Autonomic nervous system and cardiovascular in rats: a spectral analysis approach
variability
C. CERUTTI, M. P. GUSTIN, C. Z. PAULTRE, M. LO, C. JULIEN, M. VINCENT, AND J. SASSARD of Physiology and Clinical Pharmacology and Department of Mathematics Department and Computer Science, Faculty of Pharmacy, Centre National de la Recherche Scientifique, Unit@ de Recherche Associke 606, 69373 Lyon Cedex 08, France
CERUTTI, C., M. P. GUSTIN, C. 2. PAULTRE, M. Lo, C. sponded to the Mayer’s waves and were considered to be JULIEN, M. VINCENT, AND J. SASSARD. Autonomic W~VOUS nonspecific markers of the sympathetic activity (23, 26); system and cardiovascular variability in rats: a spectral analysis and 3) high-frequency (HF) oscillations (0.15-0.40 Hz) upproach. Am. J. Physiol. 261(Heart Circ. Physiol. 30): H1292- originated from respiratory activity and appeared to be
H1299, 1991.-Mechanisms underlying systolic (SBP) and diastolic (DBP) blood pressureand heart rate (HR) beat-to-beat variability were investigated using spectral analysis in conscious genetically normotensive (LN) and hypertensive (LH) adult rats from the Lyon strains. In LN rats, basal SBP, DBP, and HR spectra exhibited peaksin low (LF: 0.38-0.45 Hz) and high (HF: 1.04-1.13Hz) frequencies.The LF peak of SBP, and even more of DBP, could be attributed to the influence of the sympathetic nervous systemas it disappearedafter destruction of the sympathetic nerves or a combinedcy-and P-adrenoceptor blockade, whereasit washigher after blockadeof the parasympathetic system.The HF peak of HR, linked to the respiratory rate, was abolishedby the parasympathetic system blockade, whereasthose of SBP and DBP were enhanced. In LH rats, which exhibit a lower sympathetic activity, the LF peaks of SBP and DBP were lessdistinct comparedwith LN controls. We concludethat the LF peak of DBP and the HF peak of HR are likely to represent useful estimates of the sympathetic vascular control and of the parasympathetic cardiac control, respectively. blood pressure;heart rate; consciousrat; beat-to-beat variability; fast Fourier transform; sympathectomy
fluctuationsincardiovascular parameters has been known for a long time. The development of blood pressure (BP) and heart rate (HR) continuous recording techniques in conscious animals, associated with powerful computerized methods for signal analysis, has allowed the study of this spontaneous variability. In most cases, the spontaneous variability has often been estimated by statistical indexes such as standard deviation or variation coefficient, which quantify only the amplitude of fluctuations (9, 20). More recently, spectral analysis was used to explore harmonic and stationary variability over short periods of time (from 1 cardiac cycle to a few minutes) in humans (6, 23) and in dogs (2, 23, 26). It was demonstrated that in these species 1) very low-frequency (VLF) oscillations (0.02-0.08 Hz),. although not very reliable because of methodological problems, were likely to reflect changes in vasomotor tone, in relation to thermoregulation or blood flow adaptations to local metabolic demands; 2) low-frequency (LF) oscillations (0.08-0.15 Hz) correTHEEXISTENCEOFSPONTANEOUS
H1292
0363-6135/91
$1.50
mediated by the parasympathetic system. Therefore, such an analysis may represent a powerful tool for obtaining indexes of autonomic nervous system activity that otherwise would remain difficult to evaluate (23, 25). For that purpose, HR spectral analysis has already been used to assess the autonomic control of cardiac function in humans (3, 11, 12, 19, 21, 24, 28), and simultaneous analysis of BP and HR has been applied to obtain an index of baroreflex sensitivity (8, 27). Despite the extensive use of rats in cardiovascular research, few studies in spectral analysis (1,5,13) have been made in this species, mainly because of the technical difficulty of the registration of valid cardiovascular parameters in the conscious state. The aim of the present work was to determine with the use of spectral analysis of continuous beat-by-beat aortic BP recordings in conscious freely moving rats from the Lyon strains (30) 1) which frequencies could give estimates of the activity of the autonomic nervous system and of the major endocrine factors involved in BP regulation, and 2) their possible alterations by genetic hypertension. MATERIALS
AND METHODS
Animals
Thirty-two genetically normotensive (LN) and 12 genetically hypertensive (LH) male rats of the Lyon strains were used. They were housed in controlled conditions of temperature (21 t l”C), humidity (60 t 10%) and lighting (8-20 h) and received a standard rat chow containing 0.3% sodium (Elevage UAR, Villemoisson-sur-Orge, France), with tap water ad libitum. Chronic Sympathectomy
An early chronic destruction of the sympathetic fibers was obtained in 12 LN rats (LNSx rats) by subcutaneous injections of guanethidine sulfate (Ciba-Geigy, Basel, Switzerland) according to the following protocol (16): daily administrations of 60 mg/kg from day 7 after birth to day 25 and of 30 mg/kg from day 26 to day 70 followed by administrations every other day of 30 mg/kg from day
Copyright 0 1991 the American Physiological Society
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SPECTRAL
ANALYSIS
OF
BLOOD
71 to day 90. Control rats received an equivalent volume of physiological serum. The disappearance of the pressor response to tyramine (250 pg/kg iv; Sigma Chemical, St Louis, MO), which releases endogenous norepinephrine from sympathetic nerve terminals, was taken as a functional index of sympathectomy. Protocol
Surgery (see Methods) was performed at 14 wk of age, and the experiments were performed 1 and 3 days later. BP and HR of all the rats were continuously recorded during 1 h in baseline conditions. Blockade of cy-and P-adrenergic receptors. Each animal received in a randomized order, either on day 1 or day 3, an intravenous administration of phentolamine (5 mg/ kg; Ciba-Geigy) or propranolol (5 mg/kg; ICI Pharma, Cergy, France) followed by the injection of both antagonists. The efficacy of the blockades was assessed by the measurement of the pressor responses to an intravenous injection of an a-adrenoceptor agonist (phenylephrine, 3 pg/kg, Sigma) and the HR responses to an intravenous injection of a @-adrenoceptor agonist (isoprenaline, 1 pg/ kg, Sigma) before blockade and at the end of the recording session. Therefore, in each rat, BP and HR were recorded during three consecutive l-h periods: 1) in baseline conditions, 2) after either phentolamine (n = 5) 1 propranolol (n = 5), and 3) after combined blockade (L ’ S-BLOCK, n = 10). Lckade of cholinergic receptors. Methylatropine (2 mg/kg iv, Sigma) was given in LN ATR (n = 7) rats on day 1. The BP and HR responses to an intravenous injection of metacholine (0.1 pg/kg, Sigma) were measured before blockade and at the end of the recording session to ensure the efficacy of blockade. BP and HR were continuously recorded during two consecutive l-h periods: 1) in baseline conditions and 2) after methylatropine administration. Inhibition of angiotensin-converting enzyme and blockade of vasopressin VI receptors. The renin-angiotensin
system (RAS) was blocked by an intravenous bolus of perindopril (2 mg/kg), a potent long-acting angiotensinconverting enzyme inhibitor (Servier, Neuilly-sur-Seine, France) in LN RASx (n = 7) rats. Vasopressin V, receptors were blocked using an intravenous bolus of P-mercapto-& p-cyclopentamethylenepropionyl’, O-me-Tyr*, Ar$-vasopressin (AVPx, 10 pg/kg, Sigma) in LN AVPx (n = 8) rats. The administration of perindopril or AVPx was performed in a randomized order on either day 1 or day 3. The pressor responses to an intravenous injection of angiotensin I (300 rig/kg, Sigma) or vasopressin (50 rig/kg, Sigma) measured before blockade and at the end of the recording served as indexes of the efficacy of the blockades. In these animals, BP and HR were continuously recorded during three consecutive l-h periods: 1) in baseline conditions, 2) after an injection of either perindopril or AVPx, and 3) after combined administration of both. Methods BP and HR recording. Catheters
halothane
anesthesia
were inserted under via the femoral artery into the
PRESSURE
AND
HEART
RATE
H1293
lower abdominal aorta for continuous recording of BP and via the femoral vein into the inferior vena cava for injections. Both catheters were filled with heparinized saline (25 IU/ml). After a l-day recovery period, the rats were placed into individual recording cages, and the arterial catheter was connected to a BP transducer (P23 ID) (Gould Statham, Cleveland, OH) via a rotating swivel that allowed the animals to move freely. The BP signal real-time processing was performed by a minicomputer, MVME SYS 121 (Motorola Microsystems, Tempe, AZ), with the use of our previously described computer technique (10). It consisted of the 500-Hz digitization followed by the continuous beat-by-beat computation and storage of systolic (SBP, in mmHg), diastolic (DBP, in mmHg) BP and of HR [beats per minute (bpm)]. Spectral analysis. Data processing was performed on a workstation SUN SPARCstationl (SUN Microsystems, Mountain View, CA). Data used for spectral analysis were generated from raw beat-by-beat time series of SBP, DBP, and HR values by computing interpolated values every 130 ms (At). For each l-h recording period, 108 data sets of 512 (N) points overlapping by half were processed. In each data set, the linear trend was removed to avoid its contribution to low frequencies power. Data segments with standard deviations outside the 95 confidence interval for the l-h recording session were discarded. A Hanning window in the time domain (22) was used to attenuate side effects. The spectrum computation was performed using a direct fast Fourier transform (FFT) algorithm for discrete time series referred to as the periodogram method (17). This computation allowed the evaluation of a spectral modulus for each of the 256 frequencies. The frequency resolution was Af = l/Nat, i.e., 0.015 Hz, and the highest frequency was 3.85 Hz, where f is frequency. The spectra obtained for the different data sets were averaged so as to attenuate variable noise contributions and to sharpen reproducible spectral peaks. Within a selected frequency band of the spectrum, the existence of a peak was assessed by 1) the presence of a relative maximum of modulus in the curve after an ascending part covering at least three frequency components and 2) an amplitude, computed as the difference between the maximum modulus and the value before the beginning of the ascending part of the curve, ~0.05% of the sum of the moduli of the whole spectrum. Each peak was characterized by its frequency and its modulus, which reflects the amplitude of the oscillations at this frequency. In addition, the importance of the oscillations in each frequency band was defined by the sum of moduli of each component of the band (cumulative modulus). The peak and cumulative moduli were expressed as absolute values (in mmHg/Hz’/* for BP and bpm/Hzl/* for HR). The squared moduli of the peaks were also expressed as percentage (relative values, %) of the total power (sum of squared moduli over the whole spectrum). Statistical analysis. Nonparametric analysis of variance for repeated measures (Friedman test) was performed to compare spectral components among the three parameters. Wilcoxon’s test for paired data was used for comparisons between recordings in LN rats before and after blockades. Nonparametric Mann- Whitney’s U test was used to compare the results obtained in LNSx or LH rats with those obtained in LN rats. All data were
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HE94
SPECTRAL
ANALYSIS
expressed as means t SE, and the significance set at P < 0.05.
