inverse relationship between heart rate and blood pressure...

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Inverse Relationship Between Heart Rate and Blood Pressure Variabilities in Rats ALBERTO U. FERRARI, ANNA DAFFONCHIO, FRANCESCO ALBERGATI, AND GIUSEPPE MANCIA SUMMARY The interplay of heart rate variability, baroreceptor control of heart rate, and blood pressure (BP) variability was examined in chronically instrumented, unanesthetized, freely moving rats in which the efferent neural influences on heart rate were pharmacologically altered. In each rat, BP was recorded continuously for 90 minutes in the control condition and in one or more of the following conditions: 1) /3-adrenergic receptor blockade by propranolol, 1 mg/kg; 2) cholinergic blockade by atropine, 0.75 mg/kg, and 3) combined blockade by propranolol plus atropine. Each BP recording was analyzed beat-to-beat by a computer that calculated heart rate and BP variabilities, both expressed as variation coefficients. In addition, under each condition the sensitivity of the arterial baroreceptor control of heart rate was assessed by measuring the reflex changes in pulse interval in response to BP changes induced by bolus i.v. injections of phenylephrine and nitroprusside. As compared with the control condition, 1) propranolol (n = 10) reduced heart rate variability by 23 ± 4% (p<0.01), only slightly impaired baroreceptor reflex sensitivity, and did not significantly modify BP variability ( +11 ± 7%); 2) atropine (n = 11) reduced heart rate variability by 30 ± 7% (p<0.01), drastically impaired baroreceptor reflex sensitivity, and increased BP variability ( + 40 ± 8 % , p<0.01); 3) combined blockade (n= 10) caused variability and baroreceptor reflex changes similar to those induced by atropine alone. Thus, heart rate variability depends on both vagal and sympathetic influences. However, only the former component affects BP variability, that is, it plays an antioscillatory role. This role is likely to originate from arterial baroreceptor modulation of vagal cardiac drive. (Hypertension 10: 533-537, 1987) KEY WORDS blood pressure variability • cardiac parasympathetic nervous system cardiac sympathetic nervous system arterial baroreceptors rats S TUDIES in several animal species have demon- strated that, in the unanesthetized state, blood pressure (BP) is characterized by a large, spon- taneous variability. 12 This variability also has been documented in humans and may have clinical rel- evance. For example, BP variability is responsible for the poor correlation between cuff BP measurements and 24-hour or daytime BP values. 3 - 4 Furthermore, at any given BP mean, a greater 24-hour BP variability is accompanied by a greater rate and severity of target organ damage than is a smaller BP variability. 5 From the Centro di Fisiologia Clinica e Ipertensione, Ospedale Maggiore, CNR, Cattedra di Semeiotica Medica, and Istituto di Clinica Medica Generale e Terapia Medica, Universita di Milano, Milano, Italy. Address forreprints:Dr. Alberto Ferrari, Centro Fisiologia Clin- ica e Ipertensione, Ospedale Policlinico, Via F. Sforza 35, 20122 Milano, Italy. Received December 15, 1986; accepted June 5, 1987. Despite these considerations, our understanding of the mechanisms controlling BP variability is limited. Neurogenic influences are responsible for a substantial proportion of this phenomenon, 6 but it is unclear whether its overall magnitude depends more on central modulation of autonomic cardiovascular nerves than on the buffering action of arterial baroreceptor re- flexes. 7 A further open question concerns the relation- ship between BP variability and spontaneous heart rate variability, that is, whether heart rate variability plays no role in, enhances, or buffers the BP variations. In the present study pharmacological interventions interfering with the cardiac parasympathetic and sym- pathetic influences were used to examine the relation- ship of baroreceptor reflex sensitivity, heart rate vari- ability, and BP variability. The study was conducted in unanesthetized, freely moving rats subjected to con- tinuous BP and heart rate recordings to adequately assess the variability phenomena. 533 by guest on May 22, 2018 http://hyper.ahajournals.org/ Downloaded from

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Page 1: Inverse Relationship Between Heart Rate and Blood Pressure ...hyper.ahajournals.org/content/hypertensionaha/10/5/533.full.pdf · SUMMARY The interplay of heart rate variability, baroreceptor

