comparing spectral and invasive estimates of baroreflex gain

Comparing Spectral andInvasive Estimates ofBaroreflex GainCan Power Spectral Analysis Reproducibly EstimateChanges in Baroreflex Sensitivity?

One of the new methods to evaluate thesensitivity of the baroreceptor-heart

rate (HR) reflex involves the use of powerspectral analysis to calculate the transferfunction between blood pressure and HR.In this article, we assess the applicabilityand reproducibility of the baroreflex gainestimated by this method with traditional“invasive” techniques that induce rampchanges in mean arterial pressure (MAP)in conscious rabbits. Renal sympatheticnerve activity recordings are used to iden-tify the mid-frequency band, and we alsoidentify coherent fluctuations of MAPand HR with a 1.8 s phase delay, consis-tent with a baroreflex relationship andtherefore appropriate to estimate the crossspectral transfer function.

OverviewThe original method for assessing car-

diac reflexes in humans was the rampmethod originally developed by Sleightand colleagues [1]. This technique in-volved producing a relatively linear“ramp” rise in blood pressure by means ofpressor drugs such as phenylephrine. Thismethod was later extended to include aramp decrease in blood pressure producedby dilator drugs such as glyceryl trinitrate.In either case, the systolic blood pressureof each pulse is plotted against the periodof the succeeding cardiac beat, which pro-duces a straight-line relationship fromwhich the slope gives an indication of thebaroreflex sensitivity. However, baroreflexcurves are S-shaped rather than linear [2],and so a nonlinear (sigmoidal) regressionwas developed, which allowed the full ex-tent of the S-shaped baroreflex curve to becharacterized [2].

In order to determine the upper andlower HR plateaus, large increases and

decreases in blood pressure were neces-sary. Rather than a ramp change in bloodpressure, Korner and colleagues devel-oped a step change in pressure technique,called “steady state,” which allowed suffi-cient time for the cardiac sympatheticnerves to respond [3]. This method wassoon applied to humans [4]. However,there is justifiably increasing reluctanceto subject patients to large changes inblood pressure (BP), and thus there hasbeen increasing interest in the develop-ment and use of noninvasive measures ofbaroreceptor reflexes [5]. These newermethods quantify the naturally occurringvariations in HR and/or BP often usingspectral analysis, where oscillations atdistinct frequencies are considered to re-flect predominantly vagal with some sym-pathetic influences [6, 7].

The baroreflex gain/sensitivity hasbeen determined using spectral tech-niques by calculating the transfer gainfunction between arterial BP and HR atfrequencies associated with the oscilla-tions produced by the autonomic nervoussystem [8]. In humans, this index ofbaroreflex gain is determined at frequen-cies thought to reflect oscillations pro-duced by the parasympathetic andsympathetic nervous system, althoughtheir relative contributions are still some-what controversial.

Other techniques that have been devel-oped include the sequence technique,which uses series of three to five heartbeats and separates those series wherepulse interval and BP change in the samedirection (barosequences) from thosewhere the two variables go in different di-rections (non-barosequences) [6]. The av-erage slopes of the former indicate thebaroreflex sensitivity. Thus, naturally oc-

March/April 2001 IEEE ENGINEERING IN MEDICINE AND BIOLOGY 430739-5175/01/$10.00©2001IEEE

Geoffrey A. Head, Elena V. Lukoshkova,Sandra L. Burke, Simon C. Malpas,

Elisabeth A. Lambert, Ben J.A. JanssenNeuropharmacology Laboratory,

Baker Medical Research Institute, Prahran

©19

89-9

7Te

chPo

olStu

dios,

Inc.

curring changes, as opposed to experi-mentally induced changes, in BP and HRare used to determine baroreflex sensitiv-ity. The spectral and sequence methods,as applied to humans, appear in mostcases to give quite similar values ofbaroreflex sensitivity estimated by thephenylephrine response. There is gener-ally a good correlation among the esti-mates from the three methods [9, 10],although some studies have shown weakcorrelation and some systematic bias [11].

Despite the increased application ofthese methods to a variety of conditions,not only in humans but also animals, therehas been only limited validation of theseapproaches to estimate baroreflex sensitiv-ity. Our laboratory has examined thebaroreceptor HR reflex in conscious rab-bits and rats under a variety of experimen-tal conditions [12-16]. However, not allsituations where knowledge of thebaroreflex is desirable are applicable to thelaboratory situation or conducive to thedrug method where catheters and some de-gree of restraint of the animal is necessary.In order to effectively use the dynamicmethods, it is important to understand whatthey indicate in terms of baroreflex func-tion. However, for the rabbit at least, therehas been no systematic comparison of thedynamic and invasive baroreflex methods,nor is it clear which frequency band willgive an appropriate estimate of thebaroreflex gain. On the latter question,Marano and colleagues found a low-fre-quency peak in HR at 0.086 Hz and ahigh-frequency peak at 0.68 Hz, which isclose to the respiratory frequency of the

rabbit [17]. By contrast, other studieshave found no clear peaks [18].

The aim of the current study, therefore,was to compare the spectral “dynamic”methods of baroreflex assessment with“invasive” techniques in conscious rabbitsunder various experimental perturbations.Our approach was initially to define thefrequencies in the BP power spectrum thatmay reflect the sympathetic nervous sys-tem activity obtained from a direct record-ing of renal sympathetic nerve activity(RSNA) in conscious rabbits. This wassimilar to the approach of Brown and col-leagues, who found that sympathetic nerveactivity of conscious rats was closely cou-pled with BP at 0.4 Hz [19]. The sympa-thetically driven BP fluctuations would beexpected to produce baroreflex-inducedchanges in HR. Having determined the“sympathetic” frequency range with thehighest coherence between BP and HR, wecompared the spectral approach with twotraditional reference methods (drug infu-sion and balloon cuff) for determiningbaroreflex gain in normotensive, hyperten-sive, and sino-aortically denervated (SAD)animals.

Materials and MethodsAnimals

Experiments were performed in con-scious male and female rabbits crossbredfrom Baker Medical Research Institutestock, weighing 2.6-2.90 kg, in accor-dance with the Australian Code of Prac-tice for the Care and Use of Animals forScientific Purposes. All rabbits werehoused under controlled temperature, hu-midity, and a dark-light cycle (12 h/12 h).They were fed a restricted diet of pellets(0.5% sodium chloride) and vegetables,but with water ad libitum.

