expressed by an increased
arterial pressure variability (Shi et al., 2003; Laitinen et al.,
2004) and tendency to postural and postprandial hypoten-
sion (Ferrari et al., 2003). In addition, it is well known that
aging is associated with a reduction of heart rate variability
(Ferrari et al., 2003) and depression of cardiac baroreflex
sensitivity (BRS) in both humans (Gribbin et al., 1971;
Jones et al., 2003) and animals (Ferrari et al., 1991; Irigoyen
et al., 2000).
1566-0702/$ - see front matter D 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.autneu.2005.11.004
* Corresponding author. Tel.: +55 16 36023331; fax: +55 16 36330017.
E-mail address: [email protected] (R. Fazan Junior).
The attenuation of baroreflex control of heart rate (HR)
during aging (Gribbin et al., 1971; Ferrari et al., 1991, 2003;
Sei et al., 2002; Jones et al., 2003; Nagai et al., 2003) could
be involved in higher arterial pressure variability (Laitinen
et al., 2004), orthostatic intolerance (Sei et al., 2002;
Laitinen et al., 2004), reduced vagal control of the heart
(Ferrari et al., 2003; Shi et al., 2003) and increased
sympathetic nerve activity to the heart and vessels (Ferrari
et al., 2003). All these alterations might be associated with
electrical and morphological changes of myocardium which
significantly increase the incidence of life-threatening
cardiac arrhythmias and sudden death in aged subjects
(Molander et al., 2003; Kistler et al., 2004; Souza Neto et
al., 2004). Accordingly, therapeutic strategies which im-
prove reduced heart rate variability and cardiac baroreflex
Clinical 124 (2006) 49 – 55
V.J. Dias da Silva et al. / Autonomic Neuroscience: Basic and Clinical 124 (2006) 49–5550
dysfunction related to aging should be useful to decrease
cardiovascular-related morbidity and mortality.
Experimental and clinical studies have demonstrated that
ACE inhibitors decrease efferent sympathetic nerve activity
(Montano et al., 1993), increase cardiac baroreflex sensi-
tivity in both animals (Ichikawa et al., 1995) and humans
(Williams and Kim, 2003) with hypertension or congestive
heart failure. These drugs act through inhibiting the
conversion of angiotensin I into angiotensin II, blocking
the endogenous renin–angiotensin system (Brunner et al.,
1996). In addition, other vasodilators can be generated by
ACE inhibitors, especially bradykinin (Linz et al., 1995;
Izzo, 2000).
Studies performed in animals, especially rats, evaluated
the effects of ACE inhibitors on aging. ACE inhibitors
produced, in old rats, a variety of benefits, such as:
reduction in renal intravascular resistance and proteinuria
(Heudes et al., 1994), reduction in the thickness of media
and intima layer of large arteries (Michel et al., 1994);
improvement of endothelial function of resistance vessels
(Lang et al., 1995), and improvement of the autoregulatory
mechanism of cerebral blood flow (Lartaud et al., 1994).
With respect the effects of ACE inhibitors on aging-related
cardiac baroreflex dysfunction, in rats, treatment with the
ACE inhibitor lisinopril, during 1 month, increased reflex
bradycardia in both young (4 months) and aged (21 months)
rats (Bunag et al., 1999). However, in this study, the effect
of the ACE inhibitor was not examined on the reflex
tachycardia.
The effects of ACE inhibitors on arterial pressure (AP)
and heart rate variability have been studied extensively in
patients under several conditions, e.g. arterial hypertension
(Tomiyama et al., 1998; Guasti et al., 2001), chronic heart
failure (Binkley et al., 1993) and cardiac surgery (Souza
Neto et al., 2004). To our knowledge there are only a few
studies examining the effects of ACE inhibitors on the
sympatho/vagal balance (Grichois et al., 1992; Rimoldi et
al., 1994). Studies of HR variability in young adult rats
described no effect (Grichois et al., 1992) or an increase
(Ponchon and Elghozi, 1996) in the cardiac sympathetic
activity after inhibition of renin–angiotensin system.
However, to our knowledge, the effects of ACE inhibitors
on aging-related changes in AP and HR variability were not
investigated yet in aged rats.
Therefore, the present study was designed to examine, in
24-month aged rats, the effects of chronic ACE inhibition,
by means of captopril, on: (1) arterial pressure and heart rate
variability; (2) cardiac baroreflex sensitivity.