Inverse Relationship Between Heart Rate andBlood Pressure Variabilities in Rats

ALBERTO U. FERRARI, ANNA DAFFONCHIO, FRANCESCO ALBERGATI,

AND GIUSEPPE MANCIA

SUMMARY The interplay of heart rate variability, baroreceptor control of heart rate, and bloodpressure (BP) variability was examined in chronically instrumented, unanesthetized, freely movingrats in which the efferent neural influences on heart rate were pharmacologically altered. In each rat,BP was recorded continuously for 90 minutes in the control condition and in one or more of thefollowing conditions: 1) /3-adrenergic receptor blockade by propranolol, 1 mg/kg; 2) cholinergicblockade by atropine, 0.75 mg/kg, and 3) combined blockade by propranolol plus atropine. Each BPrecording was analyzed beat-to-beat by a computer that calculated heart rate and BP variabilities,both expressed as variation coefficients. In addition, under each condition the sensitivity of the arterialbaroreceptor control of heart rate was assessed by measuring the reflex changes in pulse interval inresponse to BP changes induced by bolus i.v. injections of phenylephrine and nitroprusside. Ascompared with the control condition, 1) propranolol (n = 10) reduced heart rate variability by23 ± 4% (p<0.01), only slightly impaired baroreceptor reflex sensitivity, and did not significantlymodify BP variability ( +11 ± 7%); 2) atropine (n = 11) reduced heart rate variability by 30 ± 7%(p<0.01), drastically impaired baroreceptor reflex sensitivity, and increased BP variability( + 40 ± 8 % , p<0.01); 3) combined blockade (n= 10) caused variability and baroreceptor reflexchanges similar to those induced by atropine alone. Thus, heart rate variability depends on both vagaland sympathetic influences. However, only the former component affects BP variability, that is, itplays an antioscillatory role. This role is likely to originate from arterial baroreceptor modulation ofvagal cardiac drive. (Hypertension 10: 533-537, 1987)

KEY WORDS • blood pressure variability • cardiac parasympathetic nervous systemcardiac sympathetic nervous system • arterial baroreceptors • rats

STUDIES in several animal species have demon-strated that, in the unanesthetized state, bloodpressure (BP) is characterized by a large, spon-

taneous variability.12 This variability also has beendocumented in humans and may have clinical rel-evance. For example, BP variability is responsible forthe poor correlation between cuff BP measurementsand 24-hour or daytime BP values.3-4 Furthermore, atany given BP mean, a greater 24-hour BP variability isaccompanied by a greater rate and severity of targetorgan damage than is a smaller BP variability.5

From the Centro di Fisiologia Clinica e Ipertensione, OspedaleMaggiore, CNR, Cattedra di Semeiotica Medica, and Istituto diClinica Medica Generale e Terapia Medica, Universita di Milano,Milano, Italy.

Address for reprints: Dr. Alberto Ferrari, Centro Fisiologia Clin-ica e Ipertensione, Ospedale Policlinico, Via F. Sforza 35, 20122Milano, Italy.

Received December 15, 1986; accepted June 5, 1987.

Despite these considerations, our understanding ofthe mechanisms controlling BP variability is limited.Neurogenic influences are responsible for a substantialproportion of this phenomenon,6 but it is unclearwhether its overall magnitude depends more on centralmodulation of autonomic cardiovascular nerves thanon the buffering action of arterial baroreceptor re-flexes.7 A further open question concerns the relation-ship between BP variability and spontaneous heart ratevariability, that is, whether heart rate variability playsno role in, enhances, or buffers the BP variations.

In the present study pharmacological interventionsinterfering with the cardiac parasympathetic and sym-pathetic influences were used to examine the relation-ship of baroreceptor reflex sensitivity, heart rate vari-ability, and BP variability. The study was conducted inunanesthetized, freely moving rats subjected to con-tinuous BP and heart rate recordings to adequatelyassess the variability phenomena.

533

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534 HYPERTENSION VOL 10, No 5, NOVEMBER 1987

Materials and MethodsThe study used 17 male and female Sprague-Dawley

rats (Charles River Italia SpA, Calco, Italy) with amean age of 11.9 ±0.6 (SE) weeks. With the ratsunder ketamine anesthesia, 80 mg/kg i.p., PE-50 cath-eters were implanted in the femoral artery and vein,tunneled subcutaneously, exteriorized at the dorsalneck region and kept patent by flushing with appropri-ate heparin solution (0.01% vol/vol). The animalswere allowed 2 days to recover from the operation andto get acquainted with the experimental environment,which consisted of wide individual cages in which ratscould walk, explore, and eat and drink ad libitum.