Measurement ofCardiovascular Variables

On the day of the experiment, the rab-bit was placed in a standard rabbit box,and the central ear artery and marginal earvein were cannulated transcutaneouslywith a 22-gauge, 25 mm Teflon catheter(Jelco, Critikon, Italy) under local anes-thesia with 1% procaine (Citanest, AstraPharmaceuticals, Australia). The arterialcatheter was then connected to a StathamP23DC pressure transducer for continu-ous measurements of MAP and HR, andthe animal was allowed a one-hour recov-ery period before commencing the experi-ment. The intravenous catheter wasconnected to a triple lumen line for the ad-

ministration of drugs without the need toflush the catheter between injections. Thevenous catheter was kept patent by infus-ing heparinized saline (3 ml/hour, 12units/ml). Arterial pressure and RSNAsignals (in four rabbits) were digitized at500 Hz using a National Instruments(Austin, TX, USA) data acquisition card(ATMI016 or PC plus) and a data acquisi-tion program written in LabVIEW graphi-cal programming language (NationalInstruments, Austin, TX, USA). MAPwas calculated instantaneously by thecomputer software, which detected sys-tolic and diastolic pressures as well asinter-heart beat interval and instantaneousHR. All hemodynamic parameters weresaved onto disk in ASCII format. One filecontained values per heart beat and wasused for off-line spectral analysis. A sec-ond file with values averaged over 2 s wasalso saved to disk and later used for theramp analysis.

Experimental ProtocolsForty-six rabbits were divided into

five groups, with each group undergoing adifferent protocol or treatment. In eachgroup, BP and HR were monitored for a20 to 30 min period. These data were usedfor determination of baroreflex gain bycalculation of the transfer gain betweenBP and HR using spectral analysis, afterwhich a ramp baroreflex assessment wasperformed.

Group 1 rabbits ( )n = 4 were instru-mented for recording RSNA to determinethe mid-frequency regions in BP and HRthat oscillate in response to rhythmic fluc-tuations in the autonomic nervous system.A bipolar renal nerve electrode was im-planted under halothane anesthesia afterinduction with propofol (Diprivan, ICI,Australia, 1 mg/kg) according to themethod of Dorward and colleagues [20] atleast five days before the experiments. Theleft kidney was exposed by retroperitonealapproach and the renal nerve was identi-fied using a dissecting microscope and wasplaced inside a coiled pair of electrodes.The nerve and recording electrode was in-sulated from the surrounding tissue bySilGel (604, Wacker-Chemie, Munich,Germany). On the day of the experiment,the end of the electrode was retrieved fromunder the skin using local anesthetic, andthe original RSNA signal was amplified10,000-100,000 times, filtered between50-5000 Hz, and integrated using a “leaky”integrator with a time constant of 20 ms.The baseline or zero position of the RSNA

44 IEEE ENGINEERING IN MEDICINE AND BIOLOGY March/April 2001

The phase of the

transfer function

indicates the temporal

relationship between

the signals in the

frequency domain.

recording system was set to the averagevalue of the recording during “silent peri-ods” between bursts of RSNA. Spectralanalysis of this integrated RSNA signalwas conducted on a 20 min period ofquiet rest.

Group 2 rabbits ( )n = 9 were SAD un-der halothane anesthesia using the methodfrom [21]. Cardiac baroreflex gain wasdetermined in these rabbits 7-10 days postdenervat ion using intravenousnitroprusside and phenylephrine. Group 3( )n = 7 were normotensive conscious rab-bits in whom baroreflexes were deter-mined using an infusion of phenylephrineand nitroprusside into the ear vein [22].

Group 4 ( )n = 18 were normotensiverabbits in whom baroreflexes were deter-mined using intravenous infusion ofphenylephrine and caval balloon constric-tion [23]. The use of the caval cuff is astandard method for this species [3], and itavoids giving nitroprusside, which as anititric oxide donor may have direct ef-fects on the sino-atrial node [24]. Thedrug and the cuff methods can also evokea different profile of activation ofbaroreceptor afferents, resulting inslightly different estimates of baroreflexgain [25, 26]. The inflatable caval balloonwas placed around the inferior vena cavain a preliminary operation at least threeweeks prior to the experiments underhalothane (Fluothane, ICI) open-circuitanesthesia, as described previously [3].

Group 5 rabbits were made hyperten-sive via continuous infusion of angioten-sin II for five days ( )n = 8 or for sevenweeks ( )n = 5 (Human; Auspep, Mel-bourne, Australia) into the external jugu-lar vein [27]. Angiotensin II was infusedat a concentration of 50 ng/kg/min usingosmotic mini-pumps (model 2ML4,ALZA Corporation, Palo Alto, USA) im-planted under halothane anaesthesia. Atthe end of the five days or seven weeksthe baroreflex gain was determined usingintravenous infusion of nitroprusside andphenylephrine.

Calculation of Baroreflex Gainby Spectral Methods

The beat-to-beat signals correspond-ing to each 20 min period were analyzedfor spectral analysis using a program de-veloped at the Baker Institute and writtenin LabVIEW. Beat-to-beat data were dis-played on screen for visual inspection,and artifacts due to obstruction of the arte-rial catheter or movement were elimi-nated by initial screening for adjacent R-R

intervals different by more than 200 ms(normal pulse interval is ~300 ms). Suchdata, usually much less than 1%, wereeliminated by interpolation based on thetrend observed from within the normaldata. In order to find periods of relativestationarity during the recording, a run-ning short-term standard deviation (SD)(30 points) was plotted for each variable,and by moving a threshold cursor, periodsof continuously low SD could be sepa-rated from periods of high SD. Usually,5-15 min of the total could be selected forfurther analysis. The data were thenresampled at 5.12 Hz according to meth-ods described by Berger and colleagues[28] and partitioned into segments of 100s (512 points) length, overlapping by50%. The subsequent spectral analysiswas performed according to the Welchperiodogram method [29]. The data werepartitioned into segments and each seg-ment was detrended using linear regres-sion, windowed with a tapered cosinefunction, and padded with zeros up to1024 points. The resulting frequency stepwas 0.005 Hz. The auto- and cross-powerspectra were calculated for each segmentusing the fast Fourier transform and thensubjected to ensemble averaging.

To investigate to what extent fluctua-tions of arterial pressure influence fluc-

tuations in HR, the magnitude and phaseof the transfer function between MAPand HR was calculated. The phase of thetransfer function indicates the temporalrelationship between the signals in thefrequency domain. In addition, thesquared coherence function was calcu-lated using the cross- and auto-power

March/April 2001 IEEE ENGINEERING IN MEDICINE AND BIOLOGY 45

ArterialPressure(mmHg)

ArterialPressure(mmHg)

150

100

50200150100

HeartRate

(b/min)

HeartRate

( )b/min

100

50

300

200

0 20 40 60 80 100 120 40 60 80 100 120Time (s) MAP (mmHg)

Phenylephrine

Nitroprusside

Heart Rate (b/min)

Max Slope =Baroreflex

Gain

300

250

200

150

1. Left Panel (Upper): Traces from one normotensive rabbit showing systolic (up-per) and diastolic (lower) pressures (mmHg) and heart rate (b/min) during restingperiod (before arrow) and during intravenous infusion of phenylephrine (after ar-row). Left Panel (Lower): Traces from the same rabbit showing systolic (upper) anddiastolic (lower) pressures (mmHg) and heart rate (b/min) during resting period(before arrow) and during intravenous infusion of nitroprusside (after arrow). RightPanel: Circles are data points derived from left panels relating mean arterial pres-sure (MAP, mmHg) to heart rate (b/min) averaged over 2 s. A sigmoidal curve hasbeen fitted to the points (solid line) with the average resting value shown as an opensquare. The sigmoidal model explains 97% of the variance.