OF BLOOD
level was
PRESSURE
AND HEART
RATE
and DBP and 0.78 t 0.04 and 1.37 t 0.10% for HR. These low values demonstrate the reproducibility of the spectral moduli and ensure the stationarity of data.
RESULTS
Effects of Chronic Sympathectomy Baseline BP and HR Spectra in LN Rats
Figure 1A shows recordings of SBP, DBP, and HR and the corresponding mean spectra obtained in one LN rat during the baseline l-h period. The SBP and DBP chronograms exhibit rapid oscillations superimposed on slower ones; these rapid oscillations are less marked in the DBP spectrum. The HR chronogram contains rapid oscillations that are less regular than those of BP. The analysis of the spectra computed in 13 LN rats led us to define three major frequency bands: a VLF band from 0.015 to 0.255 Hz, a LF band from 0.27 to 0.74 Hz, and a HF band from 0.75 to 3.85 Hz. The relative moduli and the frequency of the peaks detected in each band for each parameter are given in Table 1. Figure 2A shows the spectra computed in the 0.25-2.0 Hz frequency band throughout 1 h of recording in one LN rat. The BP spectra appeared more reproducible than those of HR. The variation coefficient of the spectral modulus of each component was calculated for the three predetermined frequency bands, each parameter, each rat, and each experimental condition. Mean variations coefficients established between 0.59 t 0.01 and 1.03 t 0.04% for SBP
The efficacy of the early destruction of the sympathetic fibers by guanethidine was demonstrated by the disappearance of the BP response to intravenous injections of tyramine (0.1 t 2.3 mmHg in LNSx vs. 44 t 2 mmHg in LN rats). As previously described (16), the mean BP level was unchanged, but BP and HR overall variability, expressed as the standard deviation of beat-by-beat data recorded during 1 h, were significantly increased in LNSx rats compared with LN rats (SBP: 10.6 t 0.5 vs 6.7 t 0.4 mmHg; DBP: 9.9 t 0.5 vs. 5.6 t 0.3 mmHg; and HR: 26.0 t 1.6 vs. 21.4 t 1.0 bpm). As indicated by Fig. 1B and Table 2, the most important observation was the disappearance of the LF peak in SBP and DBP spectra of LNSx rats leading to a marked reduction of corresponding moduli (SBP and DBP: -66% as a mean; Fig. 3A). Figure 2B shows that this observation was constant throughout the l-h recording session. In addition, the VLF oscillations of BP were increased, and, as indicated in Table 2, the frequency of the HF peak of BP and HR was higher in LNSx rats compared with LN rats. Concerning HR, the LF peak was abolished in 7 of the 12 rats studied. VLF 1401
12oL--
I
1
1
I
,
L
1
1
1
I
1
10
20
40 (SM)
so
60
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I
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11 01 I
5
30 TIME
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0
0.40.81.21.
0
FREQUENCY VLF LF
HF
10
20
(Hz)
30
40
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(set)
50
60
70
- -L-
i
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--L
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1
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0.8
1.2
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FREQUENCY
C
VLF LF 140
1 II
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HF 1
2.0
2.4
2.8
32
(Hz)
D
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30 TIME
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40 (set)
1
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01
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2.4 2.8 3.2 (Hz)
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1 30
TIME
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1 60
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(WC)
---\. : ' ' 1.2 1.6
FREQUENCY
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(Hz)
1. Time course and corresponding spectra in very low- (VLF), low- (LF), and high-frequency (HF) bands for systolic (SBP) and diastolic (DBP) blood pressures and heart rate (HR) in 1 LN rat. A: control; B: sympathectomized; C: ar- and P-adrenoceptor blocked; D: cholinergic receptor blocked. FIG.
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SPECTRAL ANALYSIS OF BLOOD PRESSURE AND HEART RATE
H1295
TABLE 1. Relative mod&i and frequencies of peaks in BP and HR spectra in LN rats Very Low Frequency Peak modulus, % SBP
DBP HR
Low Frequency
Peak frequency, HZ
Peak modulus, %
5.2M.l
0.069t0.008
5.1t0.6
0.065t,O.O07
3.6t0.4 4.4t0.6*
0.045-+0.000t
1.1kO.l
11.6kl.Ot
High Frequency Peak frequency, HZ
0.40~0.01 0.39t0.01 0.43t0.02 (10)
(lo)?
Peak modulus, %
0.52&0.10 0.16t0.03 (12)* 0.52t0.05 (12)
Peak frequency, HZ
1.08t0.02 1.06t0.02 (12) 1.1lt0.02 (12)
Values are means ,t SE; n = 13 normotensive rats of Lyon strain (LN). SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate. Numbers in parentheses indicate number of rats in which a peak was detected when different from 13. * P < 0.05 vs. SBP; t P c 0.05 vs. SBP and DBP.
A
I LF ,
B
HF
LF
HF
SBP
10 5I Oi
10 5 01
‘60
-0 0.4
1.2
2 u
FREQUENCY
(Hz)
C
FREQUENCY
LF
(Hz)
D
HF
LF
FIG. 2. Evolution throughout 1 h of systolic (SBP) and diastolic (DBP) blood pressures and heart rate (HR) spectra computed in low- (LF) and high-frequency (HF) bands from 70-s sequences in 1 LN rat. A: control; B: sympathectomized; C: cyand P-adrenoceptor blocked; D: cholinergic receptor blocked.
HF
DBP
-
FREQUENCY
6
(Hz)
6
FREQUENCY
(Hz)
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H1296
SPECTRAL
ANALYSIS
OF
BLOOD
PRESSURE
AND
HEART
RATE
2. Peak frequency in LF and HF bands of SBP, DBP, and HR spectra computed LN rats before and after adrenergic or cholinergic blockade, and in LH rats
in LN rats, LNSx
TABLE
LN
S-BLOCK
DBP HR
LF HF LF HF LF HF
ATR LH*
Baseline
SBP
LN
LNSx*
LN*
1.06kO.02 0.43t0.02
(12) (10)
ND 1.36kO.04 t ND 1.37t0.04t 0.47kO.07 (5)
1.11t0.02
(12)
1.32kO.05
0.40t0.01
1.0&0.02 0.39t0.01
rats,
0.40~0.01
1.13kO.03
1.10t0.02 0.40t0.01 1.06t0.03 0.42kO.01
(10) t
Blockade
(9) (7)
ND 1.44kO.07 ND 1.41t0.07 0.40*0.04 1.47kO.10
Baseline
Blockade
0.37*0.02
0.39t0.01
(9)$ (7)
1.09kO.03 0.36kO.02 1.08kO.03 0.34t0.02
1.09t0.02 0.39t0.01 1.07t0.03 0.39kO.02
(6)
1.11t0.05
(6) (6)
1.04
PHEN-TOUMINE
4
1.21t0.01
(5)
(1)
Values are means t SE. n = no. of rats. Peak frequency in hertz. LNSx (n = 12): sympathectomized normotensive = 13) rats; LN S-BLOCK (n = lo), LN ATR (n = 7): LN rats before (baseline) and after (blockade) phentolamine SBP, DBP: systolic and diastolic blood pressure, respectively; HR: heart rate; LF, HF: low and high frequency, hypertensive rats of Lyon strain. ND, nondetectable. Numbers in parentheses indicate number of rats in which peak from size of group. * All values are at baseline. t P < 0.05 vs. LN; $ P < 0.05 vs. baseline.
