Doi:10.1016/j.autneu.2005.11.004

Autonomic Neuroscience: Basic and Clinical 124 (2006) 49 – 55 Effects of long-term angiotensin converting enzyme inhibition on Valdo Jose´ Dias da Silva a, Nicola Montano b, Helio Cesar Salgado c, Rubens Fazan Ju´nior c,* a Department of Biological Sciences, School of Medicine of Triaˆngulo Mineiro, Uberaba, MG Brazil b Department of Clinical Sciences, Internal Medicine II, L. Sacco Hospital, University of Milan, Milano, Italy c Department of Physiology, School of Medicine of Ribeira˜o Preto, Av. Bandeirantes 3900, 14049-900, Ribeira˜o Preto, SP, Brazil Received 20 July 2005; received in revised form 28 November 2005; accepted 28 November 2005 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 –2.5 Hz). BRS was measured by linear regression between HR and MAP 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, adecrease in absolute and normalized LF oscillations and in LF/HF ratio of RRi. Captopril also reduced the variance, without changing its LF orHF components of SAP. Reflex tachycardia was reduced in aged as compared to young rats (À 1.1 T 0.2 versus À3.4 T 0.5 bpm/mm Hg) andcaptopril did not affect it. Reflex bradycardia was also reduced in aged rats (À 0.7 T 0.5 versus À 2.0 T 0.4 bpm/mm Hg), but captopril preventedthis attenuation in aged rats (À 2.3 T 0.3 versus À 0.7 T 0.5 bpm/mm Hg). These data indicate that there is a reduction in HR and SAP variabilityduring aging, suggesting impairment of cardiovascular autonomic control. Captopril was able to change the power of oscillatory components ofRRi, suggesting a shift in cardiac sympatho/vagal balance toward parasympathetic predominance. In addition, blockage of ACE improved thereflex 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 The attenuation of baroreflex control of heart rate (HR) Aging is associated with an impairment of arterial Sei et al., 2002; Jones et al., 2003; Nagai et al., 2003) could pressure regulation which is expressed by an increased be involved in higher arterial pressure variability ( 2004) and tendency to postural and postprandial hypoten- Laitinen et al., 2004), reduced vagal control of the heart aging is associated with a reduction of heart rate variability sympathetic nerve activity to the heart and vessels ( 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(al., 2004). Accordingly, therapeutic strategies which im- * Corresponding author. Tel.: +55 16 36023331; fax: +55 16 36330017.
E-mail address: [email protected] (R. Fazan Ju´nior).
prove reduced heart rate variability and cardiac baroreflex 1566-0702/$ - see front matter D 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.autneu.2005.11.004 V.J. Dias da Silva et al. / Autonomic Neuroscience: Basic and Clinical 124 (2006) 49 – 55 dysfunction related to aging should be useful to decrease Treatment with captopril consisted of a solution (0.5 mg/mL) cardiovascular-related morbidity and mortality.
dissolved in tap water, supplied ad libitum during 2 months Experimental and clinical studies have demonstrated that for the young group, or during 20 months for the aged group.
ACE inhibitors decrease efferent sympathetic nerve activity 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 heart failure. These drugs act through inhibiting the conversion of angiotensin I into angiotensin II, blocking and Mendelsohn, 1991). Age matched untreated groups the endogenous renin – angiotensin system ( received only tap water during the same period, i.e. 2 or 1996). In addition, other vasodilators can be generated by 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 Studies performed in animals, especially rats, evaluated for Ethical Care of Experimental Animals.
the effects of ACE inhibitors on aging. ACE inhibitors At the end of 2- or 20-month period, the animals were produced, in old rats, a variety of benefits, such as: instrumented, under tribromoethanol (250 mg/kg, i.p.) reduction in renal intravascular resistance and proteinuria 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 improvement of endothelial function of resistance vessels 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) With respect the effects of ACE inhibitors on aging-related and the signals of arterial pressure (AP) and ECG were cardiac baroreflex dysfunction, in rats, treatment with the amplified and continuously sampled (1000 Hz) in an IBM/ ACE inhibitor lisinopril, during 1 month, increased reflex PC equipped with a 12 bit analogic to digital interface bradycardia in both young (4 months) and aged (21 months) (CAD12/36 Lynx Eletroˆnica, Sa˜o Paulo, Brazil). During the experiment silence was maintained inside the room to avoid of the ACE inhibitor was not examined on the reflex the influence of stress on AP and ECG recording.
After at least 30 min of basal pulsatile AP and ECG The effects of ACE inhibitors on arterial pressure (AP) recording, the animals received intravenous injection of and heart rate variability have been studied extensively in angiotensin I (100 ng/kg, i.v. bolus) to verify the efficacy of patients under several conditions, e.g. arterial hypertension 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.
Neto et al., 2004). To our knowledge there are only a few Approximately 15 min after the test with angiotensin I, studies examining the effects of ACE inhibitors on the the animals received, randomly, i.v. bolus injections of phenylephrine (0.25 – 8 Ag/kg) or sodium nitroprusside (1 – al., 1994). Studies of HR variability in young adult rats 32 Ag/kg) to change AP in order to evaluate the cardiac baroreflex. At the end of the experiments the animals were activity after inhibition of renin – angiotensin system.