Which of the spectral

or traditional methods

is best to use depends

on the situation, since

there are advantages

and disadvantages

to both.

spectra. Only periods of data where theaverage coherence estimates were above0.5 where used in the estimation ofbaroreflex gain.

Calculation of Baroreflex Gainby Drug Method

The cardiac baroreflex was assessedover ±30 mmHg using the ramp method,as described previously [20]. For compar-ison with the spectral method, we usedramp changes in BP rather than thesteady-state method, since the relativelyrapid change in BP results in a baroreflexgain that mainly reflects vagal responses,and is less affected by baroreceptor reset-

ting that can occur with the steady-statemethod. We used slow ramp rises and de-clines in MAP induced by intravenous in-fusions of phenylephrine hydrochloride(0.5 mg/ml, Sigma, St Louis, MO, USA)and sodium nitroprusside (1.0 mg/ml,Fluka AG, Switzerland), respectively, orby slowly inflating the vena caval cuff.Ramp injections lasted 0.5-1 min and therate of change in MAP was manually con-trolled between 1 and 2 mmHg/s (Fig. 1).MAP and HR were averaged over 2 s in-tervals and fitted into a sigmoid logisticfunction to produce MAP-HR curvesfrom which the baroreflex gain was calcu-lated (Fig. 1).

Statistical AnalysisValues were expressed as mean ± stan-

dard error of the mean (SEM). Baroreflexand spectral parameters in all cases wereobtained from the same animals, and theywere analyzed by two- or three-way anal-ysis of variance, where the between ani-mal variance was removed from theresidual. A split plot analysis of variancewas used when parameters from differentgroups were compared. Significant ef-fects were taken at the level of P < 0.05.

ResultsSpectral Analysis of the

RSNA NeurogramIn four conscious rabbits with im-

planted renal nerve electrodes (group 1),power spectral analysis was performed onMAP, HR, and RSNA. Under resting con-ditions, there were no clear peaks in theBP or HR spectra, apart from low-fre-quency power below 0.05 Hz. However,we did observe two clear regions in theRSNA spectra. A high-frequency bandcentered around 0.9 Hz corresponded tothe respiratory frequency of the rabbit(~70 breaths/min), and is due to thewell-known respiratory modulation of theRSNA signal [30]. A lower peak was ob-served between 0.2-0.4 Hz in RSNA (Fig.2). Both regions showed significant co-herence of 0.5 between RSNA and MAP(Fig. 2), indicating that oscillations inRSNA are likely to be driving or driven byoscillations in MAP at this frequency.

Effect of Sino-Aortic DenervationIn SAD rabbits (group 2), baroreflex

gain determined by the rampphenylephrine and nitroprusside methodwas significantly reduced compared tothe baroreceptor intact group of threerabbits (Fig. 3). The MAP-HR curve forthe SAD animals was virtually flat, witha range of only 33 b/min compared to 220b/min in intact animals (Fig. 3). Spectralanalysis showed that the total MAPpower in the SAD group was twice that ofthe baroreceptor intact animals (P <0.05). By contrast, the total HR powerwas markedly reduced compared to in-tact animals (Fig. 3, P < 0.05). The abso-lute power in the 0.2-0.4 Hz frequencyband for MAP and HR and the magnitudeof the transfer gain between them werenot significantly different to those ob-served in baroreceptor intact animals.However, compared to intact animals,denervated animals had significantlylower coherence (intact 0.69 ± 0.04, SAD


0.50

0.25

0.00

0.30

0.15

0.00

1.0

0.5

0.0

10

5

0

MA

P P

ower

(m

mH

g)/

Hz

2R

SN

A P

ower

(N

U)/

Hz

2M

AP

-RS

NA

Coh

eren

ceH

R P

ower

(b/

min

)/H

z2

0.0 0.2 0.4 0.6 0.8 1.0

Frequency (Hz)

2. Average data from four normotensive rabbits (group 1) showing spectral power ofmean arterial pressure (MAP, mmHg2, upper panel), renal sympathetic nerve activity(RSNA, nu2, second panel) and heart rate (HR, b/min2, lower panel) and the coher-ence between MAP and RSNA over the frequency from 0 to 1.0 Hz. (third panel) Thedotted lines indicate the mid-frequency band (0.2-0.4 Hz where the average coherencewas 0.5 between RSNA and MAP), and the high-frequency “respiratory related” band(0.75 - 0.95 Hz, with average coherence of 0.5 between RSNA and MAP).

0.45 ± 0.08, P < 0.05) and reversed phasedelay (intact −2.1 radians, SAD +0.5 ra-dians, P < 0.05, Fig. 3) at this frequencyband. The latter was sufficient to makethe fluctuations in MAP and HR concur-rent; i.e., the two oscillations occurredtogether with their peaks and troughswithin 0.3 s of each other (normally, de-lay is 1.1 s in HR in intact animals).

Spectral Analysis ofHeart Rate and Blood PressureThe MAP and HR spectrum and the

cross-spectral coherence, transfer gain,and phase angle between MAP and HRfrom seven normotensive rabbits (group3) were averaged, as shown in Fig. 4. The0.2-0.4 Hz frequency band, which is theregion where peaks were observed inRSNA, showed a high degree of coher-ence between the two signals of 0.78 ±0.04 (range 0.63-0.94) and was the high-est coherence of any frequency examined(< 1.4 Hz). In the respiratory frequencyband, the coherence was significantly

lower (0.58). As shown in Fig. 4, therewere no distinct peaks in the 0.2-0.4 Hzband, although some could be seen in in-dividual spectra of two of the animals.This region represented only 9% of thepower for MAP and 22% of the HRpower. The average transfer gain, esti-mated from the cross spectra betweenMAP and HR, was −6.2 ± 0.2b/min/mmHg, with an average phase of−2.1 radians, corresponding to phase an-gle of −1.1 ± 0.1s (Fig. 4). This indicatesthat in this frequency band, changes in ar-terial pressure lead the change in HR.Thus, the delay between the rise in MAPand the opposite reflex change in HR isapproximately 2.8 s.

