Minute-to-minute covariations activity of conscious dogs

in cardiovascular

DAVID E. ANDERSON, JOHN E. YINGLING, AND KIICHI SAGAWA Departments of Psychiatry and Behavioral Science and Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

ANDERSON, DAVID E., JOHN E. YINGLING, AND KIICHI SAGAWA. Minute- to-minute covariations in cardiovascular activity of conscious dogs. Am. J. Physiol. 236(3): H434-H439, 1979 or Am. J. Physiol.: Heart Circ. Physiol. 5(3): H434-H439, 1979.-Cardiovascular activity of chronically instrumented conscious dogs was monitored continuously during daily sessions of rest or of intermittent aversive stimulation. Data analysis of minute-to-minute averages revealed that cardiovascular variables changed in patterns, rather than as isolated independent events. Variations in cardiac output were highly positively correlated with concurrent variations in heart rate in all subjects under both conditions (mean r = +0.93). Variations in heart rate were two to five times as great as stroke volume, which was remarkably constant (coefficient of variation averaged only 4.6%). Variations in mean arterial pressure were consistently correlated with the variations in cardiac output (mean r = +0.66) and heart rate (mean r = +0.68), but were poorly correlated with the small changes in stroke volume (mean r = -0.17) and total peripheral resistance (mean r = -0.16). resting conditions; aversive stimulation; heart rate; stroke volume; mean arterial pressure; cardiac output; total peripheral resistance

VARIABILITY

IN CARDIOVASCULAR

ACTIVITY

iS COW3iSb

ently observed in studies of man during behavioral interactions (12). Studies with chronically instrumented animals have also shown that cardiovascular measures such as heart rate (8), cardiac output, and even arterial blood pressure (5) can vary substantially, even though the subject appears to be behaviorally inactive. This variability can complicate the investigation of the effects of environmental conditions and behavioral stress on cardiovascular regulation, but provides an opportunity to observe the extent to which variations in cardiovascular activity occur in patterns, rather than as isolated and independent events. In the present study, cardiovascular activity of dogs was monitored continuously during daily sessionsin an experimental environment. Direct measures of arterial pressure and cardiac output were obtained from chronically implanted sensors, enabling a computer system to record averages over successive l-min intervals of systolic, diastolic, and mean pressures, heart rate, stroke volume, cardiac output, and total peripheral resistance. This technique enabled analyses of cardiovascular interactions that were not complicated by the effects of resH434

piratory arrhythmia and other short-term influences. The data were analyzed to determine the relative variability of the cardiovascular measures, the relative influence of heart rate and stroke volume in the mediation of minute-to-minute variations in cardiac output, and the relative influence of cardiac output and total peripheral resistance in the mediation of minute-to-minute variations in arterial pressure occurring under conditions of “rest” and during periods of intermittent aversive stimulation. METHODS

Subjects and experimental chamber. Each of seven adult male mongrel dogs, weighing 13-17 kg, was restrained in a flexible harness in a specially constructed experimental chamber (2). The harness permitted the dog to stand up, sit, or lie down, but provided protection for cardiovascular monitoring equipment in the chamber. A ventilation system provided temperature control and masking of external sounds. Behavioral activity was monitored over a closed-circuit television system (Panasonic model WV41OP). Between sessionsthe dog was housed in kennels in another part of the building where food and water were freely available. Cardiovascular monitoring procedures. After habituation to the experimental chamber over a Z-wk period, an electromagnetic flow transducer (Statham model Q2160, 16-18 mm) was implanted in each dog during aseptic surgery. The dog was anesthetized with sodium pentobarbital (30 mg/kg) and respirated automatically with a pump (Harvard model 607). The chest,was opened at the third intercostal space, and the transducer was carefully fitted around the ascending part of the aortic arch, with Dacron mesh placed between the transducer and the aorta. A transducer size was selected to prevent constriction, but to fit snugly enough so that stable tracings were obtained within 10 days after surgery. The cable was exteriorized on the dog’s back, the chest was closed, and a protective jacket was placed on the dog. Calibration of the transducer had been accomplished prior to implantation by means of a gravity-fed system in which Ringer solution was passed through an excised aorta or lambskin condom. Approximately 1 wk after the open-chest procedure, a second surgery was performed in which a polyvinyl chloride catheter (18 gauge), coated with Silastic, was inserted into the aorta via the left common carotid artery. The catheter, filled with heparin-