2. Methods
Four-month-old male Wistar rats were separated into the
following groups: young rats treated with captopril (N =8), or
tap water (N =8), during 2 months; aged rats treated with
captopril (N =7), or tap water (N =5), during 20 months.
Treatment with captopril consisted of a solution (0.5 mg/mL)
dissolved in tap water, supplied ad libitum during 2 months
for the young group, or during 20 months for the aged group.
The animals drank approximately 20–30 mL/day of the
captopril solution, receiving approximately 30 mg/kg of
captopril daily. This dosage has been used in different
pharmacokinetic and pharmacodynamic studies in rats to
evaluate its cardiovascular effects (Wilson et al., 1988; Sun
and Mendelsohn, 1991). Age matched untreated groups
received only tap water during the same period, i.e. 2 or
20 months. Body weight and fluid intake were continuously
monitored during the treatment period. All surgical proce-
dures and protocols were in accordance with the Guidelines
for Ethical Care of Experimental Animals.
At the end of 2- or 20-month period, the animals were
instrumented, under tribromoethanol (250 mg/kg, i.p.)
anesthesia, with catheters implanted into the femoral artery
and vein, and ECG electrodes (lead II) implanted into the
subcutaneous tissue. After the surgical procedures the
animals recovered in individual cages for at least 24 h.
After recovery the arterial catheter was connected to a
pressure transducer (Statham P23Gb, Hato Rey, PR, USA)
and the signals of arterial pressure (AP) and ECG were
amplified and continuously sampled (1000 Hz) in an IBM/
PC equipped with a 12 bit analogic to digital interface
(CAD12/36 Lynx Eletronica, Sao Paulo, Brazil). During the
experiment silence was maintained inside the room to avoid
the influence of stress on AP and ECG recording.
After at least 30 min of basal pulsatile AP and ECG
recording, the animals received intravenous injection of
angiotensin I (100 ng/kg, i.v. bolus) to verify the efficacy of
ACE blockade by captopril. Only animals treated with
captopril showing a pressor response to angiotensin I
smaller than 5 mm Hg were included in this study.
Approximately 15 min after the test with angiotensin I,
the animals received, randomly, i.v. bolus injections of
phenylephrine (0.25–8 Ag/kg) or sodium nitroprusside (1–
32 Ag/kg) to change AP in order to evaluate the cardiac
baroreflex. At the end of the experiments the animals were
killed by ether inhalation.
AP and ECG recordings were processed by a customized
computer software that applies an algorithm to detect cycle-
to-cycle inflection points in the pulsatile AP signal,
determining beat-by-beat values of systolic and diastolic
pressures. Beat-by-beat RR interval (RRi) series from ECG
were also generated by measuring the length of time
between adjacent R waves. From baseline 30 min recording
period, the time series of RR interval and systolic AP were
divided into contiguous segments of 300 beats, overlapped
by half. After the calculations of mean and variance of each
segment they were submitted to a model-based autoregres-
sive spectral analysis as described elsewhere (Malliani et al.,
1991; Rubini et al., 1993; Task Force, 1996). Briefly, a
modeling of the oscillatory components presented in
stationary segments of beat-by-beat time series of SAP
and RRi was calculated based on Levinson-Durbin recur-
V.J. Dias da Silva et al. / Autonomic Neuroscience: Basic and Clinical 124 (2006) 49–55 51
sion, with the order of the model chosen according to
Akaike’s criterion (Malliani et al., 1991). This procedure
allows an automatic quantification of the center frequency
and power of each relevant oscillatory component present in
the time series. The oscillatory components were labeled as
very low (VLF), low (LF) or high frequency (HF) when
their central frequency were within a band of 0.01–0.20,
0.20–0.75 or 0.75–2.50 Hz, respectively. The power of LF
and HF components of heart rate variability was also
expressed in normalized units, obtained by calculating the
percentage of the LF and HF variability with respect to the
total power after subtracting the power of the VLF
component (frequencies <0.20Hz). The normalization pro-
cedure tends to minimize the effect of the changes in total
power on the absolute values of LF and HF variabilities
(Malliani 1991, Rubini et al., 1993; Task Force, 1996).
Baroreflex sensitivity was quantified by the slope of the
regression line obtained by best-fit points relating changes
in RRi and SAP with respect to their baseline values.