SYMPATHECTOMY
0.31t0.02 1.26t0.02 0.31t0.01 0.37t0.03 1.30t0.02
(8)1 t (9)t (3)t (3) (ll)t
rats of Lyon strain (LN; n + propranolol or atropine. respectively. LH (n = l2), was detected when different
PROPRANOLOL
PERlNOOeRlL
4
AVPx
so0 uxl MO
300
m 200 200 100
100
0
0 VLF
LF
FREQUENCY
VLF
LF
FRECXJENCY
HF
BAND
VLF
LF
FREOUENCY
BAND
FREOUENCY
BAND
FIG. 3. Cumulative spectral moduli of systolic (SBP) and diastolic (DBP) blood pressures and of heart rate (HR) in very low- (VLF), low- (LF), and high- (HF) frequency bands in control and sympathectomized (LNSx) LN rats (A) and in LN rats before (baseline) and after (blockade) an intravenous injection of phentolamine (B), propranolol (C), phentolamine and propranolol (D), or perindopril and AVPx (E). *P c 0.05 LNSx vs. LN or blockade vs. baseline.
Effects of Acute CY-and ,&Adrenoceptor Blockade
The efficacy of blockade was assessed by the disappearance of the pressor response to phenylephrine (2.5 t 0.7 mmHg after vs. 43 t 3 mmHg before a-blockade) and of the HR response to isoprenaline (8 t 2 bpm after vs. 132 t 3 bpm before p-blockade). As shown by Fig. 3B, the cumulative moduli were reduced in the VLF and LF bands of BP spectra after a-adrenoceptor blockade. This decrease was especially marked for the LF band of DBP spectra (-51 t 12%). LF peaks could be detected in DBP and SBP spectra for only three of the five rats studied. HR moduli were not modified by phentolamine. ,&Adrenergic blockade significantly decreased the LF cumulative moduli in SBP and DBP spectra (Fig. 3C), and the LF peak could be detected in SBP and DBP spectra in only two of the five rats studied. Combined CYand P-adrenoceptor blockade (LN S-BLOCK) decreased BP (SBP: -30 t 4 mmHg, DBP: -18 t 4 mmHg), and peaks could no longer be detected in the LF band of SBP and DBP spectra (Fig. 1C and Table 2) during the whole l-h recording period (Fig. 2C). Compared with baseline,
the cumulative modulus in the LF band was profoundly reduced (SBP: -63 t 5%; DBP: -60 & 5%) (Fig. 30). HR spectra of LN S-BLOCK rats showed a marked reduction of moduli, evenly distributed in the three frequency bands. Effects of Parasympathetic Blockade
The efficacy of atropine was assessed by the blunting of BP (-9.9 t 0.9 mmHg after vs. -84.2 t 3.2 mmHg before blockade) and HR (18 t 3 bpm after vs. 117 t 7 bpm before blockade) responses to metacholine. Atropine did not alter the BP level of LN ATR rats but induced a significant tachycardia (433 t 8 bpm after blockade vs. 354 t 5 bpm in baseline conditions). As shown in Figs. 1D and 20, BP spectra of LN ATR rats exhibited enhanced LF (SBP: 3.5 t 0.2 vs. 2.7 t 0.1 mmHg/Hz’/‘, DBP: 3.4 t 0.1 vs. 2.5 t 0.2 mmHg/Hz’/2) and HF (SBP: 1.8 t 0.2 vs. 1.3 t 0.1 mmHg/Hz’/2, DBP: 1.3 -t 0.1 vs. 0.7 -+ 0.04 mmHg/Hz’/2) peaks as well as increased cumulative moduli. When their HR spectra were exam-
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SPECTRAL
ANALYSIS
OF
BLOOD
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AND
HEART
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H1297
as to facilitate the theoretical representation and the control of simulations. As the present work was devoted to the vascular and cardiac responses to nervous or Effects of RAS and Vasopressin VI Receptor Blockade humoral factors, we retained the expression in hertz. The sampling period used for interpolation was in most of The efficacy of blockades was demonstrated by the the cases slightly shorter than the heart period of the disappearance of the pressor responses to angiotensin I studied rats (130-210 ms), which ensured no loss of (1.9 t 1.0 mmHg after vs. 50 t 3 mmHg before perininformation. Absolute values of spectral moduli are sendopril administration) and to vasopressin (0.1 t 0.8 sitive to the total power, that is, of the variance, and mmHg after vs. 40 & 3 mmHg before AVPx administratheir use rather than that of normalized values may tion). The only significant modification of BP spectra in influence the interpretation of results. However, absolute LN RASx rats was an increase of the cumulative modulus values better reflect the true changes in variability. in the HF band of BP spectra compared with baseline When one considers the BP and HR spectra obtained values (SBP: 101 t 8 vs. 86 t 9 mmHg/Hzli2; DBP: 67 in baseline conditions in LN rats, three distinct peaks + 4 vs. 57 t 7 mmHg/Hz’j2). LN AVPx rats exhibited were observed that allowed the definition of three freonly an increase of the cumulative modulus in the HF quency bands. Similar data could be obtained in humans band in SBP spectra compared with the baseline value or dogs but at lower frequencies than in rats (2, 23). The (96 t 4 vs. 84 t 5 mmHg/Hz ‘12). After combined RAS VLF band (0.015-0.25 Hz) reflects slow oscillations with and vasopressin V, receptor blockade, as shown in Fig. 3E, the LF and HF cumulative moduli of SBP were periods between 4 and 67 s that are likely to result from increased. Furthermore, the moduli of LF and HF peaks various simultaneous influences including behavior. Beand nonstationof SBP and DBP spectra were also significantly en- cause of their probable nonperiodicity arity and the poor time resolution of the FFT in this hanced. band, a precise study of VLF oscillations will require another type of analysis. The LF peak was found to be BP and HR Spectral Components in LH Rats -0.40 Hz (period 2.5 s) as reported by Japundzic et al. Figure 4, A and B, gives chronograms and spectra of (13) but not by Akselrod et al. (l), who found it to be SBP, DBP, and HR obtained from data recorded in one between 0.10 and 0.30 Hz in Wistar-Kyoto or spontaLH rat. As indicated in Table 2, LH differed from LN neously hypertensive rats. Its modulus, normalized with by 1) a LF peak in SBP and DBP spectra that could not the total power, was higher in DBP than in SBP and HR be detected in all the rats, and, when the peak existed, spectra. It is noteworthy that the LF peak was found to its frequency was significantly lower, and 2) the HF peak be highly reproducible over time and exhibited a low frequency was significantly higher for all three parameinteranimal variability. The HF peak was -1.1 Hz ters, and this peak could be detected in three rats only (period 0.9 s) in our study, and this agrees with previous for DBP. The VLF cumulative moduli of SBP and DBP findings in spontaneously hypertensive or Wistar rats spectra were higher in LH rats than in LN rats (Fig. 4C) (l-l.5 Hz) (1, 13). It has been shown to depend on as was the HF cumulative modulus of DBP spectra, respiratory rate and indeed, in anesthetized and artifiwhereas HR spectra of LH rats exhibited smaller cu- cially ventilated rats, we found its frequency to match mulative moduli in VLF and LF bands. exactly that of the ventilation (data not shown). Its relative modulus was higher in SBP and HR than in DBP, which suggests that the HF peak could reflect the DISCUSSION effect of variations in the intrathoracic pressure on the Spectral analysis of BP and HR in conscious unrevenous return and the ejection volume. As DBP is mainly strained rats has been studied very little (1, 5, 13), dependent on the peripheral resistances, it appears logialthough it should provide a powerful tool to analyze cal that this parameter was less affected by respiration. variability and give access to the time scaling of BP When the relationships between the autonomic nerregulation. The studies performed in humans or in dogs vous system and these rapid fluctuations of BP and HR used either the FFT (2, 6, 25) or an autoregressive were considered, the various pharmacological experimodelization (11, 12, 23) to compute spectral power. ments reported here allow the following conclusions. Some theoretical considerations (17) lead to the preferFirst, the LF oscillations of BP were demonstrated to ence of the autoregressive method to avoid restrictive reflect the influence of the sympathetic fibers acting on hypotheses such as stationarity and side effects. Neverthe cardiovascular system through cy- more than P-adretheless, the FFT method was chosen because of the noceptors. The importance of the sympathetic nervous similar conclusions reached by the authors whatever system (SNS) fibers was clearly shown by the disappearmethod used and because of the easier implementation ance of the LF peak and the large reduction of the of algorithms. To ensure correct computations, the linear cumulative moduli of the LF band after chronic lesion of trend of each data segment was subtracted, the second these fibers by guanethidine, which suppressed the presorder stationarity was verified, and side effects were sor response to tyramine. An acute blockade of CY-and premoved using a classical windowing in the time domain adrenoceptors induced the same effects and, in that (22). Another methodological point concerns the choice respect, phentolamine was more efficient than propranof the expression of frequency in cycles per second (in 0101. In addition, the increase of LF oscillations of BP Hz) rather than in cycles per cardiac beat. Authors that after atropine reflects the lack of direct influence of the developed mathematical models to describe the cardioparasympathetic system on these oscillations and sugvascular function chose beat-by-beat expression (4,8) so gests an enhanced stimulation of the sympathetic fibers. ined, a HF peak was detectable LN ATR rats (Table 2).
in only one of the seven
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H1298
SPECTRAL
ANALYSIS
OF
BLOOD
PRESSURE
Hf
AND
HEART
RATE
B
C 100 00 00 40 P ?!