0363-6135/79/0000-oo~oo$o1.25

Copyright

0 1979 the American

Physiological

Society

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CQVARIATIONS

IN

CARDIOVASCULAR

H435

ACTIVITY

ized saline, was exteriorized at the nape of the neck and protected by a bandage worn under a broad leather collar. After recovery from surgery as determined by body temperature, appetite, and general activity level, each dog was monitored during a series of daily sessions in the experimental chamber. During these sessions, arterial pressure was monitored continuously by attaching the catheter to a strain gauge transducer (Statham model P23de) connected to the restraint harness in the chamber. Catheter patency was assured during these sessions by slow and continuous infusion of lightly heparinized saline (7 USP U/ml) at a constant rate of 12 ml/h via a peristaltic pump (Harvard model 1201). Aortic blood flow was monitored continuously by coupling the flow transducer to the flowmeter (Medicon model K2000) located on top of the chamber. Aortic blood flow and arterial pressure were displayed on the polygraph (Grass model 7C). The diastolic portion of the flo6 curve was assumed to represent the zero-flow line. Stroke volume was integrated on the polygraph. Heart rate was displayed on the polygraph via a cardiotachometer. Systolic and diastolic pressure (mmHg), stroke volume (ml), and heart rate (interbeat interval in milliseconds) were recorded at each heartbeat in a digital minicomputer (DEC-PDO-BE) after appropriate shaping of the electronic pulse in an interfacing system and analog-to-digital converter. Mean arterial pressure was calculated at each beat by the computer as one-third of the pulse pressure plus diastolic pressure. Cardiac output was determined by summing successive values of stroke volume over 1-min intervals. Total peripheral resistance was obtained by dividing mean arterial pressure by cardiac output. Mean values of systolic, diastolic, and mean pressures, heart rate, stroke volume, cardiac output, and total peripheral resistance were determined once per minute and printed on-line on a teletype. Experimental procedures and data analysis. Each dog was introduced to the experimental chamber during daily sessions of increasing duration before implantation of cardiovascular sensors, for purposes of habituation to the environment. After cardiovascular surgery, each subject was monitored during daily sessions in the chamber in which no stimulation was presented and no behavioral activity was required. (These sessions were designed to provide base-line samples of cardiovascular activity prior to cardiovascular conditioning experiments.) The number of hours of monitoring for each dog under this condition were as follows: dog 1, 50 h over 10 sessions; dog 2, 20 h over 4 sessions;dog 3, 17 h over 4 sessions;dog 4, 15 h over 4 sessions;dog 5, 10 h over 3 sessions;dog 6,10 h over 2 sessions;dog 7, 5 h over 2 sessions. Subsequently, aversive stimulation was presented on a nonsystematic basis during several sessionsin which an originally neutral auditory stimulus (conditioned stimulus) was paired at offset on some occasions with electric shock of 2-5 mA intensity and 0.5 s duration (unconditioned stimulus). Data for three subjects under these conditions were analyzed, including the following numbers of hours: dog 1, 1.0 h over three sessions;dog 3, 8 h over three sessions;dog 8, 12 h over three sessions. The basic unit of measurement was the l-min interval average, determined from beat-to-beat measurements of

each cardiovascular variable. All subsequent analyses were performed on l-h blocks of data. Means and standard deviations of each cardiovascular measure were calculated for each hour of each session with each dog. Coefficients of variation were calculated by dividing the standard deviation by the mean, to determine the relative variability of each cardiovascular measure (15). Frequency distributions of the 1-min averages during l-h periods were plotted for all 122 h of monitoring during resting sessions,and a composite frequency distribution was plotted in which the mean of each hour served as the center of the distribution. Relationships between pairs of cardiovascular measures were evaluated by calculation of Pearson productmoment correlations and of multiple correlations that correct for the influence of other measures on the relationship of any two (9). Frequency distributions of sets of correlation coefficients were plotted for all pairs of measures for which the mean correlation coefficient was statistically significant (r > 0.33; P < 0.01). Mean correlation coefficients for all pairs of measures were determined for all hours of monitoring under both resting and aversive stimulation conditions. In addition, correlation coefficients were calculated between the total peripheral resistance and the ratio of mean pressure to heart rate (the total peripheral resistance index). RESULTS