AP and ECG recordings were processed by a customized However, to our knowledge, the effects of ACE inhibitors computer software that applies an algorithm to detect cycle- on aging-related changes in AP and HR variability were not to-cycle inflection points in the pulsatile AP signal, determining beat-by-beat values of systolic and diastolic Therefore, the present study was designed to examine, in pressures. Beat-by-beat RR interval (RRi) series from ECG 24-month aged rats, the effects of chronic ACE inhibition, were also generated by measuring the length of time by means of captopril, on: (1) arterial pressure and heart rate between adjacent R waves. From baseline 30 min recording variability; (2) cardiac baroreflex sensitivity.
period, the time series of RR interval and systolic AP weredivided into contiguous segments of 300 beats, overlappedby 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 ( Four-month-old male Wistar rats were separated into the 1991; Rubini et al., 1993; Task Force, 1996). Briefly, a following groups: young rats treated with captopril (N = 8), or modeling of the oscillatory components presented in tap water (N = 8), during 2 months; aged rats treated with stationary segments of beat-by-beat time series of SAP captopril (N = 7), or tap water (N = 5), during 20 months.
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 sion, with the order of the model chosen according to sponse to angiotensin I in aged untreated rats was 68 T 18 mm Hg while in aged rats treated with captopril it was 1 T 2 mm allows an automatic quantification of the center frequency Hg ( P < 0.0001), an attenuation of the pressor response of and power of each relevant oscillatory component present in the time series. The oscillatory components were labeled as shows representative spectra of RRi and SAP of very low (VLF), low (LF) or high frequency (HF) when young and aged rats treated or not with captopril. The their central frequency were within a band of 0.01 – 0.20, spectral pattern of RRi and SAP of young rats were not 0.20 – 0.75 or 0.75 – 2.50 Hz, respectively. The power of LF and HF components of heart rate variability was also young rats, untreated aged rats presented a significant expressed in normalized units, obtained by calculating the reduction, not only in variance, but also in LF and HF percentage of the LF and HF variability with respect to the oscillations of RRi and SAP variability (Captopril total power after subtracting the power of the VLF induced, in aged rats, a decrease in both, absolute and component (frequencies < 0.20Hz). The normalization pro- normalized LF component, and also in LF/HF ratio of RRi cedure tends to minimize the effect of the changes in total (Captopril also reduced the SAP variance, in aged power on the absolute values of LF and HF variabilities rats, without changing SAP LF or HF components ( Reflex bradycardia and tachycardia induced by the Baroreflex sensitivity was quantified by the slope of the increase, or decrease, in MAP were not different between regression line obtained by best-fit points relating changes young rats treated, or not, with captopril (The reflex in RRi and SAP with respect to their baseline values.
tachycardia was significantly reduced in aged untreated rats Data are expressed as mean T S.E.M. Two-way analysis as compared with young untreated rats (À 1.1 T 0.2 versus of variance followed by a Tukey’s multiple comparison test À 3.4 T 0.5 bpm/mm Hg, P < 0.05). Captopril did not affect was performed to evaluate the effects of treatment (captopril the reduced reflex tachycardia of aged rats (À 1.1 T 0.4 bpm/ versus tap water) and age (young versus aged). The mm Hg versus À 1.1 T 0.2 bpm/mm Hg in aged untreated differences were considered significant when P < 0.05.
rats, P < 0.05). The reflex bradycardia was also significantlyreduced in aged untreated rats as compared with younguntreated rats (À 0.7 T 0.5 versus À2.0 T 0.4 bpm/mm Hg, P < 0.05). However, captopril prevented the attenuation ofthe reflex bradycardia of aged rats (À 2.3 T 0.3 bpm/mm Hg Untreated aged rats were significantly heavier than the versus À 0.7 T 0.5 bpm/mm Hg in aged untreated rats, untreated young rats (512 T 22 versus 461 T15 g, P < 0.05).
On the other hand, aged and young rats treated with captoprilhad similar body weights (434 T 26 versus 460 T 24 g,respectively). Aged rats treated with captopril weighed less than their untreated counterparts (434 T 26 versus 512 T 22,respectively P < 0.01).
The results of the present study indicate that during the Baseline values of mean arterial pressure (MAP) and HR aging process, in rats, there is a significant reduction in HR from conscious rats are shown in MAP and HR and SAP variability, suggesting an impairment of the were significantly lower in aged rats treated with captopril autonomic modulation of the cardiovascular system. Al- though long-term ACE inhibition with captopril did not The pressor response to angiotensin I in young untreated prevent the reduction of HR and SAP variability, it was able rats was 35 T 3 mm Hg while in young rats treated with to change the power of oscillatory components of RRi, captopril it was 4 T 2 mm Hg ( P < 0.001), an attenuation of the shifting the cardiac sympatho/vagal balance towards a pressor response of approximately 89%. The pressor re- parasympathetic predominance. In addition, blockage ofACE improved the reflex bradycardia, but not the reflextachycardia in aged rats.