Data are expressed as meanTS.E.M. Two-way analysis
of variance followed by a Tukey’s multiple comparison test
was performed to evaluate the effects of treatment (captopril
versus tap water) and age (young versus aged). The
differences were considered significant when P <0.05.
3. Results
Untreated aged rats were significantly heavier than the
untreated young rats (512T22 versus 461T15 g, P <0.05).
On the other hand, aged and young rats treated with captopril
had similar body weights (434T26 versus 460T24 g,
respectively). Aged rats treated with captopril weighed less
than their untreated counterparts (434T26 versus 512T22,respectively P <0.01).
Baseline values of mean arterial pressure (MAP) and HR
from conscious rats are shown in Table 1. MAP and HR
were significantly lower in aged rats treated with captopril
as compared to the other groups.
The pressor response to angiotensin I in young untreated
rats was 35T3 mm Hg while in young rats treated with
captopril it was 4T2mmHg (P <0.001), an attenuation of the
pressor response of approximately 89%. The pressor re-
Table 1
Baseline values (meanTS.E.M.) of systolic (SAP), diastolic (DAP) and
mean arterial pressure (MAP) and heart rate (HR) in conscious young and
aged rats treated (Captopril) or not (Untreated) with captopril
Young Aged
Untreated
(N =8)
Captopril
(N =8)
Untreated
(N =5)
Captopril
(N =7)
SAP (mm Hg) 126T4 131T5 138T4 131T4
DAP (mm Hg) 69T3 73T4 77T2 62T3*
MAP (mm Hg) 89T2 93T4 97T2 85T2*
HR (bpm) 381T11 374T15 405T11 311T25*
* P< 0.05 versus aged untreated rats.
sponse to angiotensin I in aged untreated rats was 68T18 mm
Hg while in aged rats treated with captopril it was 1T2 mm
Hg (P <0.0001), an attenuation of the pressor response of
approximately 98%.
Fig. 1 shows representative spectra of RRi and SAP of
young and aged rats treated or not with captopril. The
spectral pattern of RRi and SAP of young rats were not
affected by captopril (Fig. 1, Table 2). As compared to
young rats, untreated aged rats presented a significant
reduction, not only in variance, but also in LF and HF
oscillations of RRi and SAP variability (Table 2). Captopril
induced, in aged rats, a decrease in both, absolute and
normalized LF component, and also in LF/HF ratio of RRi
(Table 2). Captopril also reduced the SAP variance, in aged
rats, without changing SAP LF or HF components (Table 2).
Reflex bradycardia and tachycardia induced by the
increase, or decrease, in MAP were not different between
young rats treated, or not, with captopril (Fig. 2). The reflex
tachycardia was significantly reduced in aged untreated rats
as compared with young untreated rats (�1.1T0.2 versus
�3.4T0.5 bpm/mm Hg, P <0.05). Captopril did not affect
the reduced reflex tachycardia of aged rats (�1.1T0.4 bpm/
mm Hg versus �1.1T0.2 bpm/mm Hg in aged untreated
rats, P <0.05). The reflex bradycardia was also significantly
reduced in aged untreated rats as compared with young
untreated rats (�0.7T0.5 versus �2.0T0.4 bpm/mm Hg,
P <0.05). However, captopril prevented the attenuation of
the reflex bradycardia of aged rats (�2.3T0.3 bpm/mm Hg
versus �0.7T0.5 bpm/mm Hg in aged untreated rats,
P <0.05).
4. Discussion
The results of the present study indicate that during the
aging process, in rats, there is a significant reduction in HR
and SAP variability, suggesting an impairment of the
autonomic modulation of the cardiovascular system. Al-
though long-term ACE inhibition with captopril did not
prevent the reduction of HR and SAP variability, it was able
to change the power of oscillatory components of RRi,
shifting the cardiac sympatho/vagal balance towards a
parasympathetic predominance. In addition, blockage of
ACE improved the reflex bradycardia, but not the reflex
tachycardia in aged rats.
Despite that plasma and tissue renin activities were not
evaluated, the attenuation (82% and 98%) of the pressor
response elicited by angiotensin I indicated that chronic
treatment with captopril was effective to block ACE,
leading to a decreased activity of the renin–angiotensin
system.