ProtocolAll recordings were performed during the daytime.

The arterial catheter was connected to a StathamP23Dc pressure transducer (Oxnard, CA, USA) forarterial pressure recording; the venous catheter wasconnected to a long extension so that drug administra-tion could be performed out of the animal's sight. Carewas taken to keep the room noiseless and to maintain alow degree of illumination.

For the assessment of BP and heart rate variability,the pressor trace was chart-displayed on a Grass poly-graph (Quincy, MA, USA) and recorded on a RacalStore 4 tape recorder (Southampton, Hampshire, Eng-land) for subsequent analysis. A continuous recordinglasting at least 90 minutes was obtained under eachexperimental condition.

After the continuous BP recording was completed,the baroreceptor control of heart rate was examined.To this aim, the pressor trace was ink-written at a paperspeed of 2.5 mm/sec and simultaneously derived totrigger a tachograph for beat-to-beat heart rate display.Bolus i.v. injections of phenylephrine and nitroprus-side (1—4 /ig/kg for both drugs) were administeredrespectively to stimulate and to deactivate arterial bar-oreceptors, thus eliciting reflex heart rate changes.Two to three boluses of each drug were given in arandom order.

Both the study of BP and heart rate variability andthe baroreceptor reflex study were performed undercontrol conditions and during 1) cholinergic blockadeby atropine sulfate, 0.75 mg/kg i.v. (n = 11); 2) £-adrenergic blockade by propranolol, 1 mg/kg i.v.(n = 10); and 3) combined blockade by propranololplus atropine (n = 10). The effectiveness of autonomicblockades was checked immediately after the atropineor propranolol injection and every 30 minutes there-after. /3-Adrenergic blockade was considered effectiveif an i.v. injection of isoproterenol, 0.2 Atg/kg, causedno tachycardic response. Cholinergic blockade wasconsidered effective if the small, residual bradycardicresponse to phenylephrine injection that was observedimmediately after atropine injection showed no recov-ery. Supplemental doses of either blocking agent weregiven as needed.

The experimental session under control conditionswas the initial one in each rat. The session employingeither atropine or propranolol was then performed and

was followed by the session using combined blockade.Finally, after a 24-hour drug washout interval, thesession in which a single drug was omitted (atropine orpropranolol) was performed. Only four rats wentthrough all four experimental sessions, however. Ofthe remaining rats, seven underwent the study with asingle drug and six were additionally given combinedblockade.

Data AnalysisTo measure BP and heart rate variability, each 90-

minute BP recording was analyzed beat-to-beat by aPDP11 computer (Digital Equipment, Maynard, MA,USA) that scanned the trace every 60 msec and calcu-lated 1) the mean values of heart rate and systolic,diastolic, and mean arterial pressures for each 10-min-ute period during the 90-minute cycle, 2) the corre-sponding variation coefficients (i.e., the standard devi-ation divided by the mean multiplied by 100), and 3)the average of the nine 10-minute values to obtain asingle measure for each variable examined.

Baroreceptor control of heart rate was analyzed bycalculating the ratio of the peak change in pulse inter-val to the peak change in mean arterial pressure in-duced by the vasoactive drug. In each rat, the ratiosobtained by the various injections of phenylephrinewere averaged. The same procedure was adopted forthe nitroprusside injections.

The statistical comparison of control and drug treat-ment conditions was performed by the nonparametricWilcoxon rank sum test (variability data) and thepaired t test (all other data). Because more than onecomparison was made for the same group of animals(control vs 3 types of autonomic blockade), the/j levelof statistical significance was set below 0.01.

ResultsAs shown in Table 1, under control conditions mean

arterial pressure and heart rate were similar in the threegroups. Autonomic interventions did not significantlyalter BP, whereas they induced the expected heart ratechanges; namely, a slight bradycardia and a more pro-nounced tachycardia accompanying, respectively,propranolol and atropine administration. During com-bined blockade a modest but significant tachycardiawas observed. After administration of all autonomicblocking drugs, the behavior of the animal (physicalactivity, grooming, eating, drinking, exploring pat-terns) showed no apparent variations from that ob-served during control conditions.