We chose the 0.2-0.4 Hz frequencyrange for subsequent analysis of theMAP-HR transfer gain due to i) the pres-ence of the main RSNA peak, ii) an appro-priate phase delay, and iii) the highestdegree of coherence between the MAPand HR.

Comparison of Spectral and RampAssessments of Baroreflex GainThe maximum baroreflex MAP-HR

gain, which is the maximum slope of the fit-ted curve obtained from the ramp method,was determined in two normotensive groupsof rabbits (groups 3 and 4) and the eight hy-pertensive (group 5) rabbits, and comparedto the values obtained from the cross spectra(Fig. 4). In seven normotensive rabbits(group 3), the baroreflex gain assessed by theinfusions of phenylephrine and nitroprussidewas −6.8 ± 0.4 b/min/mmHg, which wasclosely similar to the gain determined fromthe average transfer gain between MAP andHR using spectral analysis (−6.2 ± 0.2b/min/mmHg) (Fig. 5). However, in the 18animals in whom the perivascular cuffmethodwasused to lowerandphenylephrineused to increase MAP, the average maxi-mum baroreceptor- heart rate reflex gain wassignificantly higher (−8.0 ± 0.4b/min/mmHg, P < 0.05) than that estimatedby the spectral technique.


(a) Spectral Analysis (b) Ramp

Total MAP Power MAP Power 0.2-0.4 Hz Gain Gain

50

40

30

20

10

0

(mm

Hg2 )

(mm

Hg2 )

(b/m

in/m

mH

g)

(b/m

in/m

mH

g1−

−1)

0.8

0.4

0.0

400

200

0

(b/m

in2 )

(b/m

in2 )

(rad

ians

)

−8 −8

−6 −6

−4 −4

−2 −2

−0 −0

Total HR Power HR Power 0.2-0.4 Hz Phase

40

20

0

−4

−3

−2

−1

0

1

2

3

300

200

100

HR(b/min)

SAD

Intact

40 80 120MAP (mmHg)

Intact SAD

3. (a) Spectral analysis in intact (group 3, n = 7, open bars) and sino-aortically denervated (group 2, n = 9, hatched bars) rabbits.Panels show total spectral power and 0.2-0.4 Hz power for mean arterial pressure (mmHg2) and heart rate (b/min2), spectraltransfer gain (b/min/mmHg), and phase between blood pressure peak and heart rate (phase, radians). (b) (upper): Estimation ofbaroreflex ramp gain in same intact (open bars) and sino-aortically denervated (hatched bars) rabbits; (lower): heart ratebaroreflex curves in intact (black line) and sino-aortically denervated (gray line) rabbits. Circles on the curves represent restingvalues (open circle intact, solid circle denervated). * Significant (P < 0.05).

The rabbits that were made hyperten-sive with an IV infusion of angiotensin IIfor one week (group 5) had markedlyhigher MAP and a slightly lower HR com-pared to normotensive animals (MAP =119 ± 5 mmHg, HR =174 ± 6 b/min). Thebaroreceptor-heart rate reflex gain wassignificantly less than the values observedin normotensive animals (−4.4 ± 0.7b/min/mmHg), with the gains estimatedby the ramp and spectral techniques notsignificantly different (Fig. 4). In theseanimals, however, the phase of −0.96 ±0.08 radians and coherence of 0.57 werenot significantly different from those innormotensive animals (see above for val-ues, P = 0.7 for difference, n = 11), indi-cating that although changes in arterialpressure no longer induced the sameamount of change in HR, the change thatwas present occurred with the same timedelay. Baroreflexes were also measured infive of these animals after seven weeks ofangiotensin II infusion (MAP = 112 ± 6mmHg, HR = 179 ± 6 b/min), at whichtime the baroreceptor-heart rate reflex

gain estimated by both ramp and spectralmethods remained less than values ob-served in normotensive animals, andclosely similar to the values at one weekof hypertension (Fig. 5).

Reproducibility ofGain Measurements

The reproducibility of baroreflex gainwas determined by estimating spectraland ramp (drug/cuff) methods on fivesubsequent occasions (each on a separateday, one week apart) in the same 18 ani-mals of group 4. The individual data andmeans are shown in Fig. 6. While therewas considerable variation between esti-mates from individual rabbits, thereproducibility as indicated by the varia-tion, was similar for the two methods. Thecoefficient of variation (which includedbetween-animal estimates) was 36% forthe ramp method and 33% for the spectralmethod, which is similar for the two meth-ods but much higher than other variablessuch as HR (17%) and MAP (8%). Analy-sis of variance showed a significantly

greater baroreceptor-heart rate reflex gainby the ramp method compared to the spec-tral method (P < 0.001, as also shown inFig. 5). Both were reproducible withineach method, as shown by the similar av-erage values across time (maximum vari-ation between means 5% and 17% forramp and spectral methods, respectively).Reproducibility was also indicated by thesignificance of the between-animals ef-fect (P < 0.05).

Correlation Between Methods inIndividual Normotensive

and Hypertensive AnimalsThe data from the 18 normotensive an-

imals (group 4) and the 8 rabbits made hy-pertensive for one week by angiotensininfusion (group 5) were combined for de-termining the correlation between thebaroreceptor-heart rate reflex gain esti-mated by the spectral and ramp methods.There was a significant linear relationshipbetween the two estimates, with a reason-able degree of correlation between thetwo methods (r = 0.63, P < 0.001, n = 26,Fig. 7). The slope of the line was 0.3, withan intercept greater than zero, indicatingsystematic bias between the two mea-sures. As most of the studies correlatingthese two estimates are in humans, wherepulse interval (heart period) is used, wealso calculated the regressions for gain interms of heart period. In this case, wefound a similar linear relation between thespectral and ramp estimates (r = 0.67, P <0.001, Fig. 7) with 0.5 being the slope. HPestimates showed markedly higher coeffi-cient of variation than did those using HR(44% versus 22% respectively).