Young untreated rats presented a MAP within the range
expected for their age, i.e. 6 month olds; a value not
significantly different was observed for aged untreated rats.
These findings indicate that basal MAP of rats did not
change, significantly, during 24 months of aging. Chronic
Fig. 1. Examples of representative autoregressive spectra calculate from series of RR interval (ms2/Hz, top) and systolic arterial pressure (mm Hg2/Hz, bottom)
of young and aged rats, untreated or chronically treated, with captopril. PSD=power spectral density.
V.J. Dias da Silva et al. / Autonomic Neuroscience: Basic and Clinical 124 (2006) 49–5552
treatment with captopril did not affect the MAP of young
rats, but decreased, significantly, the MAP of aged rats, as
compared to their untreated counterparts. The mechanism of
the reduction of MAP of aged rats by means of captopril
was not examined in the present study. A possible
Table 2
Spectral parameters of RR interval (RRi) and systolic arterial pressure
(SAP) calculated from time series using autoregressive spectral analysis
Young Aged
Untreated
(N =8)
Captopril
(N =8)
Untreated
(N =5)
Captopril
(N =7)
SAP
Variance (mm Hg2) 20.0T4.4 19.9T4.4 2.0T0.7T 1.3T0.5TLF (mm Hg2) 6.2T1.4 7.0T1.2 0.5T0.4T 0.5T0.3THF (mm Hg2) 7.0T2.1 7.1T2.0 0.4T0.1T 0.4T0.2T
RRi
Variance (ms2) 27T8 31T8 17T6T 11T6TLF (ms2) 1.9T0.6 2.3T0.6 1.2T0.4T 0.2T0.1T.LF (nu) 18T2 19T2 22T4.5 9T3T.HF (ms2) 7.2T1.6 8.2T1.6 4.7T1.7T 3.8T2.3THF (nu) 82T2 81T2 78T4 91T3T.LF/HF ratio 0.2T0.1 0.2T0.1 0.3T0.1 0.1T0.1T.
All values were expressed as meanTS.E.M.
TP <0.05 versus young untreated rats, .P <0.05 versus aged untreated rats.
‘‘nu’’ indicates normalized units.
explanation may involve an increase in sensitivity to RAS
stimulation as observed in the kidneys of early aging rats
(Thompson et al., 2000), which could make aged rats more
sensitive to blockage of ACE in peripheral tissues.
In the present study we are not able to detect a significant
difference in baseline HR among young and aged rats.
Despite of the small number of animals, this finding seems
to confirm previous observations from the literature (Tanabe
and Bunag, 1989; Werner et al., 1995, Irigoyen et al. 2000).
Despite that Berg (1955) found no changes in HR in rats 7
to 18 months old, a lower HR was found in rats 28 to 31
months old. In the present study, prolonged (20 months)
ACE inhibition with captopril reduced the basal HR of aged
rats as compared with aged untreated rats. This finding may
be related to changes of the sympatho/vagal balance to the
heart, with a predominance of vagal activity in aged rats
submitted to chronic ACE inhibition with captopril.
Aged untreated rats exhibited a smaller variability of HR
as compared with young untreated rats. The reduced
variability of HR is demonstrated by the significant
attenuation of variance, which quantified the total variability
of the time series of RRi. The spectral analysis of HR
variability displayed also a significant reduction of the HF
band, which is widely accepted as a marker of vagal
modulation of the heart associated with respiratory sinus
Fig. 2. Group data of reflex changes in heart rate (HR) due to induced changes in mean arterial pressure (MAP) in young and aged rats receiving captopril (open
circles, dotted line), or tap water (solid circles, solid line). Lines represent the linear regressions between changes in heart rate and mean arterial pressure. The
slope of linear regression was used as the index of the baroreflex sensitivity. TP <0.05 compared to rats treated with captopril. TTP <0.01 compared to young
rats.
V.J. Dias da Silva et al. / Autonomic Neuroscience: Basic and Clinical 124 (2006) 49–55 53
arrhythmia (Akselrod et al., 1981; Malliani et al., 1991;
Task Force, 1996). This finding suggests an impairment of
vagal modulation of the heart of aged untreated rats,
providing support to previous data from the literature which
demonstrate an impaired vagal function during aging
process (Kelliher and Conahan, 1980).