Effects of Autonomic Blockade on BP andHeart Rate Variabilities

As shown in Figure 1, following atropine adminis-tration heart rate increased markedly and became lessvariable, whereas BP oscillations were markedly en-hanced. This response was apparent in 10 of the 11animals studied, and the results were significant for thegroup as a whole (Figure 2). The average reductionin heart rate variability induced by atropine was30 ± 7%, and the corresponding average increase inBP variability was 40 ± 8%.

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BP VARIABILITY AND BARORECEPTOR REFLEXES IN RATS/Ferrari et al. 535

TABLE 1. Average Values of Mean Arterial Pressure and Heart Rate Under Control Conditions and During Treatmentwith Autonomic Blocking Drugs

Variable

MAP (mm Hg)

HR (beats/min)

Control

105 ±3

38O±8

Atropine

106 + 3

417 + 3*

Control(n=10)

101 ±2

361 ±6

Propranolol(71=10)

100±3

334 + 7

Control(n=10)

100 + 2

355 + 2

Atropine +Propranolol

(71=10)

106±5

379 + 5*

Entries are means ± SE of the data obtained in single animals by computer analysis of a 90-minute continuous BPrecording under each experimental condition. MAP = mean arterial pressure; HR = heart rate.

*p<0.01, compared with control values.

The results obtained after propranolol administra-tion are shown in Figure 3. Propranolol reduced heartrate variability in nine of the 10 animals studied, andthe average change (— 23 ± 4%) was significant forthe group as a whole. However, the reduction in heartrate variability was not accompanied by a significantchange in BP variability.

The results of combined autonomic blockade areshown in Figure 4. The effects of this interventionclosely mimicked those observed after administrationof atropine alone, that is, a marked reduction in heartrate variability (— 40 ± 5%) and a marked increase inBP variability (+ 33 ± 7%) occurred.

Effects of Autooomlc Blockade on BaroreceptorControl of Heart Rate

As shown in Figure 5 (left panels), following atro-pine administration the reflex increase and reduction inpulse interval induced by phenylephrine and nitroprus-side, respectively, were drastically blunted. In con-trast, propranolol administration (see Figure 5, middlepanels) did not affect the pulse interval response tophenylephrine, and it reduced the pulse interval re-sponse to nitroprusside to a much lesser extent thanwas observed after the administration of atropine. Thepulse interval responses to phenylephrine and nitro-prusside were almost completely abolished by com-bined autonomic blockade (see Figure 5, right panels).

DiscussionIn our unrestrained rats, a 30% reduction in heart

rate variability induced by cholinergic blockade wasaccompanied by an increase in BP variability. In con-trast, a comparable reduction in heart rate variabilityinduced by J9-adrenergic blockade was not accompa-nied by any changes in BP variability. Finally, com-bined cholinergic and /3-adrenergic blockade causedalterations in heart rate and BP variability that weresuperimposable on those induced by cholinergicblockade alone. These results cannot be explained bybehavioral differences induced by the central effects ofatropine or propranolol because no drug-related behav-ioral changes were observed. Thus, they indicate thatin the unrestrained condition 1) cardiac neural drive isresponsible for a substantial fraction of spontaneousheart rate variability, 2) the oscillatory role is playedby both the vagi and the sympathetic cardiac nerves,and 3) only the vagally mediated heart rate oscillationssubserve a BP-stabilizing effect (i.e., display a trendtoward a reduction in the magnitude of the spontaneousBP oscillations that characterize the unrestrainedstate).

As to the mechanisms underlying these results, aplausible hypothesis is that the vagally mediated oscil-lations in heart rate are triggered by the arterial barore-ceptors, reflecting the ability of this reflex system tobuffer BP changes through opposite changes in cardiac

I ATROPINE 0.75mg/Kg

ABP

HR

200

mm

Hg

0

500

15secL250

FIGURE 1. Original recording showing the effects of atropine administration on arterial blood pressure (ABP)and heart rate (HR) in an unanesthetized normotensive rat. Note the increase in ABP variability and the decreasein HR variability after injection of the drug (arrow).