DiscussionThe present study shows that in con-

scious rabbits the frequency range be-tween 0.2 and 0.4 Hz had the highestcoherence between MAP and HR, and thiscan effectively be used to estimatebaroreceptor-heart rate reflex gain usingcross spectral techniques. The central fre-quency of 0.3 Hz corresponds to that ofthe main sympathetic region and is analo-gous to the 0.1 Hz peak (Mayer wave) inhumans [31] and the 0.4 Hz peak observedin rats [19]. There is a constant relation-ship across species between the restingHR and the frequency of the Mayer wave.In each case, this frequency correspondsto ~11-12 heart beats per wave. The find-ings with rabbits are consistent with thisrelationship, with a 0.3 Hz oscillation oc-curring over 11 heart beats (HR = 200


−40.0 0.2 0.4 0.6 0.8 1.0

Frequency (Hz)

1.0

0.5

0.0

10

5

0

1.0

0.5

0.0

−10

−5

0

0

−2

MA

P S

pect

rum

(mm

Hg

)2H

R S

pect

rum

(b/m

in2 )

Gai

n(b

/min

/mm

Hg)

Coh

eren

ceP

hase

(rad

ians

)

4. Averaged spectral power for mean arterial pressure (MAP, mmHg2) and heartrate (HR, b/min2), coherence, transfer gain (b/min/mmHg), and phase (radians)from 0 to 1 Hz from seven normotensive rabbits. (data averaged from all seven ani-mals of group 3).

b/min). There may also be an upper limitto this relationship, since recent studieshave shown the frequency is also 0.4 Hz inthe mouse [32]. The most popular expla-nation for the mid-frequency peak is that itis a resonance property of the baroreflex,being due to the time constants and delaysin the baroreflex mechanisms [33-36]. Inthe rabbit, the region of 0.2-0.4 Hz iswhere there is a strong fluctuation inRSNA, supporting the view that this issympathetic in origin. Peaks in RSNA at0.2-0.4 Hz are not always apparent underresting conditions, but they can be in-duced by increasing sympathetic activity[37]. Nevertheless, even when RSNApeaks were observed, we saw only verysmall peaks in MAP or HR, and relativelylittle spectral power in this region. ClearHR peaks were observed in this region inabout 25% of spectra from individual ani-mals (e.g., 8 of 30). However, we did ob-serve relatively high coherence and anappropriate phase delay between MAPand HR, suggesting that although theMAP oscillations are small they are ableto induce reflex oscillations in the 0.2-0.4Hz range of HR (baroreflex resonance).Thus, the transfer function can be used ef-fectively to estimate baroreflex sensitivityfor a group of normotensive or hyperten-sive rabbits. Much of the difficulty associ-ated with nonstationary data fromconscious animals has been reduced byour current approach, which uses a “run-ning SD” to choose periods of low vari-ability in MAP and HR.

Our results show that estimates ofbaroreflex gain from such “stationary pe-riods” are generally in close agreementwith the group mean estimates ofbaroreflex gain by the ramp methods. Thiswould not have been the case if thehigh-frequency (0.4-1.4 Hz) or low-fre-quency (0.05-0.2 Hz) bands were used.The gain would be over- and underesti-mated, respectively. A narrow definitionof the respiratory peak (e.g., 0.7-0.9 Hz) isnot a suitable choice, as its location is notconsistent among animals. Furthermore,if a wide HF band is used, the gain ishigher but the coherence is lower (Fig. 4).There appears to be a relatively linear re-lationship between transfer gain and fre-quency (Fig. 4), which is also the case inhumans [38]. This may be due to a greatercontribution of the vagus and lesser con-tribution of the sympathetic to the higherfrequencies, or perhaps due to the propen-sity of arterial baroreceptors to rapidly re-set [33]. The cardiac sympathetic effect


10

8

6

4

2

0

Bar

oref

lex

Gai

n (b

/min

/mm

Hg)

(a)Drug Methodcoh = 0.76

(b)Cuff Methodcoh = 0.70

(c)Drug Methodcoh = 0.57

(d)Drug Methodcoh = 0.70

N = 7 N = 18 N = 8 N = 5

NT NT 1 Week HT 7 Week HT

Spectral Ramp

5. Comparison of spectral transfer gain (open bars) and baroreceptor-HR reflexgain obtained from ramp changes in arterial pressure (hatched bars). (a) Averagegain from seven normotensive rabbits (group 3) in which the drug method was usedto determine baroreflex gain; (b) Average gain from 18 normotensive rabbits (group4) in which a caval cuff was used to lower arterial pressure and phenylephrine usedto raise pressure; (c) Average gain from eight rabbits (group 5) made hypertensivefor one week by peripheral angiotensin infusion and in which the drug method wasused for baroreflex assessments; (d) Average gain from five rabbits made hyperten-sive for seven weeks by angiotensin infusion. *Significant difference between meth-ods, � Significant difference from normotensive (P < 0.05).

0

−5

−10

−15

Gai

n b/

min

/mm

Hg

1 2 3 4 5 1 2 3 4 5Day

Ramp Method Spectral Method

6. Plot of individual estimates (open symbols) of baroreflex gain by the ramp (leftpanel) and spectral (right panel) methods from 18 rabbits (group 5) on five separateoccasions (each separated by one week). Data from individual animals joined by dot-ted lines. Histograms represent the mean values. ANOVA showed that there was sig-nificant variation between animals (P < 0.05) and methods (P < 0.001), but nodifference between days.

on HR has not only a lower gain in con-scious rabbits [39] but also a relativelylong time constant and cannot readilycontribute to fast frequencies such as thatof the respiratory oscillation [12]. Esti-mating baroreflex gain at very low fre-quencies (below 0.2 Hz) is not optimalbecause there would be a tendency for thebaroreceptors to reset more with slow os-cillations, which will have the effect ofunderestimating the gain [40]. Thus, thechoice of the mid-frequency (0.2-0.4 Hz)band is most appropriate to compare withthe ramp method, since there is the high-est coherence between MAP and HR inthis range.

By using repeated estimates in thesame animals, we found that despite therelatively large coefficient of variation of~30%, the mean value estimated for agroup of animals was quite reproducible.The higher variability was most likely dueto the gain being a ratio of two variables,each with its own degree of variability.

While there was a good deal of scatter inthe correlation plots of the two methods(Fig. 7), there was a significant correla-tion between the spectral and drug values,which has also been observed in some hu-man studies [38, 41]. We did not observeany difference in the correlation whenheart period rather than HR was used inthe calculations. While the effect of usingeither measure has been well described[42], we chose in our study to use HR,since it showed a much lower coefficientof variance and is now most commonlyused for rabbits [15]. We observed sys-tematically higher ramp gains in animalswhere a venous cuff was used to deter-mine the reflex, compared to the drugmethod or both spectral estimates, whichis a finding consistent with previous re-ports [43] and may be due to differentialrecruitment of afferents [43]. Both rampand spectral methods give a similarlylower baroreflex gain in hypertensive ani-mals, as would be expected [15, 44, 45].