0
10
20
30 TIME
FIG. 4. Time course bands for systolic (SBP) in LN and LH rats. *P
40
50
60
70
0
0.4
(mc)
12
1.6
FREQUENCY
(A) and corresponding and diastolic
0.8
(DBP)
2.0
2.4
2.8
0
3.2
(Hz)
spectra (B) in very low (VLF), low- (LF), and high-frequency blood pressures and heart rate (HR) in 1 LH rat. C: cumulative
FREQUENCY
BAND
(HF) moduli
< 0.05 vs. LN.
Such a role of the SNS in the LF oscillations of BP is in accordance with other reports. When the cardiovascular system was considered to be a closed-loop feedback system in humans, several authors (2, 4, 8) suggested that the LF peak, located -0.1 Hz, may be generated by a resonance phenomenon of the sympathetic control loop of the baroreflex. In dogs, pharmacological blockade, chronic stellectomy, or sinoaortic denervation also decreased the LF oscillations (2, 23, 26). The most recent studies (23, 26) suggest that the LF peak of BP could be a nonspecific marker of the sympathetic vascular control. In the present work, the influence of alterations of the SNS activity was especially marked on the LF band of DBP spectra. As DBP depends on the vascular resistances and because LF oscillations of DBP were highly reproducible, we suggest that the moduli of the LF band may be an interesting index of the influence of sympathetic fibers on the vascular walls. In that respect, the enhanced LF peak of DBP spectra observed after RAS or vasopressin receptor blockade is likely to be due to a compensatory increase in sympathetic drive (2). Concerning HR, the results observed after adrenergic and parasympathetic blockade suggest that the oscillations in LF partially depend on both systems, and this agrees with results obtained in humans (2, 25). We cannot conclude for rats as some authors did for humans or dogs (23, 26) that the LF peak of HR is a nonspecific marker of the sympathetic activity directed to the sinoatrial node. Second, the HF peak of HR spectra was almost abolished by atropine, which demonstrates that it reflects the respiration-dependent control of HR by the vagus. On the contrary, the HF peaks were enhanced in BP spectra, which may account for a buffering role of the parasympathetic system in BP oscillations at respiratory frequency as has already been suggested (7). The SNS
does not influence the HF features of BP spectra; however, SNS does participate, by means of P-receptor activation, in the HF oscillations of HR. Because a direct influence of cy- or P-receptor stimulation on such rapid oscillations is unlikely, this result may be explained by a diminished vagal tonus in response to the decrease in BP induced by the adrenergic receptor blockade. Therefore, it can be suggested that the HF peak of HR spectra only could be an index of the vagal influence on the cardiovascular system. The influence of humoral systems, such as RAS and vasopressin, on the BP and HR spectra was insignificant, which is not surprising since the frequencies of the oscillations studied are much too high to be controlled by such slow-acting factors. Finally, where LH rats that exhibit an increase in DBP variability over 24 h (15, 29) are concerned, the present work demonstrates that LH rats differ from LN controls by 1) an increase of HF oscillations of DBP, which may be linked to the similar increase observed after parasympathetic blockade in LN rats and to the impairment of the vagal component of the cardiac baroreflex in LH rats (18), 2) an elevated frequency of the HF peak that reflects an elevated respiratory frequency, and 3) in DBP spectra a less distinct and less frequent LF peak but no change in the cumulative modulus of the band. This latter finding is in good agreement with lower urinary excretion of catecholamines exhibited by adult LH rats compared with LN controls (14) and further supports our hypothesis that the LF peak of DBP spectra is an index of the SNS activity on the cardiovascular system. In conclusion, spectral analysis of beat-to-beat variability of BP and HR continuously recorded in conscious freely moving rats should be an interesting tool as it gives access to 1) the respiratory rate with the HF peak frequency, 2) an index of the vagal cardiac control with
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SPECTRAL
ANALYSIS
OF
BLOOD
PRESSURE
the HF peak of HR, and 3) an index of the sympathetic control of the peripheral resistances with the LF peak of DBP.
15. JULIEN
We acknowledge the Institut National de la Sante’et de la Recherche Medicale for its financial support (CRE 89-5001/11). Address for reprint requests: C. Cerutti, Departement de Physiologie et Pharmacologic Clinique, Faculte de Pharmacie, 8 avenue Rockefeller, 69373 Lyon Cedex 08, France Received 5 July 1990; accepted in final form 23 May 1991. REFERENCES S., S. ELIASH, 0. Oz, AND S. COHEN. Hemodynamic regulation in SHR: investigation by spectral analysis. Am. J. Phys-
1. AKSELROD,
iol. 253 (Heart Circ. Physiol. 22): H176-H183, 1987. 2. AKSELROD, S., D. GORDON, J. B. MADWED, D. C. SNIDMAN, D. C. SHANNON, AND R. J. COHEN. Hemodynamic regulation: investigation by spectral analysis. Am. J. Physiol. 249 (Heart Circ. Physiol. 18): H867-H875, 1985. 3. ARAI, Y., J. P. SAUL, P. ALBRECHT, L. H. HARTLEY, L. S. LILLY, R. J. COHEN, AND W. S. COLUCCI. Modulation of cardiac autonomic activity during and immediately after exercise. Am. J. Physiol. 256 (Heart Circ. Physiol. 25): H132-H141, 1989. 4, BASELLI, G., S. CERUTTI, S. CIVARDI, A. MALLIANI, AND M. PAGANI. Cardiovascular variability signals: towards the identifi-
cation of a closed-loop model of the neural control mechanisms. IEEE Trans. Biomed. Eng. 35: 1033-1046,1988. 5. DANIELS, F. H., E. F. LEONARD, AND S. CORTELL. Spectral analysis of arterial blood pressure in the rat. IEEE Trans. Biomed. Eng. 30: 154-158, 1983. 6. DE BOER, R. W., J. M. KAREMAKER, AND J. STRACKEE. Relation-
ships between short-term blood pressure fluctuations and heart rate variability in resting subjects. I. A spectral analysis approach. Med. Biol. 7. DE BOER,
Eng. Comput.
23: 352-358,
1985.
R. W., J. M. KAREMAKER, AND J. STRACKEE. Relationships between short-term blood pressure fluctuations and heart rate variability in resting subjects. II: A simple model. Med. Biol.
Eng. Comput. 23: 359-364,1985. 8. DE BOER, R. W., J. M. KAREMAKER,
AND J. STRACKEE. Hemodynamic fluctuations and baroreflex sensitivity in humans: a beatto-beat model. Am. J. Physiol. 253: 680-689, 1987. 9. FRIBERG, P., B. KARLSSON, AND M. NORDLANDER. Autonomic control of the diurnal variation in arterial blood pressure and heart rate in spontaneously hypertensive and Wistar-Kyoto rats. J.
Hypertens. 10. GUSTIN,
7: 799-807, 1989. M. P., C. CERUTTI,
AND C. 2. PAULTRE. Heterogeneous computer network for real-time hemodynamic signals processing.
Comput. Biol. Med. 20: 205-215,199O. 11. HAYANO, J., Y. SAKAKIBARA, M. YAMADA, N. OHTE, T. FUJINAMI, K. YOKOYAMA, Y. WATANABE, AND K. TAKATA. Decreased mag-
nitude of heart rate spectral components in coronary artery disease. Circulation 81: 1217-1224, 1990. 12. INOUE, K., S. MIYAKE, M. KUMASHIRO, H. OGATA, AND 0. YOSHIMURA. Power spectral analysis of heart rate variability in traumatic quadriplegic humans. Am. J. Physiol. 258 (Heart Circ. Physiol. 27): H1722-H1726, 1990. 13. JAPUNDZIC, N., M. L. GRICHOIS, P. ZITOUN, D. LAUDE, AND J. L. ELGHOZI. Spectral analysis of blood pressure and heart rate in conscious rats: effects of autonomic blockers. J. Auton. New. Syst. 30: 91-100, 1990. 14. JULIEN, C., C. BARRES, J. SACQUET, P. KANDZA, G. CUISINAUD, M. VINCENT, AND J. SASSARD. Urinary catecholamines and blood pressure in genetically normotensive and hypertensive rats. Biog. Amine. 6: 525-534. 1989.