Despite that plasma and tissue renin activities were not Baseline values (mean T S.E.M.) of systolic (SAP), diastolic (DAP) and evaluated, the attenuation (82% and 98%) of the pressor mean arterial pressure (MAP) and heart rate (HR) in conscious young andaged rats treated (Captopril) or not (Untreated) with captopril response elicited by angiotensin I indicated that chronictreatment with captopril was effective to block ACE, leading to a decreased activity of the renin – angiotensin 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 * P < 0.05 versus aged untreated rats.
change, significantly, during 24 months of aging. Chronic V.J. Dias da Silva et al. / Autonomic Neuroscience: Basic and Clinical 124 (2006) 49 – 55 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.
treatment with captopril did not affect the MAP of young explanation may involve an increase in sensitivity to RAS rats, but decreased, significantly, the MAP of aged rats, as stimulation as observed in the kidneys of early aging rats compared to their untreated counterparts. The mechanism of the reduction of MAP of aged rats by means of captopril sensitive to blockage of ACE in peripheral tissues.
was not examined in the present study. A possible 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 Spectral parameters of RR interval (RRi) and systolic arterial pressure to confirm previous observations from the literature ( (SAP) calculated from time series using autoregressive spectral analysis and Bun˜ag, 1989; Werner et al., 1995, Irigoyen et al. 2000).
Despite that 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 ratssubmitted 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 All values were expressed as mean T S.E.M.
TP < 0.05 versus young untreated rats, band, which is widely accepted as a marker of vagal .P < 0.05 versus aged untreated rats.
‘‘nu’’ indicates normalized units.
modulation of the heart associated with respiratory sinus V.J. Dias da Silva et al. / Autonomic Neuroscience: Basic and Clinical 124 (2006) 49 – 55 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 (opencircles, dotted line), or tap water (solid circles, solid line). Lines represent the linear regressions between changes in heart rate and mean arterial pressure. Theslope 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 youngrats.
the prolonged treatment with captopril did not affect the Task Force, 1996). This finding suggests an impairment of reduced total variability of HR in aged rats, it did affect the vagal modulation of the heart of aged untreated rats, spectral components LF and HF, displacing the LF/HF ratio providing support to previous data from the literature which toward predominance of HF. This finding indicates that the demonstrate an impaired vagal function during aging sympatho/vagal balance was changed toward a predomi- nance of vagal modulation of the heart due to chronic On the other hand, a remarkable reduction of total variability (variance) and spectral components (LF and HF) Overall, the data related to cardiovascular variability in of SAP was observed in aged untreated rats, as compared rats point to a disorder of the autonomic modulation of the with their young counterparts. In contrast to the findings in cardiovascular system associated with aging. Long-term old human beings who display an increased variability of the blockade of ACE with captopril seems to prevent some of arterial pressure attributed to a derangement of the baroreflex these alterations at the level of the heart.
Values obtained for reflex bradycardia in aged control SAP observed in aged untreated rats may suggest a loss of rats were smaller than those observed in young rats, autonomic control of the peripheral vessels associated with indicating that aging, up to 2 years, is accompanied by aging, since the normal variability of AP depends of an intact depression of the vagal control of the heart, corroborating autonomic nervous system. However, we cannot discard previous observations from the literature ( other mechanisms, e.g. as angiotensin II, physical activity, 1999; Irigoyen et al., 2000). Treatment with captopril during etc. Previous data in animals and humans have suggested that 2 months in young normotensive rats did not change the AP fluctuations, mainly in very low frequency range, may baroreflex sensitivity as previously demonstrated in the depend on modulation of vasomotor tone by humoral months) treatment was able to prevent the depressed reflex Dutrey-Dupagne et al., 1991). Because the renin – angioten- bradycardia, corroborating previous observations of sin system is less active in the elderly ( et al. (1999) with the ACE inhibitor lisinopril.
it could contribute to a lower total SAP variability observed Evaluation of the baroreflex control of HR indicated that in untreated aged rats. Other data also suggest that AP and the reflex tachycardia and bradycardia were significantly HR oscillations depend on physical activity ( depressed in aging untreated rats as compared to their young 1996). As spontaneous physical activity declines with age counterparts. This reduction indicates an impairment of the whole baroreflex arch. The methodological approach used marked reduction in total SAP variability.
in the present study does not allow to determine what part of Chronic blockade of ACE with captopril did not change the baroreflex arch is impaired, i.e. peripherally (afferents variance or the spectral components of RR interval and SAP in young rats. In addition, captopril did not affect the Chronic blockade of ACE with captopril did not prevent reduced variability of SAP observed in aging rats. Although 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 – 55 did prevent the impairment of the reflex bradycardia. It is Cheng, S.W., Swords, B.H., Kirk, K.A., Berecek, K.H., 1989. Baroreflex well known that converting enzyme inhibitors improve the function in lifetime-captopril-treated spontaneously hypertensive rats.
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