On the other hand, a remarkable reduction of total
variability (variance) and spectral components (LF and HF)
of SAP was observed in aged untreated rats, as compared
with their young counterparts. In contrast to the findings in
old human beings who display an increased variability of the
arterial pressure attributed to a derangement of the baroreflex
(Mancia et al., 1985), the results of a reduced variability of
SAP observed in aged untreated rats may suggest a loss of
autonomic control of the peripheral vessels associated with
aging, since the normal variability of AP depends of an intact
autonomic nervous system. However, we cannot discard
other mechanisms, e.g. as angiotensin II, physical activity,
etc. Previous data in animals and humans have suggested that
AP fluctuations, mainly in very low frequency range, may
depend on modulation of vasomotor tone by humoral
substances such as angiotensin II (Akselrod et al., 1981;
Dutrey-Dupagne et al., 1991). Because the renin–angioten-
sin system is less active in the elderly (Hayduk et al., 1973),
it could contribute to a lower total SAP variability observed
in untreated aged rats. Other data also suggest that AP and
HR oscillations depend on physical activity (Bernardi et al.,
1996). As spontaneous physical activity declines with age
(Dawson and Crowne, 1988), it could also contribute to the
marked reduction in total SAP variability.
Chronic blockade of ACE with captopril did not change
variance or the spectral components of RR interval and SAP
in young rats. In addition, captopril did not affect the
reduced variability of SAP observed in aging rats. Although
the prolonged treatment with captopril did not affect the
reduced total variability of HR in aged rats, it did affect the
spectral components LF and HF, displacing the LF/HF ratio
toward predominance of HF. This finding indicates that the
sympatho/vagal balance was changed toward a predomi-
nance of vagal modulation of the heart due to chronic
blockage of ACE.
Overall, the data related to cardiovascular variability in
rats point to a disorder of the autonomic modulation of the
cardiovascular system associated with aging. Long-term
blockade of ACE with captopril seems to prevent some of
these alterations at the level of the heart.
Values obtained for reflex bradycardia in aged control
rats were smaller than those observed in young rats,
indicating that aging, up to 2 years, is accompanied by
depression of the vagal control of the heart, corroborating
previous observations from the literature (Bunag et al.,
1999; Irigoyen et al., 2000). Treatment with captopril during
2 months in young normotensive rats did not change the
baroreflex sensitivity as previously demonstrated in the
literature (Cheng et al., 1989), whereas a prolonged (20
months) treatment was able to prevent the depressed reflex
bradycardia, corroborating previous observations of Bunag
et al. (1999) with the ACE inhibitor lisinopril.
Evaluation of the baroreflex control of HR indicated that
the reflex tachycardia and bradycardia were significantly
depressed in aging untreated rats as compared to their young
counterparts. This reduction indicates an impairment of the
whole baroreflex arch. The methodological approach used
in the present study does not allow to determine what part of
the baroreflex arch is impaired, i.e. peripherally (afferents
and/or efferents) and/or centrally.
Chronic blockade of ACE with captopril did not prevent
in aged rats the attenuation of the reflex tachycardia, but it
V.J. Dias da Silva et al. / Autonomic Neuroscience: Basic and Clinical 124 (2006) 49–5554
did prevent the impairment of the reflex bradycardia. It is
well known that converting enzyme inhibitors improve the
depressed reflex bradycardia associated with diseases like
arterial hypertension and heart failure (Tomiyama et al.,
1998; Guasti et al., 2001; Binkley et al., 1993). This
favorable effect of captopril may be related to the blockade
of renin–angiotensin system within the central nervous
system (Montano et al., 1993; Rimoldi et al., 1994; Francis
et al., 2004), even though a peripheral effect on baror-
eceptors and/or autonomic nervous system cannot be ruled
out as well (Dias da Silva et al., 1994).
In conclusion, aging in rats is characterized by the
development of alterations of the sympathetic nervous
system that controls heart and vessels, characterized by a
reduced HR and AP variability, and attenuation of reflex
bradycardia and reflex tachycardia as well. These observa-
tions point out to a derangement of both segments of the
autonomic nervous system during aging, i.e. sympathetic
and parasympathetic arms of the reflex arch. Interestingly,
the new finding of the present study is that chronic treatment
with captopril decreased the LF/HF ratio leading to a shift of
the sympatho/vagal balance towards a predominance of
parasympathetic modulation associated with an increase of
baroreflex sensitivity, suggesting an improvement of cardiac
vagal function in aged rats treated with captopril. Therefore,
because it is well documented that reduced HR variability
and depressed baroreflex are associated with life threatening
cardiovascular risks, the findings obtained in the present
study suggest a benefic effect on long-term ACE inhibition
during aging.