AND
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C., C. CERUTTI, P. KANDZA, C. BARRES, D. F. Su, M. AND J. SASSARD. Cardiovascular response to emotional stress and spontaneous blood pressure variability in genetically hypertensive rats of the Lyon strain. Clin. Exp. Pharmacol. Physiol. VINCENT,
15: 533-538, 1988. 16. JULIEN C., P. KANDZA, C. BARRES, M. Lo, C. CERUTTI, AND J. SASSARD. Effects of sympathectomy on blood pressure and its variability in conscious rats. Am. J. Physiol. 259 (Heart Circ. Physiol. 28): H1337-H1342, 1990. 17. KAY, S. M., AND S. L. MARPLE. Spectrum analysis-a modern perspective. Proceedings IEEE 69: 1380-1419, 1981. C. JULIEN, D. F. Su, M. VINCENT, AND J. 18. Lo, M., C. CERU?TI, SASSARD. Evolution with age of baroreflex sensitivity and its
autonomic nervous components in conscious hypertensive rats of the Lyon strain. Clin. Exp. Pharmacol. Physiol. 15, Suppl.: 81-84, 1989. 19. LOMBARDI, IMOLDI,
F., G. SANDRONE, S. PERNPRUNER, R. SALA, M. CARS. CERUTTI, G. BASELLI, M. PAGANI, AND A. MALLIANI. Heart rate variability as an index of sympatho-vagal interaction after acute myocardial infection. Am. J. Cardiol. 60: 1239-1245,
1987. 20. MANCIA, G., G. PARATI, G. POMIDOSSI, R. CASADEI, M. DI RIENZO, AND A. ZANCHETTI. Arterial baroreflexes and blood pressure and heart rate variabilities in humans. Hypertension Dallas 8: 147-153, 1986. 21. MYERS, G. A., G. J. MARTIN, N. M. MAGID, P. S. BARNEW, J. W. SCHAAD, J. S. WEISS, M. LESCH, AND D. H. SINGER. Power
spectral analysis of heart rate variability in sudden cardiac death: comparison to other methods. IEEE Trans. Biomed. Eng. 33: 11491156,1986. 22. OPPENHEIM,
A. V., AND R. W. SCHAFER. Digital Signal Processing. Englewood Cliffs, NJ: Prentice-Hall, 1975. 23. PAGANI, M., F. LOMBARDI, S. GUZZETTI, 0. RIMOLDI, R. FURLAN, P. PIZZINELLI, G. SANDRONE, G. MALFATTO, S. DELL’ORTO, E. PICCALUGA, M. TURIEL, G. BASELLI, S. CERU~I, AND A. MALLIANI. Power spectral analysis of heart rate and arterial pressure variabilities as a marker of sympatho vagal interaction in man and conscious dog. Circ. Res. 59: 178-193, 1986. 24. PAGANI, M., V. SOMERS, R. FURLAN, S. DELL’ORTO, J. CONWAY, G. BASELLI, S. CERUTTI, P. SLEIGHT, AND A. MALLIANI. Changes in autonomic regulation induced by physical training in mild hypertension. Hypertension Dallas 12: 600-610,1988. 25. POMERANZ, B., R. J. B. MACAULAY, M. A. CAUDILL, I. KUTZ, D. ADAM, D. GORDON, K. M KILBORN, A. C. BARGER, D. C. SHANNON, R. J. COHEN, AND H. BENSON. Assessment of autonomic function in humans by heart rate spectral analysis. Am. J. Physiol. 248 (Heart Circ. Physiol. 27): H151-H153, 1985. O., S. PIERINI, A. FERRARI, S. CERUTTI, M. PAGANI, 26. RIMOLDI, AND A. MALLIANI. Analysis of short-term oscillations of R-R and arterial pressure in conscious dogs. Am. J. Physiol. 258 (Heart Circ. Physiol. 27): H967-H976, 1990. 27. ROBBE, H. W., L. J. M. MULDER, H. R~DDEL, W. A. LANGEWITZ, J. B. P. VELDMAN, AND G. MULDER. Assessment of baroreceptor reflex sensitivity by means of spectral analysis. Hypertension Dallas 10: 538-543,1987. 28. SAUL, J. P., Y. ARAI, R. D. BERGER, L. S. LILLY, W. S. COLUCCI, AND R. J. COHEN. Assessment of autonomic regulation in chronic congestive heart failure by heart rate spectral analysis. Am. J. Cardiol. 61: 1292-1299, 1988. 29. Su, D. F., C. CERU~TI, C. BARRES, M. VINCENT, AND J. SASSARD.
Blood pressure and baroreflex sensitivity in conscious hypertensive rats of the Lyon strain. Am. J. Physiol. 251 (Heart Circ. Physiol. 20): Hllll-H1117,1986. 30. VINCENT, M., J. SACQUET,
AND J. SASSARD. The Lyon strains of hypertensive, normotensive and low blood pressure rats. In: Handbook of Hypertension. Amsterdam: Elsevier, 1984, vol. 4, p. 314327.
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variability
C. CERUTTI, M. P. GUSTIN, C. Z. PAULTRE, M. LO, C. JULIEN, M. VINCENT, AND J. SASSARD of Physiology and Clinical Pharmacology and Department of Mathematics Department and Computer Science, Faculty of Pharmacy, Centre National de la Recherche Scientifique, Unit@ de Recherche Associke 606, 69373 Lyon Cedex 08, France
CERUTTI, C., M. P. GUSTIN, C. 2. PAULTRE, M. Lo, C. sponded to the Mayer’s waves and were considered to be JULIEN, M. VINCENT, AND J. SASSARD. Autonomic W~VOUS nonspecific markers of the sympathetic activity (23, 26); system and cardiovascular variability in rats: a spectral analysis and 3) high-frequency (HF) oscillations (0.15-0.40 Hz) upproach. Am. J. Physiol. 261(Heart Circ. Physiol. 30): H1292- originated from respiratory activity and appeared to be
H1299, 1991.-Mechanisms underlying systolic (SBP) and diastolic (DBP) blood pressureand heart rate (HR) beat-to-beat variability were investigated using spectral analysis in conscious genetically normotensive (LN) and hypertensive (LH) adult rats from the Lyon strains. In LN rats, basal SBP, DBP, and HR spectra exhibited peaksin low (LF: 0.38-0.45 Hz) and high (HF: 1.04-1.13Hz) frequencies.The LF peak of SBP, and even more of DBP, could be attributed to the influence of the sympathetic nervous systemas it disappearedafter destruction of the sympathetic nerves or a combinedcy-and P-adrenoceptor blockade, whereasit washigher after blockadeof the parasympathetic system.The HF peak of HR, linked to the respiratory rate, was abolishedby the parasympathetic system blockade, whereasthose of SBP and DBP were enhanced. In LH rats, which exhibit a lower sympathetic activity, the LF peaks of SBP and DBP were lessdistinct comparedwith LN controls. We concludethat the LF peak of DBP and the HF peak of HR are likely to represent useful estimates of the sympathetic vascular control and of the parasympathetic cardiac control, respectively. blood pressure;heart rate; consciousrat; beat-to-beat variability; fast Fourier transform; sympathectomy
fluctuationsincardiovascular parameters has been known for a long time. The development of blood pressure (BP) and heart rate (HR) continuous recording techniques in conscious animals, associated with powerful computerized methods for signal analysis, has allowed the study of this spontaneous variability. In most cases, the spontaneous variability has often been estimated by statistical indexes such as standard deviation or variation coefficient, which quantify only the amplitude of fluctuations (9, 20). More recently, spectral analysis was used to explore harmonic and stationary variability over short periods of time (from 1 cardiac cycle to a few minutes) in humans (6, 23) and in dogs (2, 23, 26). It was demonstrated that in these species 1) very low-frequency (VLF) oscillations (0.02-0.08 Hz),. although not very reliable because of methodological problems, were likely to reflect changes in vasomotor tone, in relation to thermoregulation or blood flow adaptations to local metabolic demands; 2) low-frequency (LF) oscillations (0.08-0.15 Hz) correTHEEXISTENCEOFSPONTANEOUS
H1292
0363-6135/91
$1.50
mediated by the parasympathetic system. Therefore, such an analysis may represent a powerful tool for obtaining indexes of autonomic nervous system activity that otherwise would remain difficult to evaluate (23, 25). For that purpose, HR spectral analysis has already been used to assess the autonomic control of cardiac function in humans (3, 11, 12, 19, 21, 24, 28), and simultaneous analysis of BP and HR has been applied to obtain an index of baroreflex sensitivity (8, 27). Despite the extensive use of rats in cardiovascular research, few studies in spectral analysis (1,5,13) have been made in this species, mainly because of the technical difficulty of the registration of valid cardiovascular parameters in the conscious state. The aim of the present work was to determine with the use of spectral analysis of continuous beat-by-beat aortic BP recordings in conscious freely moving rats from the Lyon strains (30) 1) which frequencies could give estimates of the activity of the autonomic nervous system and of the major endocrine factors involved in BP regulation, and 2) their possible alterations by genetic hypertension. MATERIALS
AND METHODS
Animals
Thirty-two genetically normotensive (LN) and 12 genetically hypertensive (LH) male rats of the Lyon strains were used. They were housed in controlled conditions of temperature (21 t l”C), humidity (60 t 10%) and lighting (8-20 h) and received a standard rat chow containing 0.3% sodium (Elevage UAR, Villemoisson-sur-Orge, France), with tap water ad libitum. Chronic Sympathectomy
An early chronic destruction of the sympathetic fibers was obtained in 12 LN rats (LNSx rats) by subcutaneous injections of guanethidine sulfate (Ciba-Geigy, Basel, Switzerland) according to the following protocol (16): daily administrations of 60 mg/kg from day 7 after birth to day 25 and of 30 mg/kg from day 26 to day 70 followed by administrations every other day of 30 mg/kg from day
Copyright 0 1991 the American Physiological Society
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SPECTRAL
ANALYSIS
OF
BLOOD
71 to day 90. Control rats received an equivalent volume of physiological serum. The disappearance of the pressor response to tyramine (250 pg/kg iv; Sigma Chemical, St Louis, MO), which releases endogenous norepinephrine from sympathetic nerve terminals, was taken as a functional index of sympathectomy. Protocol