Which of the spectral or traditionalmethods is best to use depends on the situ-ation, since there are advantages and dis-advantages to both. While the invasivemethod is restricted to the laboratory,where cannulations can be made, it doesgive the full reflex curve and indicatesboth the gain at the center of the curve andthe range of the reflex. This can be partic-ularly important to distinguish betweendifferent mechanisms of influence on thereflex, such as produced by hypertension(fora review, see [15]). Neither the rampnor spectral methods are good for estimat-ing the cardiac sympathetic componentbecause of the long lag for thesympathetics to produce a change in HR,due to the slow change in levels of c-AMPfollowing β-adrenoceptor stimulation. Inthis case, the steady-state method is ap-propriate. The advantage of the spectralmethod is that it can be applied wheneverBP and HR recordings have been made,not only at the time of particular drug ad-ministration. This is particularly useful infreely moving animals, for example,where MAP is recorded by telemetry.

One of the interesting aspects of ourstudy has been the observation that in theabsence of baroreceptors (SAD), oscilla-tions in BP and HR can produce an appar-ent “gain” in the 0.2-0.4 Hz range, similarto baroreceptor intact animals. This con-trasts the recent study of Mancia [46] andcolleagues who found in conscious SADcats that mid-frequency (0.1 Hz) gain wasmarkedly reduced. While these research-

ers observed some inconsistencies in theeffect of SAD on the higher respiratory es-timates, they did recommend using onlythe mid-frequency peak for baroreflex es-timates. It might be concluded that spec-tral methods are not so reliable in therabbit, as they do not appear to distinguishbetween the presence and absence ofbaroreceptors, as does the ramp method.The reduced phase value indicates thatMAP and HR are oscillating together, andnot with the expected “baroreflex delay,”and as such they are most probably notdue to baroreflex mechanisms. This co-herent and in-phase oscillation of BP andHR is normally masked by baroreflex re-sponses when baroreceptors are intact. In-deed, Legremante and colleaguessuggested a feed-forward relationship be-tween MAP and HR from their analysis ofsequences [47]. This relationship may beexpected to result in some apparent gainvalue, with little phase delay betweenMAP and HR.

Thus, we need to use the gain from thespectral method “only” when coherenceand phase delay is appropriate for thebaroreflex. From this point of view, thesequence method has some advantagesover the spectral method, as it has phasebuilt into the algorithm. Furthermore, the“barosequences” and the “non-barose-quences” are readily separated and quan-tifiable [46, 48]. The apparent transfergain we observed may be the spectralequivalent of non-barosequences, whichis the situation when MAP and HR in-crease or decrease together. Thesechanges have been described in intact andSAD animals and in humans [46, 48]. In-deed, in humans, an index of thebaroreflex has been defined as the ratio ofthe barosequences over the total BP ramps[48]. In SAD animals, presumably thenon-barosequence number increasescompared to intact animals, and such os-cillations (BP and HR increasing or de-creasing together) would be evident in thespectral analysis.

In conclusion, our results show thatthe spectral power for MAP and HR inthe frequency range between 0.2 and 0.4Hz is relatively small in conscious rab-bits, but the high coherence betweenMAP and HR means that the transferfunction can be used effectively toreproducibly estimate the baroreflex sen-sitivity for a group of normotensive orhypertensive animals, provided that thephase relationship and coherence be-tween the variables are considered.


−10

−5

0

Spe

ctra

l Gai

n (b

/min

/mm

Hg)

Spe

ctra

l Gai

n (m

s/m

mH

g)

0 −5 −10

Heart Rater = 0.63

−30

−30

−25

−25

−20

−20

−15

−15

−10

−10

−5

−50

Heart Periodr = 0.67

0

Ramp Gain (b/min/mmHg)

Ramp Gain (ms/mmHg)

7. Relationship between baroreflex gainestimated by the spectral method (yaxis) and the ramp method (x axis) us-ing heart rate (upper panel,b/min/mmHg) and heart period (lowerpanel, ms/mmHg). Data from eight hy-pertensive (group 5) and 18normotensive (group 4) rabbits. Linesindicate regression line and 95% confi-dence limits.

AcknowledgmentsThis study at the Baker Medical Re-

search Institute was supported by a BlockInstitute Grant from the Australian Na-tional Health and Medical ResearchCouncil. Dr Elena Lukoshkova was a vis-iting scientist at the Baker Institute sup-ported by the Russian-Australianexchange program. Dr. Simon Malpaswas supported from a project grant by theNational Heart Foundation of Australia.Dr. Ben Janssen was supported by a travelgrant supplied by the Dutch Kidney Foun-dation, the Dutch Heart Foundation, andthe Foundation “De Drie Lichten (TheNetherlands). We are grateful to ShirleyGodwin for her technical assistance and toDmitri Maiorov for the preparation of therenal nerve electrode implanted animals.

Geoffrey A. Head re-ceived his B.Sc.(Hons)in pharmacology fromthe University of Mel-bourne, Australia, in1976 and a Ph.D. fromMonash University,Australia, in 1981. Fol-lowing a postdoctorate

position at the Rudolf Magnus Instituteof Pharmacology, Utrecht, The Nether-lands, and the National Institute ofHealth, Bethesda, Maryland, USA, he re-turned to the Baker Medical Research In-stitute, Melbourne, Australia, in 1985.He currently holds the position of princi-ple research fellow as the head of theNeuropharmacology Laboratory at theBaker Institute, and he is an honorary as-sociate professor with the Department ofPharmacology at Monash University.Geoff’s research interests include the un-derstanding of mechanisms involved inthe control of the heart and circulation bythe central nervous system, including theaction of centrally acting antihy-pertensive agents, baroreflex mecha-nisms in hypertension, CNS control ofrenal sympathetic nerve activity, spectralanalysis, and radiotelemetry.

Elena Lukoshkova re-ceived the B.Sc. degreein physics and mathe-matics and the M.Sc.degree in biophysicsfrom Moscow Instituteof Physics and Technol-ogy, Moscow, Russia,in 1968 and 1970, re-

spectively, and Ph.D. and D.Sci. (biology)degrees from the Institute of Normal and

Pathological Physiology, Academy ofMedical Sciences, Moscow, Russia, in1973 and 1999. Her M.Sc., Ph.D., andD.Sci theses were in the field of centralneural control of circulation. Since 1979she has been a senior scientist of the De-partment of Cardiovascular Regulation atthe National Cardiology Research Center,Moscow, Russia. In 1994-1995, 1996,and 1999 she was also a guest scientist inthe Neuropharmacology Laboratory at theBaker Institute, Melbourne, Australia.Her current research interests include au-tonomic and cardiovascular control, bio-medical signal processing, and analysis offluctuations and oscillations in cardiovas-cular system.