Acknowledgements
Research supported by PRONEX I, CNPq, FAPESP and
FUNEPU. N.M. was supported by a COFIN 2003 Grant.
References
Akselrod, S., Gordon, D., Ubel, F.A., Shannon, D.C., Berger, A.C., Cohen,
R.J., 1981. Power spectrum analysis of heart rate fluctuation: a
quantitative probe of beat-to-beat cardiovascular control. Science 213,
220–222.
Berg, B.N., 1955. The electrocardiogram in aging rats. J. Gerontol. 10,
420–423.
Bernardi, L., Valle, F., Coco, M., Calciati, A., Slight, P., 1996.
Physical activity influences heart rate variability and very low
frequency components in Holter electrocardiograms. Cardiovasc. Res.
32, 234–237.
Binkley, P.F., Haas, G.J., Starling, R.C., Nunziata, E., Hatton, P.A., Leier,
C.V., Cody, R.J., 1993. Sustained augmentation of parasympathetic tone
with angiotensin-converting enzyme inhibition in patients with conges-
tive heart failure. J. Am. Coll. Cardiol. 21, 655–661.
Brunner, H.R., Waeber, B., Nussberger, J., 1996. Angiotensin-converting
enzyme inhibitors. In: Messerli, F. (Ed.), Cardiovascular Drug Therapy,
2nd edition. W.B. Saunders, Philadelphia, pp. 690–771.
Bunag, R., Mellick, J., Allen, B., 1999. Abated cardiovascular responses to
chronic oral lisinopril treatment in conscious elderly rats. Am. J.
Physiol., Regul. Integr. Comp. Physiol. 276, R1408–R1415.
Cheng, S.W., Swords, B.H., Kirk, K.A., Berecek, K.H., 1989. Baroreflex
function in lifetime-captopril-treated spontaneously hypertensive rats.
Hypertension 13, 63–69.
Dawson, K.A., Crowne, D.P., 1988. Longitudinal development of activity
rhythms in Long Evans rats. J. Gerontol. 43, 85–86.
Dias da Silva, V.J., Vargas da Silva, S., Salgado, M.C.O., Salgado, H.C.,
1994. Chronic converting enzyme inhibition facilitates baroreceptor
resetting to hypertensive levels. Hypertension 23, 68–72.
Dutrey-Dupagne, C., Girard, A., Ulmann, A., Elghozi, J.L., 1991. Effects of
the converting enzyme inhibitor trandolapril on short-term variability of
blood pressure in essential hypertension. Clin. Auton. Res. 1, 303–307.
Ferrari, A.U., Daffonchio, A., Albergati, F., Mancia, G., 1991. Differential
effects of aging on the heart rate and blood pressure influences of
arterial baroreceptors in awake rats. J. Hypertens. 9, 615–621.
Ferrari, A.U., Radaelli, A., Centola, M., 2003. Aging and the cardiovascular
system. J. Appl. Physiol. 95, 2591–2597.
Francis, J., Wei, S.G., Weiss, R.M., Felder, R.B., 2004. Brain angiotensin-
converting enzyme activity and autonomic regulation in heart failure.
Am. J. Physiol., Heart Circ. Physiol. 287, H2138–H2146.
Gribbin, B.T., Pickering, T.G., Sleight, P., Peto, R., 1971. Effect of age and
high blood pressure on baroreflex sensitivity in man. Circ. Res. 29,
424–431.
Grichois, M.L., Blanc, J., Deckert, V., Elghozi, J.L., 1992. Differential
effects of enalapril and hydralazine on short-term variability of
blood pressure and heart rate in rats. J. Cardiovasc. Pharmacol. 19,
863–869.
Guasti, L., Petrozzino, M.R., Mainardi, L.T., Grimoldi, P., Zanotta, D.,
Garganico, D., Diolisi, A., Simoni, C., Grandi, A.M., Gaudio, G.,
Cerutti, S., Venco, A., 2001. Autonomic function and baroreflex
sensitivity during angiotensin-converting enzyme inhibition or angio-
tensin II AT-1 receptor blockade in essential hypertensive patients. Acta
Cardiol. 56, 289–295.