Surgery (see Methods) was performed at 14 wk of age, and the experiments were performed 1 and 3 days later. BP and HR of all the rats were continuously recorded during 1 h in baseline conditions. Blockade of cy-and P-adrenergic receptors. Each animal received in a randomized order, either on day 1 or day 3, an intravenous administration of phentolamine (5 mg/ kg; Ciba-Geigy) or propranolol (5 mg/kg; ICI Pharma, Cergy, France) followed by the injection of both antagonists. The efficacy of the blockades was assessed by the measurement of the pressor responses to an intravenous injection of an a-adrenoceptor agonist (phenylephrine, 3 pg/kg, Sigma) and the HR responses to an intravenous injection of a @-adrenoceptor agonist (isoprenaline, 1 pg/ kg, Sigma) before blockade and at the end of the recording session. Therefore, in each rat, BP and HR were recorded during three consecutive l-h periods: 1) in baseline conditions, 2) after either phentolamine (n = 5) 1 propranolol (n = 5), and 3) after combined blockade (L ’ S-BLOCK, n = 10). Lckade of cholinergic receptors. Methylatropine (2 mg/kg iv, Sigma) was given in LN ATR (n = 7) rats on day 1. The BP and HR responses to an intravenous injection of metacholine (0.1 pg/kg, Sigma) were measured before blockade and at the end of the recording session to ensure the efficacy of blockade. BP and HR were continuously recorded during two consecutive l-h periods: 1) in baseline conditions and 2) after methylatropine administration. Inhibition of angiotensin-converting enzyme and blockade of vasopressin VI receptors. The renin-angiotensin
system (RAS) was blocked by an intravenous bolus of perindopril (2 mg/kg), a potent long-acting angiotensinconverting enzyme inhibitor (Servier, Neuilly-sur-Seine, France) in LN RASx (n = 7) rats. Vasopressin V, receptors were blocked using an intravenous bolus of P-mercapto-& p-cyclopentamethylenepropionyl’, O-me-Tyr*, Ar$-vasopressin (AVPx, 10 pg/kg, Sigma) in LN AVPx (n = 8) rats. The administration of perindopril or AVPx was performed in a randomized order on either day 1 or day 3. The pressor responses to an intravenous injection of angiotensin I (300 rig/kg, Sigma) or vasopressin (50 rig/kg, Sigma) measured before blockade and at the end of the recording served as indexes of the efficacy of the blockades. In these animals, BP and HR were continuously recorded during three consecutive l-h periods: 1) in baseline conditions, 2) after an injection of either perindopril or AVPx, and 3) after combined administration of both. Methods BP and HR recording. Catheters
halothane
anesthesia
were inserted under via the femoral artery into the
PRESSURE
AND
HEART
RATE
H1293
lower abdominal aorta for continuous recording of BP and via the femoral vein into the inferior vena cava for injections. Both catheters were filled with heparinized saline (25 IU/ml). After a l-day recovery period, the rats were placed into individual recording cages, and the arterial catheter was connected to a BP transducer (P23 ID) (Gould Statham, Cleveland, OH) via a rotating swivel that allowed the animals to move freely. The BP signal real-time processing was performed by a minicomputer, MVME SYS 121 (Motorola Microsystems, Tempe, AZ), with the use of our previously described computer technique (10). It consisted of the 500-Hz digitization followed by the continuous beat-by-beat computation and storage of systolic (SBP, in mmHg), diastolic (DBP, in mmHg) BP and of HR [beats per minute (bpm)]. Spectral analysis. Data processing was performed on a workstation SUN SPARCstationl (SUN Microsystems, Mountain View, CA). Data used for spectral analysis were generated from raw beat-by-beat time series of SBP, DBP, and HR values by computing interpolated values every 130 ms (At). For each l-h recording period, 108 data sets of 512 (N) points overlapping by half were processed. In each data set, the linear trend was removed to avoid its contribution to low frequencies power. Data segments with standard deviations outside the 95 confidence interval for the l-h recording session were discarded. A Hanning window in the time domain (22) was used to attenuate side effects. The spectrum computation was performed using a direct fast Fourier transform (FFT) algorithm for discrete time series referred to as the periodogram method (17). This computation allowed the evaluation of a spectral modulus for each of the 256 frequencies. The frequency resolution was Af = l/Nat, i.e., 0.015 Hz, and the highest frequency was 3.85 Hz, where f is frequency. The spectra obtained for the different data sets were averaged so as to attenuate variable noise contributions and to sharpen reproducible spectral peaks. Within a selected frequency band of the spectrum, the existence of a peak was assessed by 1) the presence of a relative maximum of modulus in the curve after an ascending part covering at least three frequency components and 2) an amplitude, computed as the difference between the maximum modulus and the value before the beginning of the ascending part of the curve, ~0.05% of the sum of the moduli of the whole spectrum. Each peak was characterized by its frequency and its modulus, which reflects the amplitude of the oscillations at this frequency. In addition, the importance of the oscillations in each frequency band was defined by the sum of moduli of each component of the band (cumulative modulus). The peak and cumulative moduli were expressed as absolute values (in mmHg/Hz’/* for BP and bpm/Hzl/* for HR). The squared moduli of the peaks were also expressed as percentage (relative values, %) of the total power (sum of squared moduli over the whole spectrum). Statistical analysis. Nonparametric analysis of variance for repeated measures (Friedman test) was performed to compare spectral components among the three parameters. Wilcoxon’s test for paired data was used for comparisons between recordings in LN rats before and after blockades. Nonparametric Mann- Whitney’s U test was used to compare the results obtained in LNSx or LH rats with those obtained in LN rats. All data were
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HE94
SPECTRAL
ANALYSIS
expressed as means t SE, and the significance set at P < 0.05.
OF BLOOD
level was
PRESSURE
AND HEART
RATE
and DBP and 0.78 t 0.04 and 1.37 t 0.10% for HR. These low values demonstrate the reproducibility of the spectral moduli and ensure the stationarity of data.
RESULTS
Effects of Chronic Sympathectomy Baseline BP and HR Spectra in LN Rats
Figure 1A shows recordings of SBP, DBP, and HR and the corresponding mean spectra obtained in one LN rat during the baseline l-h period. The SBP and DBP chronograms exhibit rapid oscillations superimposed on slower ones; these rapid oscillations are less marked in the DBP spectrum. The HR chronogram contains rapid oscillations that are less regular than those of BP. The analysis of the spectra computed in 13 LN rats led us to define three major frequency bands: a VLF band from 0.015 to 0.255 Hz, a LF band from 0.27 to 0.74 Hz, and a HF band from 0.75 to 3.85 Hz. The relative moduli and the frequency of the peaks detected in each band for each parameter are given in Table 1. Figure 2A shows the spectra computed in the 0.25-2.0 Hz frequency band throughout 1 h of recording in one LN rat. The BP spectra appeared more reproducible than those of HR. The variation coefficient of the spectral modulus of each component was calculated for the three predetermined frequency bands, each parameter, each rat, and each experimental condition. Mean variations coefficients established between 0.59 t 0.01 and 1.03 t 0.04% for SBP
The efficacy of the early destruction of the sympathetic fibers by guanethidine was demonstrated by the disappearance of the BP response to intravenous injections of tyramine (0.1 t 2.3 mmHg in LNSx vs. 44 t 2 mmHg in LN rats). As previously described (16), the mean BP level was unchanged, but BP and HR overall variability, expressed as the standard deviation of beat-by-beat data recorded during 1 h, were significantly increased in LNSx rats compared with LN rats (SBP: 10.6 t 0.5 vs 6.7 t 0.4 mmHg; DBP: 9.9 t 0.5 vs. 5.6 t 0.3 mmHg; and HR: 26.0 t 1.6 vs. 21.4 t 1.0 bpm). As indicated by Fig. 1B and Table 2, the most important observation was the disappearance of the LF peak in SBP and DBP spectra of LNSx rats leading to a marked reduction of corresponding moduli (SBP and DBP: -66% as a mean; Fig. 3A). Figure 2B shows that this observation was constant throughout the l-h recording session. In addition, the VLF oscillations of BP were increased, and, as indicated in Table 2, the frequency of the HF peak of BP and HR was higher in LNSx rats compared with LN rats. Concerning HR, the LF peak was abolished in 7 of the 12 rats studied. VLF 1401
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1. Time course and corresponding spectra in very low- (VLF), low- (LF), and high-frequency (HF) bands for systolic (SBP) and diastolic (DBP) blood pressures and heart rate (HR) in 1 LN rat. A: control; B: sympathectomized; C: ar- and P-adrenoceptor blocked; D: cholinergic receptor blocked. FIG.