After receiving a B.Sc.(Hons) from SydneyUniversi ty , SandraBurke worked in theElectrophysiology Lab-oratory before joiningthe Baker Medical Re-search Institute in 1979,where she helped de-

velop a chronic renal nerve recordingelectrode. After a period in Bad Nauheim,Germany, where she studied temperatureregulation, she gained her M.Sc.(Monash) in physiology in 1990. In theNeuropharmacology Laboratory at theBaker Institute, Sandra has studied car-diovascular control during hemorrhageand hypertension using techniques suchas single fiber and chronic sympatheticnerve recording as well as microinjectiontechniques to determine central neural re-ceptors and pathways.

Simon Malpas receivedhis B.Sc. (Hons) inphysiology from Victo-ria University, Welling-ton, New Zealand in1986 and a Ph.D. fromthe University of Otago,Dunedin, New Zealand,in 1990. This was fol-

lowed by postdoctoral research at the Na-tional Cardiovascular Research Center,Osaka, Japan; the Department of Physiol-ogy, University of Birmingham, UnitedKingdom; and at the Baker Medical Re-search Institute, Melbourne, Australia. Hecurrently holds the position of senior lec-turer and head of the Circulatory ControlLaboratory in the Department of Physiol-ogy, University of Auckland, New Zea-land. Simon’s research interests focus onthe how the sympathetic nervous systemcontrols blood pressure. A particular fo-cus is on the dynamic relationship be-

tween sympathetic activity, renal bloodflow, and blood pressure.

Elisabeth Lambert, as part of her Ph.D.candidature at the Medical University ofParis, spent one year at the Baker MedicalInstitute in Australia examining the influ-ence of brain angiotensin II on cardiovas-cular reflexes. In 1997, she was therecipient of an award from the French So-ciety of Hypertension and conductedstudies in Paris and Lyon investigating theassociation between blood pressure vari-ability and arterial compliance. She hasrecently returned to Australia and is cur-rently working in the Human Neuro-transmitter laboratory at the BakerInstitute, working on a variety of cardio-vascular diseases including subarach-noid hemorrhage.

Ben Janssen was born in Sittard, TheNetherlands (NL), in 1958. He receivedthe M.S. degree in biology from the Uni-versity of Nijmegen, NL, in 1983 and thePh.D. degree in pharmacology from theUniversity of Maastricht, NL, in 1988. Heis currently an assistant professor in theDepartment of Pharmacology and in theCardiovascular Research InstituteMaastr icht of the Universi ty ofMaastricht, NL. His research interests arefocussed on integrative hemodynamiccontrol mechanisms and autonomic phar-macology in diseases of the cardiovascu-lar system.

Address for Correspondence: Dr.Geoffrey A. Head, Baker Medical Re-search Institute, P.O. Box 6492, St KildaRd. Central, Melbourne, Victoria, 8008,Australia. Phone: +61 3 5224333 Fax:+61 3 5211362. E-mail: [email protected].

References1. Smyth HS, Sleight P, and Pickering GW: Re-flex regulation of arterial pressure during sleep inman: A quantitative method of assessingbaroreflex sensitivity. Circ Res 24: 109-121,1969.2. Kent BB, Drane JW, and Manning JW:Suprapontine contributions to the carotid sinus re-flex in the cat. Circ Res 29: 534-541, 1971.3. Korner PI, Shaw J, West MJ, and Oliver JR:Central nervous system control of baroreceptorreflexes in the rabbit. Circ Res 31: 637-652, 1972.4. Korner PI, West MJ, Shaw J, and Uther JB:“Steady-state” properties of the baroreceptor-heart rate reflex in essential hypertension in man.Clin Exp Pharmacol Physiol 1: 65-76, 1974.5. Parati G , Di Rienzo M , and Mancia G, Neu-ral cardiovascular regulation and 24-hour blood


pressure and heart rate variability. Ann N Y AcadSci 783: 47-63, 1996.6. Parati G, Saul JP, Rienzo M Di, and ManciaG: Spectral analysis of blood pressure and heartrate variability in evaluating cardiovascular regu-lation. J Hypertension 25: 1276-1286, 1995.7. Hughson RL, Quintin L, Annat G,Yamamoto Y, and Gharib C: Spontaneousbaroreflex by sequence and power spectral meth-ods in humans. Clin Physiol 13: 663-676, 1993.8. Robbe HWJ, Mulder LJM, Ruddel H,Langewitz WA, Veldman JBP, and Mulder G:Assessment of baroreceptor reflex sensitivity bymeans of spectral analysis. Hypertension 10:538-543, 1987.9. Honzikova N, Fiser B, and Honzik J:Noninvasive determination of baroreflex sensi-tivity in man by means of spectral analysis.Physiol Res 41: 31-37, 1992.10. James MA, Panerai RB, and Potter JF: Ap-plicability of new techniques in the assessment ofarterial baroreflex sensitivity in the elderly: Acomparison with established pharmacologicalmethods. Clin Sci 94: 245-253, 1998.11. Maestri R, Pinna GD, Mortara A,LaRovere MT, and Tavazzi L: Assessingbaroreflex sensitivity in post-myocardial infarc-tion patients: Comparison of spectral andphenylephrine techniques. J Am Coll Cardiol 31:344-351, 1998.12. Head GA and McCarty R: Vagal and sym-pathetic components of the heart rate range andgain of the baroreceptor-heart rate reflex in con-scious rats. J Auto Nerv Syst 21: 203-213, 1987.13. Head GA, Elghozi J-L, and Korner PI:Baroreflex modulation of central angiotensin IIpressor responses in conscious rabbits. J Hyper-tension 6(Suppl 6): S505-S507, 1988.14. Minami N and Head GA: Effect ofperindopril on the cardiac baroreflex in consciousspontaneously hypertensive (SHR) and stroke pronehypertensive rats (SHRSP). In Genetic Hyperten-sion, vol. 218, J. Sassard (Ed.) Paris: INSERM/JohnLibbey Eurotext Ltd, 1992, pp. 69-71.15. Head GA: Cardiac baroreflexes and hyper-tension. Clin Exp Pharmacol Physiol 21:791-802, 1994.16. Godwin SJ, Tortelli CF, Parkin ML, andHead GA: Comparison of the baroreceptor-heartrate reflex effects of rilmenidine, moxonidine andclonidine. J Auto Nerv Syst 72: 195-204, 1998.17. Marano G, Grigioni M, Tiburzi F, VergariA, and Zanghi F: Effects of isoflurane on cardio-vascular system and sympathovagal balance inNew Zealand white rabbits. J CardiovascPharmacol 28: 513-518, 1996.18. Moguilevski VA, Shiel L, Oliver J, andMcGrath BP: Power spectral analysis ofheart-rate variability reflects the level of cardiacautonomic activity in rabbits. J Auto Nerv Syst 58:18-24, 1996.19. Brown DR, Brown LV, Patwardhan A, andRandall DC: Sympathetic activity and bloodpressure are tightly coupled at 0.4 Hz in consciousrats Am J Physiol 36: R1378-R1384, 1994.20. Dorward PK, Riedel W, Burke SL, Gipps J,and Korner PI: The renal sympathetic baroreflex