Table 1 presents the means of the means and standard deviations, and the coefficients of variation, of each cardiovascular measure during l-h monitoring intervals of the rest and aversive stimulation sessionsfor each dog. The table shows that a relatively broad range of absolute values of cardiovascular activity are represented in this sample of subjects, but that the coefficients of variation, an index of relative variability, show a remarkable consistency both between dogs and across experimental conditions. Figure 1 shows the mean coefficient of variation for each cardiovascular measure for each dog under both conditions and illustrates that relative variability was greatest for all dogs in heart rate (overall mean, 16.3%) and cardiac output (overall mean, 14.6%), followed by total peripheral resistance (mean, 11.0%)) mean arterial pressure (mean, 7.5%), and stroke volume (mean, 4.4%). Thus, the two determinants of variability in cardiac output, heart rate, and stroke volume were the most and least variable measures, respectively, in the group. These relationships were maintained whether arterial pressure remained within normotensive limits (e.g., dogs 2, 3, 6, and 7 at rest), or was elevated within the context of aversive stimulation (Ta bLe 1) . Figure 2 shows the overall frequency distributions of 1-min interval averages within a l-h period for each cardiovascular measure, for all resting intervals for the group of seven dogs. The figure shows that the distributions approximate normal curves, with positive skewing for heart rate, cardiac output, and arterial pressure, indicating that the majority of the variations in these measures occurred in the direction of increases from tonic levels. However, variations from modal values occurred in both directions for all measures.

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H436

ANDERSON,

1. Means of means and standard deviations, a,nd coefficients of variation (SD/mean), under resting condition and aversive stimulation

TABLE

Resting

Dog No. n

1

50

MAP

sv

co

TPR

100 8 8

75 12 16

21.6 0.9 4

1624 224 14

0.062 0.006 10

99 8 8

84 15 18

17.9 1.0 6

1510 212 14

0.065 0.010 15

88 8 9

63 11 18

18.4 0.6 3

1160 204 18

0.065 0.008 10

105 7 7

108 12 11

16.7 0.7 4

1804 246 14

0.059 0.007 12

107 8 8

104 18 17

17.3 1.0 6

1797 316 18

0.062 0.009 15

84 5 6

84 9 11

18.2 1.2 7

1529 127 8

0.055 0.004 7

SD cv

94 6 6

69 14 20

19.4 0.8 4

1339 316 24

0.072 0.013 18

x SD cv

2

20

x SD cv

3

17

x SD cv

4

10

x SD cv

5

10

x SD cv

6

10

x SD cv

7

5

x

HR

Aversive

-~~

YINGLING,

AND

SAGAWA

was not statistically significant. Covariations between systolic, diastolic, and mean pressures were all highly positive (Table 2), and both systolic and diastolic pressure varied in the same manner with other cardiovascular measures as mean pressure. Stroke volume was not significantly correlated with any other cardiovascular measure. Figure 3 shows frequency distributions of all the correlations calculated for the individual hour periods of the rest sessions for all seven dogs that had a significant mean value. The data show that all of the correlations between heart rate and cardiac output were positive and that all of the correlations between cardiac output and total peripheral resistance were negative. Similarly, 92% of the correlations between mean arterial pressure and cardiac output were positive, and 72% of the correlations between mean pressure and total peripheral resistance were negative. The results of a multiple correlation analysis performed on the data from the resting sessions were in accord with the results of the Pearson product-moment correlational analysis. The mean correlation between heart rate and mean pressure was +0.67, between stroke

n

l 2O t

#l

#6

.20

Stimulation

3

10

x SD cv

114 7 6

89 10 11

23.8 0.6 3

2109 216 10

0.054 0.005 9

6

8

x SD cv

109 8 8

74 15 20

18.1 0.7 4

1347 290 22

0.081 0.010 12

8

12

x SD cv

93 7 6

84 12 11

20.6 0.8 3

1722 251 10

0.054 0.008 9

0 .20

0

MAP, mean arterial pressure (mmHg); HR, heart rate (beats/min); SV, stroke volume (mlj; CO, cardiac output (ml/min); TPR, total peripheral resistance (mmHg/(ml/min)); n, number of sessions of monitoring for each dog.