Hayduk, K., Krause, D.K., Kaufman, W., Huenges, R., Schillmoller, U.,
Unbehaun, B., 1973. Age-dependent changes of plasma renin concen-
tration in humans. Clin. Sci. 45, 273s–278s.
Heudes, D., Michel, O., Chevalier, J., Scalbert, E., Ezan, E., Bariety, J.,
Zimmerman, A., Corman, B., 1994. Effect of chronic ANG I-converting
enzyme inhibition on aging processes: I. Kidney structure and function.
Am. J. Physiol., Regul. Integr. Comp. Physiol. 266, R1038–R1051.
Ichikawa, M., Suzuki, H., Kumagai, K., Kumagai, H., Ryuzaki, M.,
Nishizawa, M., Saruta, T., 1995. Differential modulation of barorecep-
tor sensitivity by long-term antihypertensive treatment. Hypertension
26, 425–431.
Irigoyen, M.C., Moreira, E.D., Werner, A., Ida, F., Pires, M.D., Cestari,
I.A., Krieger, E.M., 2000. Aging and baroreflex control of RSNA and
heart rate in rats. Am. J. Physiol., Regul. Integr. Comp. Physiol. 279,
R1865–R1871.
Izzo Jr., J.L., 2000. The role of the renin–angiotensin system in vascular
health: use of ACE inhibition to improve vascular function. Heart Dis.
2, 380–383.
Jones, P.P., Christou, D.D., Jordan, J., Seals, D.R., 2003. Baroreflex
buffering is reduced with age in healthy men. Circulation 107,
1770–1774.
Kelliher, G.J., Conahan, S.T., 1980. Changes in vagal activity and response
to muscarinic receptor agonists with age. J. Gerontol. 35, 842–849.
Kistler, P.M., Sanders, P., Fynn, S.P., Stevenson, I.H., Spence, S.J., Vohra,
J.K., Sparks, P.B., Kalman, J.M., 2004. Electrophysiologic and electro-
anatomic changes in the human atrium associated with age. J. Am. Coll.
Cardiol. 44, 109–116.
Laitinen, T., Niskanen, L., Geelen, G., Lansimies, E., Hartikainen, J., 2004.
Age dependency of cardiovascular autonomic responses to head-up tilt
in healthy subjects. J. Appl. Physiol. 96, 2333–2340.
Lang, M.G., Noll, G., Luscher, T.F., 1995. Effect of aging and hypertension
on contractility of resistance arteries: modulation by endothelial factors.
Am. J. Physiol., Heart Circ. Physiol. 269, H837–H844.
Lartaud, I., Makki, T., Bray-Des-Boscs, L., Niederhoffer, N., Atkinson, J.,
Corman, B., Capdeville-Atkinson, C., 1994. Effect of chronic ANG I-
V.J. Dias da Silva et al. / Autonomic Neuroscience: Basic and Clinical 124 (2006) 49–55 55
converting enzyme inhibition on aging processes: IV. Cerebral blood
flow. Am. J. Physiol., Regul. Integr. Comp. Physiol. 267, R687–R694.
Linz, W., Wiemer, G., Gohlke, P., Unger, T., Scholkens, B.A., 1995.
Contribution of kinins to the cardiovascular actions of angiotensin
converting enzyme inhibitors. Pharmacol. Rev. 47, 25–40.
Malliani, A., Pagani, M., Lombardi, F., Cerutti, S., 1991. Cardiovascular
neural regulation explored in the frequency domain. Circulation 84,
482–492.
Mancia, G., Bertinieri, G., Cavallazzi, A., Di Rienzo, M., Parati, G.,
Pomidossi, G., Ramirez, A.J., Zanchetti, A., 1985. Mechanisms of
blood pressure variability in man. Clin. Exp. Hypertens. A 7, 167–178.
Michel, J.B., Heudes, D., Michel, O., Poitevin, P., Philippe, M., Scalbert,
E., Corman, B., Levy, B.I., 1994. Effect of chronic ANG I-converting
enzyme inhibition on aging processes: II. Large arteries. Am. J.
Physiol., Regul. Integr. Comp. Physiol. 267, R124–R135.