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SPECTRAL ANALYSIS OF BLOOD PRESSURE AND HEART RATE
H1295
TABLE 1. Relative mod&i and frequencies of peaks in BP and HR spectra in LN rats Very Low Frequency Peak modulus, % SBP
DBP HR
Low Frequency
Peak frequency, HZ
Peak modulus, %
5.2M.l
0.069t0.008
5.1t0.6
0.065t,O.O07
3.6t0.4 4.4t0.6*
0.045-+0.000t
1.1kO.l
11.6kl.Ot
High Frequency Peak frequency, HZ
0.40~0.01 0.39t0.01 0.43t0.02 (10)
(lo)?
Peak modulus, %
0.52&0.10 0.16t0.03 (12)* 0.52t0.05 (12)
Peak frequency, HZ
1.08t0.02 1.06t0.02 (12) 1.1lt0.02 (12)
Values are means ,t SE; n = 13 normotensive rats of Lyon strain (LN). SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate. Numbers in parentheses indicate number of rats in which a peak was detected when different from 13. * P < 0.05 vs. SBP; t P c 0.05 vs. SBP and DBP.
A
I LF ,
B
HF
LF
HF
SBP
10 5I Oi
10 5 01
‘60
-0 0.4
1.2
2 u
FREQUENCY
(Hz)
C
FREQUENCY
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(Hz)
D
HF
LF
FIG. 2. Evolution throughout 1 h of systolic (SBP) and diastolic (DBP) blood pressures and heart rate (HR) spectra computed in low- (LF) and high-frequency (HF) bands from 70-s sequences in 1 LN rat. A: control; B: sympathectomized; C: cyand P-adrenoceptor blocked; D: cholinergic receptor blocked.
HF
DBP
-
FREQUENCY
6
(Hz)
6
FREQUENCY
(Hz)
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H1296
SPECTRAL
ANALYSIS
OF
BLOOD
PRESSURE
AND
HEART
RATE
2. Peak frequency in LF and HF bands of SBP, DBP, and HR spectra computed LN rats before and after adrenergic or cholinergic blockade, and in LH rats
in LN rats, LNSx
TABLE
LN
S-BLOCK
DBP HR
LF HF LF HF LF HF
ATR LH*
Baseline
SBP
LN
LNSx*
LN*
1.06kO.02 0.43t0.02
(12) (10)
ND 1.36kO.04 t ND 1.37t0.04t 0.47kO.07 (5)
1.11t0.02
(12)
1.32kO.05
0.40t0.01
1.0&0.02 0.39t0.01
rats,
0.40~0.01
1.13kO.03
1.10t0.02 0.40t0.01 1.06t0.03 0.42kO.01
(10) t
Blockade
(9) (7)
ND 1.44kO.07 ND 1.41t0.07 0.40*0.04 1.47kO.10
Baseline
Blockade
0.37*0.02
0.39t0.01
(9)$ (7)
1.09kO.03 0.36kO.02 1.08kO.03 0.34t0.02
1.09t0.02 0.39t0.01 1.07t0.03 0.39kO.02
(6)
1.11t0.05
(6) (6)
1.04
PHEN-TOUMINE
4
1.21t0.01
(5)
(1)
Values are means t SE. n = no. of rats. Peak frequency in hertz. LNSx (n = 12): sympathectomized normotensive = 13) rats; LN S-BLOCK (n = lo), LN ATR (n = 7): LN rats before (baseline) and after (blockade) phentolamine SBP, DBP: systolic and diastolic blood pressure, respectively; HR: heart rate; LF, HF: low and high frequency, hypertensive rats of Lyon strain. ND, nondetectable. Numbers in parentheses indicate number of rats in which peak from size of group. * All values are at baseline. t P < 0.05 vs. LN; $ P < 0.05 vs. baseline.
SYMPATHECTOMY
0.31t0.02 1.26t0.02 0.31t0.01 0.37t0.03 1.30t0.02
(8)1 t (9)t (3)t (3) (ll)t
rats of Lyon strain (LN; n + propranolol or atropine. respectively. LH (n = l2), was detected when different
PROPRANOLOL
PERlNOOeRlL
4
AVPx
so0 uxl MO
300
m 200 200 100
100
0
0 VLF
LF
FREQUENCY
VLF
LF
FRECXJENCY
HF
BAND
VLF
LF
FREOUENCY
BAND
FREOUENCY
BAND
FIG. 3. Cumulative spectral moduli of systolic (SBP) and diastolic (DBP) blood pressures and of heart rate (HR) in very low- (VLF), low- (LF), and high- (HF) frequency bands in control and sympathectomized (LNSx) LN rats (A) and in LN rats before (baseline) and after (blockade) an intravenous injection of phentolamine (B), propranolol (C), phentolamine and propranolol (D), or perindopril and AVPx (E). *P c 0.05 LNSx vs. LN or blockade vs. baseline.
Effects of Acute CY-and ,&Adrenoceptor Blockade
The efficacy of blockade was assessed by the disappearance of the pressor response to phenylephrine (2.5 t 0.7 mmHg after vs. 43 t 3 mmHg before a-blockade) and of the HR response to isoprenaline (8 t 2 bpm after vs. 132 t 3 bpm before p-blockade). As shown by Fig. 3B, the cumulative moduli were reduced in the VLF and LF bands of BP spectra after a-adrenoceptor blockade. This decrease was especially marked for the LF band of DBP spectra (-51 t 12%). LF peaks could be detected in DBP and SBP spectra for only three of the five rats studied. HR moduli were not modified by phentolamine. ,&Adrenergic blockade significantly decreased the LF cumulative moduli in SBP and DBP spectra (Fig. 3C), and the LF peak could be detected in SBP and DBP spectra in only two of the five rats studied. Combined CYand P-adrenoceptor blockade (LN S-BLOCK) decreased BP (SBP: -30 t 4 mmHg, DBP: -18 t 4 mmHg), and peaks could no longer be detected in the LF band of SBP and DBP spectra (Fig. 1C and Table 2) during the whole l-h recording period (Fig. 2C). Compared with baseline,
the cumulative modulus in the LF band was profoundly reduced (SBP: -63 t 5%; DBP: -60 & 5%) (Fig. 30). HR spectra of LN S-BLOCK rats showed a marked reduction of moduli, evenly distributed in the three frequency bands. Effects of Parasympathetic Blockade
The efficacy of atropine was assessed by the blunting of BP (-9.9 t 0.9 mmHg after vs. -84.2 t 3.2 mmHg before blockade) and HR (18 t 3 bpm after vs. 117 t 7 bpm before blockade) responses to metacholine. Atropine did not alter the BP level of LN ATR rats but induced a significant tachycardia (433 t 8 bpm after blockade vs. 354 t 5 bpm in baseline conditions). As shown in Figs. 1D and 20, BP spectra of LN ATR rats exhibited enhanced LF (SBP: 3.5 t 0.2 vs. 2.7 t 0.1 mmHg/Hz’/‘, DBP: 3.4 t 0.1 vs. 2.5 t 0.2 mmHg/Hz’/2) and HF (SBP: 1.8 t 0.2 vs. 1.3 t 0.1 mmHg/Hz’/2, DBP: 1.3 -t 0.1 vs. 0.7 -+ 0.04 mmHg/Hz’/2) peaks as well as increased cumulative moduli. When their HR spectra were exam-
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SPECTRAL
ANALYSIS
OF
BLOOD
PRESSURE
AND
HEART
RATE
H1297
as to facilitate the theoretical representation and the control of simulations. As the present work was devoted to the vascular and cardiac responses to nervous or Effects of RAS and Vasopressin VI Receptor Blockade humoral factors, we retained the expression in hertz. The sampling period used for interpolation was in most of The efficacy of blockades was demonstrated by the the cases slightly shorter than the heart period of the disappearance of the pressor responses to angiotensin I studied rats (130-210 ms), which ensured no loss of (1.9 t 1.0 mmHg after vs. 50 t 3 mmHg before perininformation. Absolute values of spectral moduli are sendopril administration) and to vasopressin (0.1 t 0.8 sitive to the total power, that is, of the variance, and mmHg after vs. 40 & 3 mmHg before AVPx administratheir use rather than that of normalized values may tion). The only significant modification of BP spectra in influence the interpretation of results. However, absolute LN RASx rats was an increase of the cumulative modulus values better reflect the true changes in variability. in the HF band of BP spectra compared with baseline When one considers the BP and HR spectra obtained values (SBP: 101 t 8 vs. 86 t 9 mmHg/Hzli2; DBP: 67 in baseline conditions in LN rats, three distinct peaks + 4 vs. 57 t 7 mmHg/Hz’j2). LN AVPx rats exhibited were observed that allowed the definition of three freonly an increase of the cumulative modulus in the HF quency bands. Similar data could be obtained in humans band in SBP spectra compared with the baseline value or dogs but at lower frequencies than in rats (2, 23). The (96 t 4 vs. 84 t 5 mmHg/Hz ‘12). After combined RAS VLF band (0.015-0.25 Hz) reflects slow oscillations with and vasopressin V, receptor blockade, as shown in Fig. 3E, the LF and HF cumulative moduli of SBP were periods between 4 and 67 s that are likely to result from increased. Furthermore, the moduli of LF and HF peaks various simultaneous influences including behavior. Beand nonstationof SBP and DBP spectra were also significantly en- cause of their probable nonperiodicity arity and the poor time resolution of the FFT in this hanced. band, a precise study of VLF oscillations will require another type of analysis. The LF peak was found to be BP and HR Spectral Components in LH Rats -0.40 Hz (period 2.5 s) as reported by Japundzic et al. Figure 4, A and B, gives chronograms and spectra of (13) but not by Akselrod et al. (l), who found it to be SBP, DBP, and HR obtained from data recorded in one between 0.10 and 0.30 Hz in Wistar-Kyoto or spontaLH rat. As indicated in Table 2, LH differed from LN neously hypertensive rats. Its modulus, normalized with by 1) a LF peak in SBP and DBP spectra that could not the total power, was higher in DBP than in SBP and HR be detected in all the rats, and, when the peak existed, spectra. It is noteworthy that the LF peak was found