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536 HYPERTENSION VOL 10, No 5, NOVEMBER 1987

r saooco

HR MAP

Control Atropin* Control Atroplne

* p < 0 0 1 vs Control

FIGURE 2. Modifications in the heart rate (HR) and meanarterial pressure (MAP) variation coefficients caused by atro-pine-induced cholinergic blockade in 11 individual rats ( )and in the group as a whole (o o).

a> 3ooo '

p<0 .01 p c C .01

T T

T

J

%

i1•

HR MAP

I I C o n t r o l

Y//,:i P r o p r a n o l o l + A t r o p i n e ( n - 1 0 )

FIGURE 4. Effects of combined autonomic blockade by pro-pranolol plus atropine on the variation coefficients of heart rate(HR) and mean arterial pressure (MAP).

output. This hypothesis is supported by the observa-tion made in this and in previous studies that the vagusis primarily responsible for the bradycardia accompa-nying baroreceptor stimulation8 and for the tachycardiaaccompanying baroreceptor deactivation, with thesympathetic nervous system playing a minor role. It isalso supported by the results of studies conducted inanimals and humans. In animals, the increased BPvariability that follows denervation of the arterialbaroreceptors has been shown to be accompanied by areduced heart rate variability.2910 Likewise, thesensitivity of the baroreceptor-heart rate control hasbeen found to correlate positively with 24-hour heart

36 HR MAP

c 6

e73

Io

Control Propranolol

* p<0.01 vs ControlControl Proprsnolol

FIGURE 3. Modifications in the heart rate (HR) and meanarterial pressure (MAP) variation coefficients caused by pro-pranolol-induced fi-adrenergic blockade in 10 individual rats( ) and in the group as a whole (o o).

rate variability and negatively with 24-hour BPvariability."'12

Three further comments should be made. The firstcomment concerns the report by Buchholz and Na-than13 that administration of methylatropine to con-scious rats caused a reduction in heart rate variabilitybut no change in BP variability.13 However, BP vari-ability was measured by analyzing a single pressurewave every 15 seconds (i.e., 1-2% of all BP waves),and intermittent sampling is known to limit preciseestimation of this phenomenon.14 Furthermore, meth-ylatropine is endowed with ganglionic blocking prop-erties" that may blunt sympathetic influences on pe-ripheral circulation. This blunting effect may haveprevented an increased BP variability from beingobserved.

The second aspect concerns the role of the sympa-thetically mediated heart rate variability in overall car-diovascular control. This question arises because thepropranolol-induced reduction in heart rate oscillationsdid not cause any change in BP variability. As wementioned, failure of BP variability to increase follow-ing propranolol-induced reduction in heart rate vari-ability can be easily explained by the fact that barore-ceptor reflex influences on the sinus node are mediatedlargely by the vagus. It is more difficult, however, toexplain why a propranolol-induced reduction in thevariability of heart rate (and probably of cardiac out-put) was not followed by a reduction in BP variability.One possibility is that, at variance with the suddenvagally evoked heart rate alterations, the slower-devel-oping changes in heart rate mediated by the sympathet-ic system are not easily transformed into BP changes.An alternative possibility is that when the /3-adrenergicdrive is removed, BP oscillations are maintained bysympathetic influences on a-adrenergic receptors.

The third aspect relates to the finding that combined

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BP VARIABILITY AND BARORECEPTOR REFLEXES IN RATS/Ferrari et al. 537

BARORECEPTOR STIMULATION1

_ 1,5-p<0.01 , I

BARORECEPTOR DEACTIVATION

< 1.0

u u• •o a

-p<0.01 -

ZZ2 ControlCD Atropin* (»:11)

ropr.nolol (n = 10>n* (n-.IO)

.- p<0.01-<

FIGURE 5. Effects of cholinergic (left pan-els), fi-adrenergic (middle panels), and com-bined (right panels) blockade on baroreceptorcontrol of heart rate as studied by the vasoac-tive drug technique. Baroreceptor reflex sensi-tivity was calculated as the ratio of the peakchange in pulse interval (PI) to the peakchange in mean arterial pressure (MAP)following baroreceptor stimulation by phenyl-ephrine administration (upperpanels) or baro-receptor deactivation by nitroprusside admin-istration (lower panels).