Molander, U., Dey, D.K., Sundh, V., Steen, B., 2003. ECG abnormalities in
the elderly: prevalence, time and generation trends and association with
mortality. Aging Clin. Exp. Res. 15, 488–493.
Montano, N., Gnecchi-Ruscone, T., Contini, M., Finocchiaro, M.L.,
Lombardi, F., Malliani, A., 1993. Effect of captopril on sympa-
thetic preganglionic efferent activity in cats. Am. J. Physiol. 264,
H345–H351.
Nagai, R., Nagata, S., Fukuya, F., Higaki, J., Rakugi, H., Ogihara, T., 2003.
Changes in autonomic activity and baroreflex sensitivity with the
hypertension process and age in rats. Clin. Exp. Pharmacol. Physiol. 30,
419–425.
Ponchon, P., Elghozi, J.L., 1996. Contribution of the renin–angiotensin and
kallikrein–kinin systems to short-term variability of blood pressure in
two-kidney, one-clip hypertensive rats. Eur. J. Pharmacol. 297, 61–70.
Rimoldi, O., Pagani, M.R., Piazza, S., Pagani, M., Malliani, A., 1994.
Restraining effects of captopril on sympathetic excitatory responses in
dogs: a spectral analysis approach. Am. J. Physiol. 267, H1608–H1618.
Rubini, R., Porta, A., Baselli, G., Cerutti, S., Paro, M., 1993. Power
spectrum analysis of cardiovascular variability monitored by telemetry
in conscious unrestrained rats. J. Auton. Nerv. Syst. 45, 181–190.
Sei, H., Sano, A., Ohno, H., Yamabe, K., Nishioka, Y., Sone, S., Morita, Y.,
2002. Age-related changes in control of blood pressure and heart rate
during sleep in the rat. Sleep 25, 279–285.
Shi, X., Huang, G., Smith, S.A., Zhang, R., Formes, K.J., 2003. Aging and
arterial blood pressure variability during orthostatic challenge. Geron-
tology 49, 279–286.
Souza Neto, E.P., Loufouat, J., Saroul, C., Paultre, C., Chiari, P., Lehot, J.J.,
Cerutti, C., 2004. Blood pressure and heart rate variability changes
during cardiac surgery with cardiopulmonary bypass. Fundam. Clin.
Pharmacol. 18, 387–396.
Sun, Y., Mendelsohn, F.A., 1991. Angiotensin converting enzyme
inhibition in heart, kidney, and serum studied ex vivo after
administration of zofenopril, captopril, and lisinopril. J. Cardiovasc.
Pharmacol. 18, 478–486.
Tanabe, S., Bunag, R.D., 1989. Age-related central and baroreceptor
impairment in female Sprague–Dawley rats. Am. J. Physiol., Heart
Circ. Physiol. 256, H1399–H1406.
Task Force of the European Society of Cardiology and the North American
Society of Pacing and Electrophysiology, 1996. Heart rate variability:
standards of measurement, physiological interpretation and clinical use.
Circulation 93, 1043–1065.
Thompson, M.M., Oyama, T.T., Kelly, F.J., Kennefick, T.M., Anderson, S.,
2000. Activity and responsiveness of the renin–angiotensin system in
the aging rat. Am. J. Physiol., Regul. Integr. Comp. Physiol. 279,
R1787–R1794.
Tomiyama, H., Kimura, Y., Sakuma, Y., Shiojima, K., Yamamoto, A., Saito,
I., Ishikawa, Y., Yoshida, H., Morita, S., Doba, N., 1998. Effects of an
ACE inhibitor and a calcium channel blocker on cardiovascular
autonomic nervous system and carotid distensibility in patients with
mild to moderate hypertension. Am. J. Hypertens. 11, 682–689.
Werner, A., Rosa, N.R., Oliveira, A.R., Fernandes, T.G., Bello, A.A.,
Irigoyen, M.C., 1995. Changes in blood pressure control in aged rats.
Braz. J. Med. Biol. Res. 28, 603–607.
Williams, B.R., Kim, J., 2003. Cardiovascular drug therapy in the elderly:
theoretical and practical considerations. Drugs Aging 20, 445–463.
Wilson, K.M., Magargal, W., Berecek, K.H., 1988. Long-term captopril
treatment. Angiotensin II receptors and responses. Hypertension 11,
148–152.
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