in the rabbit. Arterial and cardiac baroreceptor in-fluences, resetting, and effect of anesthesia. CircRes 57: 618-633, 1985.21. Chalmers JP, Korner PI, and White SW:The relative roles of the aortic and carotid sinusnerves in the rabbit in the control of respiration andcirculation during arterial hypoxia andhypercapnia. J Physiol (Lond) 188: 435-450, 1967.22. Maiorov DN, Malpas SC, and Head GA: In-fluence of the pontine A5 region on renal sympa-thetic nerve activity in conscious rabbits. Am JPhysiol 278: R311-R319, 2000.23. Gaudet E, Godwin S, and Head G: Effectsof central infusion of angiotension II and losartanon baroreflex control of heart rate in rabbits Am JPhysiol 278: H558-H566, 2000.24. Musialek P, Lei M, Brown HF, PatersonDJ, and Casadei B: Nitric oxide can increaseheart rate by stimulating the hyperpolarization-activated inward current, I(f). Circ Res 81: 60-8,1997.25. Faris IB, Iannos J, Jamieson GG, andLudbrook J: Comparison of methods for elicit-ing the baroreceptor-heart rate reflex in consciousrabbits. Clin Exp Pharmacol Physiol 7: 281-291,1980.26. Weinstock M, Korner PI, Head GA, andDorward PK: Differentiation of cardiacbaroreflex properties by cuff and drug methods intwo rabbit strains. Am J Physiol 255: R654-R664,1988.27. Groom AW and Malpas SC: Baroreflex con-trol of heart rate during hypoxia and hypercapniain chronically hypertensive rabbits. Clin ExpPharmacol Physiol 24: 229-234, 1997.28. Berger RD, Akselrod S, Gordon D, and Co-hen R: An efficient algorithm for spectral analy-sis of heart rate variability. IEEE Trans BiomedEng 33: 900-904, 1986.29. Kay SM and Marple SL: Spectrum analysis -A modern perspective. Proc IEEE 69, 1981.30. Dorward PK, Burke SL, Janig W, andCassell J: Reflex responses to baroreceptor,chemoreceptor and nociceptor inputs in single re-nal sympathetic neurones in the rabbit and the ef-fects of anaesthesia on them. J Auto Nerv Syst 18:39-54, 1987.31. Akselrod S: Spectral analysis of fluctuationsin cardiovascular parameters: A quantitative toolfor the investigation of autonomic control. TrendsPharmacol Sci 9: 6-9, 1988.32. Janssen BJ, Leenders PJ, and Smits JF :Short-term and long-term blood pressure and heartrate variability in the mouse. Am J Physiol RegulIntegr Comp Physiol 278: R215-R225, 2000.33. DeBoer R, Karemaker J, and Strackee J:Hemodynamic fluctuations and baroreflex sensi-tivity in humans: A beat-to-beat model. Am JPhysiol 253: 680-689, 1987.34. Wessel ing KH and Settels JJ:Baromodulat ion explains short termblood-pressure variability. In Psychophysiologyof Cardiovascular Control, JF Orlebeke, JMulder, and LJP VanDoornen (Eds). New York:Plenum, 1985, pp. 69-97.35. Madwed JB, Albrecht P, Mark RG, andCohen RJ: Low-frequency oscillations in arterial

pressure and heart rate: A simple computer model.Am J Physiol 256: H1573-H1579, 1989.36. Bertram D, Barres C, Cuisinaud G, andJulien C: The arterial baroreceptor reflex of therat exhibits positive feedback properties at the fre-quency of Mayer waves. J Physiol (Lond) 513:251-261, 1998.37. Janssen BJA, Malpas SC, Burke SL, andHead GA: Frequency dependent modulation of re-nal blood flow by renal nerve activity in consciousrabbits. Am J Physiol 273: R597-R608, 1997.38. Munakata M, Imai Y, Takagi H, Nakao M,Yamamoto M, and Abe K: Altered fre-quency-dependent characterisitics of the cardiacbaroreflex in essential hypertension. J Auto NervSyst 49: 34-45, 1994.39. Kingwell BA, McPherson GA, and KornerPI: Assessment of gain of tachycardia andbradycardia responses of cardiac baroreflex. Am JPhysiol 260: H1254-H1263, 1991.40. Scher AM, O’Leary DS, and Sheriff DD:Arterial baroreceptor regulation of peripheral re-sistance and of cardiac performance. InBaroreceptor reflexes : Integrative functions andclinical aspects, PB Persson and HR Kirchheim,(Eds). Berlin: Springer-Verlag, pp. 75-125, 1991.41. Watkins LL, Grossman P, and SherwoodA: Noninvasive assessment of baroreflex controlin borderline hypertension: Comparison with thephenylephrine method. Hypertension 28:238-243, 1996.42. Castiglioni P: Evaluation of heart rhythmvariability by heart rate or heart period:Differences, pitfalls and help from logarithms.Med Biol Eng Comput 33: 323-330, 1995.43. Weinstock M and Rosin AJ: Relative contri-butions of vagal and cardiac sympathetic nervesto the reflex bradycardia induced by a pressorstimulus in the conscious rabbit: comparison of“steady state” and “ramp” methods. Clin ExpPharmacol Physiol 11: 133-141, 1984.44. Head GA and Malpas SC: Baroreflex mech-anisms in hypertension. Fundam Clin Pharmacol11(suppl 1): 65s-69s, 1997.45. Head GA: Baroreflexes and cardiovascularregulation in hypertension. J CardiovascPharmacol 26 (Suppl. 2): S7-S16, 1995.46. Mancia G, Parati G, Castiglioni P, andDiRienzo M: Effect of sinoaortic denervation onfrequency-domain estimates of baroreflex sensi-tivity in conscious cats. Amer J Physiol 276:H1987-H1993, 1999.47. Legramante JM, Raimondi G, Massaro M,Cassarino S, Peruzzi G, and Iellamo F: Investi-gating feed-forward neural regulation of circula-tion from analysis of spontaneous arterialpressure and heart rate fluctuations. Circulation99: 1760-1766, 1999.48. Di Rienzo M, Tordi R, Parati G, Mancia G,Pedotti A, and Castiglioni P: A new measure ofbaroreflex effectiveness in modulating heart ratein daily life. In Methodology and Clinical Appli-cations of Blood Pressure and Heart Rate Analy-sis, M. Di Rienzo (Ed). Amsterdam: IOS Press,1999, pp. 13-20.


comparing spectral and invasive estimates of baroreflex gain

Documents