cholinergic and /3-adrenergic blockade of the heart,although more effective than selective blockade of ei-ther autonomic division, reduced spontaneous heartrate variability by only slightly more than 40%. Be-cause the effectiveness of total autonomic cardiacblockade was well established (see Materials andMethods), this finding indicates that in the rat morethan 50% of this phenomenon is unrelated to neuralmodulation, at least as far as the traditional autonomicpathways are concerned. The factors involved in thisresidual heart rate variability are unknown, althoughvarious humoral and physical mechanisms'6 can beregarded as possible candidates. Our propranolol data,however, allow us to exclude the possibility that,among the humoral factors, circulating catecholaminesplay a role.

AcknowledgmentsTbe authors gratefully acknowledge the contributions of Dr. Car-

la Zanchetti (illustrations), Mr. Riccardi Sarri (photography), andMrs. Paola Boccaccini (manuscript typing).

References1. Anderson DE, Yingling JE, Sagawa K. Minute-to-minute co-

variations in cardiovascular activity in conscious dogs. Am JPhysiol 1979;236:H434-H439

2. Ramirez J, Bertinieri G, Belli G, et al. Reflex control of bloodpressure and heart rate by arterial baroreceptors and by cardio-pulmonary receptors in the unanesthetized cat. J Hypertens1985^:327-335

3. Sokolow M, Werdegar D, Kain HK, Hineman AT. Relation-ship between level of blood pressure measured casually and by

portable recorders and severity of complications in essentialhypertension. Circulation 1966^6:279-298

4. Perloff D, Sokolow M, Cowan R. The prognostic value ofambulatory blood pressure. JAMA 1983;240:2792-2798

5. Parati G, Pomidossi G, Albini F, Malaspina D, Mancia G.Relationship of 24 hour blood pressure mean and variability toseverity of target organ damage in hypertension. J Hypertens1987;5:93-98

6. Mancia G, Ferrari A, Gregorini L, et al. Blood pressure andheart rate variabilities in normotensive and hypertensive hu-man beings. Circ Res 1983;53:96-1O4

7. Mancia G, Zanchetti A. Blood pressure variability. In: Zan-chetti A, Tarazi RC, eds. Pathophysiology of hypertension —cardiovascular aspects. Amsterdam: Elsevier Science Publish-ers, 1986:125-152 (Handbook of hypertension; vol 7)

8. Coleman TG. Arterial baroreceptor control of heart rate in theconscious rat. Am J Physiol 1980;238:H515-H520

9. Ito CS, Scher AM. Hypertension following arterial barorecep-tor denervation in the unanesthetized dog. Circ Res 1981;48:576-586

10. Buchholz RA, Hubbard JW, Nathan MA. Comparison of 1-hour and 24-hour blood pressure recordings in central or pe-ripheral baroreceptor-denervated rats. Hypertension 1986;8:1154-1163

11. Conway J, Boon N, Davies C, Jerres JV, Sleight P. Neural andhumoral mechanisms involved in blood pressure variability. JHypertens 1984;2:203-208

12. Mancia G, Parati G, Pomidossi G, Casadei R, Di Rienzo M,Zanchetti A. Arterial baroreflcxes and blood pressure and heartrate variabilities in humans. Hypertension 1986;8:147-153

13. Buchholz RA, Nathan MA. Chronic lability of the arterialblood pressure produced by electrolytic lesion of the nucleustractus solitarii in the rat. Circ Res 1984|54:227-238

14. Di Rienzo M, Grassi G, Pedotti A, Mancia G. Continuous vsintermittent blood pressure measurements in estimating 24-hour average blood pressure. Hypertension 1983^:264-269

15. Fink LD, Cervoni P. Ganglionic blocking action of atropineand methylatropine. J Pharmacol Exp Ther 1953; 109:372-376

16. Lange G, Lee HH, Chang A, McBrooks C. Effect of stretchon the isolated cat sinoarrial node. Am J Physiol 1966;211:1192-1196

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A U Ferrari, A Daffonchio, F Albergati and G ManciaInverse relationship between heart rate and blood pressure variabilities in rats.

Print ISSN: 0194-911X. Online ISSN: 1524-4563 Copyright © 1987 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Hypertension doi: 10.1161/01.HYP.10.5.533

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