to its frequency was significantly lower, and 2) the HF peak be highly reproducible over time and exhibited a low frequency was significantly higher for all three parameinteranimal variability. The HF peak was -1.1 Hz ters, and this peak could be detected in three rats only (period 0.9 s) in our study, and this agrees with previous for DBP. The VLF cumulative moduli of SBP and DBP findings in spontaneously hypertensive or Wistar rats spectra were higher in LH rats than in LN rats (Fig. 4C) (l-l.5 Hz) (1, 13). It has been shown to depend on as was the HF cumulative modulus of DBP spectra, respiratory rate and indeed, in anesthetized and artifiwhereas HR spectra of LH rats exhibited smaller cu- cially ventilated rats, we found its frequency to match mulative moduli in VLF and LF bands. exactly that of the ventilation (data not shown). Its relative modulus was higher in SBP and HR than in DBP, which suggests that the HF peak could reflect the DISCUSSION effect of variations in the intrathoracic pressure on the Spectral analysis of BP and HR in conscious unrevenous return and the ejection volume. As DBP is mainly strained rats has been studied very little (1, 5, 13), dependent on the peripheral resistances, it appears logialthough it should provide a powerful tool to analyze cal that this parameter was less affected by respiration. variability and give access to the time scaling of BP When the relationships between the autonomic nerregulation. The studies performed in humans or in dogs vous system and these rapid fluctuations of BP and HR used either the FFT (2, 6, 25) or an autoregressive were considered, the various pharmacological experimodelization (11, 12, 23) to compute spectral power. ments reported here allow the following conclusions. Some theoretical considerations (17) lead to the preferFirst, the LF oscillations of BP were demonstrated to ence of the autoregressive method to avoid restrictive reflect the influence of the sympathetic fibers acting on hypotheses such as stationarity and side effects. Neverthe cardiovascular system through cy- more than P-adretheless, the FFT method was chosen because of the noceptors. The importance of the sympathetic nervous similar conclusions reached by the authors whatever system (SNS) fibers was clearly shown by the disappearmethod used and because of the easier implementation ance of the LF peak and the large reduction of the of algorithms. To ensure correct computations, the linear cumulative moduli of the LF band after chronic lesion of trend of each data segment was subtracted, the second these fibers by guanethidine, which suppressed the presorder stationarity was verified, and side effects were sor response to tyramine. An acute blockade of CY-and premoved using a classical windowing in the time domain adrenoceptors induced the same effects and, in that (22). Another methodological point concerns the choice respect, phentolamine was more efficient than propranof the expression of frequency in cycles per second (in 0101. In addition, the increase of LF oscillations of BP Hz) rather than in cycles per cardiac beat. Authors that after atropine reflects the lack of direct influence of the developed mathematical models to describe the cardioparasympathetic system on these oscillations and sugvascular function chose beat-by-beat expression (4,8) so gests an enhanced stimulation of the sympathetic fibers. ined, a HF peak was detectable LN ATR rats (Table 2).
in only one of the seven
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H1298
SPECTRAL
ANALYSIS
OF
BLOOD
PRESSURE
Hf
AND
HEART
RATE
B
C 100 00 00 40 P ?!
0
10
20
30 TIME
FIG. 4. Time course bands for systolic (SBP) in LN and LH rats. *P
40
50
60
70
0
0.4
(mc)
12
1.6
FREQUENCY
(A) and corresponding and diastolic
0.8
(DBP)
2.0
2.4
2.8
0
3.2
(Hz)
spectra (B) in very low (VLF), low- (LF), and high-frequency blood pressures and heart rate (HR) in 1 LH rat. C: cumulative
FREQUENCY
BAND
(HF) moduli
< 0.05 vs. LN.
Such a role of the SNS in the LF oscillations of BP is in accordance with other reports. When the cardiovascular system was considered to be a closed-loop feedback system in humans, several authors (2, 4, 8) suggested that the LF peak, located -0.1 Hz, may be generated by a resonance phenomenon of the sympathetic control loop of the baroreflex. In dogs, pharmacological blockade, chronic stellectomy, or sinoaortic denervation also decreased the LF oscillations (2, 23, 26). The most recent studies (23, 26) suggest that the LF peak of BP could be a nonspecific marker of the sympathetic vascular control. In the present work, the influence of alterations of the SNS activity was especially marked on the LF band of DBP spectra. As DBP depends on the vascular resistances and because LF oscillations of DBP were highly reproducible, we suggest that the moduli of the LF band may be an interesting index of the influence of sympathetic fibers on the vascular walls. In that respect, the enhanced LF peak of DBP spectra observed after RAS or vasopressin receptor blockade is likely to be due to a compensatory increase in sympathetic drive (2). Concerning HR, the results observed after adrenergic and parasympathetic blockade suggest that the oscillations in LF partially depend on both systems, and this agrees with results obtained in humans (2, 25). We cannot conclude for rats as some authors did for humans or dogs (23, 26) that the LF peak of HR is a nonspecific marker of the sympathetic activity directed to the sinoatrial node. Second, the HF peak of HR spectra was almost abolished by atropine, which demonstrates that it reflects the respiration-dependent control of HR by the vagus. On the contrary, the HF peaks were enhanced in BP spectra, which may account for a buffering role of the parasympathetic system in BP oscillations at respiratory frequency as has already been suggested (7). The SNS
does not influence the HF features of BP spectra; however, SNS does participate, by means of P-receptor activation, in the HF oscillations of HR. Because a direct influence of cy- or P-receptor stimulation on such rapid oscillations is unlikely, this result may be explained by a diminished vagal tonus in response to the decrease in BP induced by the adrenergic receptor blockade. Therefore, it can be suggested that the HF peak of HR spectra only could be an index of the vagal influence on the cardiovascular system. The influence of humoral systems, such as RAS and vasopressin, on the BP and HR spectra was insignificant, which is not surprising since the frequencies of the oscillations studied are much too high to be controlled by such slow-acting factors. Finally, where LH rats that exhibit an increase in DBP variability over 24 h (15, 29) are concerned, the present work demonstrates that LH rats differ from LN controls by 1) an increase of HF oscillations of DBP, which may be linked to the similar increase observed after parasympathetic blockade in LN rats and to the impairment of the vagal component of the cardiac baroreflex in LH rats (18), 2) an elevated frequency of the HF peak that reflects an elevated respiratory frequency, and 3) in DBP spectra a less distinct and less frequent LF peak but no change in the cumulative modulus of the band. This latter finding is in good agreement with lower urinary excretion of catecholamines exhibited by adult LH rats compared with LN controls (14) and further supports our hypothesis that the LF peak of DBP spectra is an index of the SNS activity on the cardiovascular system. In conclusion, spectral analysis of beat-to-beat variability of BP and HR continuously recorded in conscious freely moving rats should be an interesting tool as it gives access to 1) the respiratory rate with the HF peak frequency, 2) an index of the vagal cardiac control with
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SPECTRAL
ANALYSIS
OF
BLOOD
PRESSURE
the HF peak of HR, and 3) an index of the sympathetic control of the peripheral resistances with the LF peak of DBP.
15. JULIEN
We acknowledge the Institut National de la Sante’et de la Recherche Medicale for its financial support (CRE 89-5001/11). Address for reprint requests: C. Cerutti, Departement de Physiologie et Pharmacologic Clinique, Faculte de Pharmacie, 8 avenue Rockefeller, 69373 Lyon Cedex 08, France Received 5 July 1990; accepted in final form 23 May 1991. REFERENCES S., S. ELIASH, 0. Oz, AND S. COHEN. Hemodynamic regulation in SHR: investigation by spectral analysis. Am. J. Phys-
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