Table 2 presents frequency distributions of the correlation coefficients calculated for all pairs of cardiovascular measures for 1-min interval averages within l-h monitoring periods for both rest and aversive stimulation conditions. The table shows that several of the mean values are statistically significant beyond the 0.01 level. Specifically, significant positive covariation was observed under both conditions for cardiac output and heart rate (0.93, 0.95), cardiac output and mean arterial pressure (0.65, 0.67), and heart rate and mean arterial pressure (0.67, 0.70), and significant negative covariation was observed under both conditions between heart rate and total peripheral resistance (-0.67, -0.69) and between cardiac output and total peripheral resistance (-0.75, -0.76). The mean correlation between mean arterial pressure and total peripheral resistance, though negative,

t

.20

#6

0

CO

HR TPR

AP

SV

CO

HR

TPR

AP

SV

CO HR TPR AP SV 1. Means of coefficients of variation (standard deviation/mean) for cardiac output (CO), heart rate (HR), total peripheral resistance (TPR), mean arterial pressure (AP), and stroke volume (SV) for dogs 1-7 during a total of 122 h of rest and dogs 3, 6, and 8 during a total of 30 h of aversive stimulation. Standard errors are shown for group means. FIG.

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COVARIATIONS

IN

CARDIOVASCULAR

H437

ACTIVITY

STROKE VOLUME

HEART RATE

66

_;,. 79

w

FIG. 2. Frequency distributions of 1-min interval averages within 60-min periods of mean arterial pressure (mmEIg), heart rate (beats/min), stroke volume (ml), cardiac output (ml/min), and total peripheral resistance (mmIIg/(ml/min)), averaged for a total of 122 h of rest for the 7 dogs. Mean and standard deviations are shown on the abscissas of each distribution.

(bpm)

TOTAL PERIPHERAL RESISTANCE

TABLE 2. Correlation matrix between averages of cardiovascular variables Variable

co HR sv TPR MAP SP

co R A R A R A R A R A R A

d-0.93* +0.95* -0.02 +0.13 -0.76* -0.75* +0.65* +0.67* +0.54* +0.65*

HR

sv

+0.93 * +0.95*

-0.02 +0.13 -0.03 -0.05 1 1 -0.10 -0.23 -0.17 -0.06 -0.05 +0.02

-0.03 -0.05 -0.69 * -0.67* +0.67* +0.70* +0.53* +0.67*

TPR -0.76* -0.75* -0.69* -0.67* -0.10 -0.23 1 1 -0.16 -0.17 -0.09 -0.23

minute- to-minute MAP +0.65* +0.67* +0.67 * +0.70* -0.17 -0.06 -0.16 -0.17

+0.&3* +0.94*

SP +0.54* +0.65* +0.53* +0.67* -0.05 +0.02 -0.09 -0.23 +0.88* +0.94*

DP +0.68* +0.67* +0.74* +0.71* -0.26 -0.09 -0.22 -0.21 +0.94* +0.99* +0.78* +0.92*

Correlations of variables for 7 dogs over 122 h of resting condition (R) and 30 h of aversive stimulation (A). CO, cardiac output; HR, heart rate; SV, stroke volume; TPR, total peripheral resistance; MAP, mean arterial pressure; SP, systolic pressure; DP, diastolic pressure. *P I 0.01.

volume and mean pressure +0.04, and between mean pressure and total peripheral resistance -0.22. The mean correlation between cardiac output and total peripheral resistance was -0.75 and between cardiac output and mean pressure +0.70. These results indicate that the relationships between any two cardiovascular measures were not highly dependent upon their relationship to other measures. Finally, correlation coefficients were calculated to determine the relationship between variations in total peripheral resistance (mean pressure/cardiac output) and another calculated measure, the index of total peripheral resistance, obtained by dividing mean pressure by heart rate. To the extent that stroke volume is constant, the correlations should approach +l. For the 122 h of monitoring under resting conditions, the mean correlation was

+0.90 t 0.03, and for the 30 h of intermittent aversive stimulation, the mean correlation was +0.89 t 0.02, indicating that minute-to-minute variations in the ratio of mean pressure to heart rate were highly positively related to concurrent variations in total peripheral resistance. DISCUSSION

The results of this study show that minute-to-minute variations in heart rate and cardiac output are highly positively correlated and that variations in the cardiac output are highly negatively correlated in conscious dogs, both at rest and during periods of intermittent aversive stimulation. Stroke volume remained relatively constant under both conditions, compared to the concurrent variability in heart rate. Arterial pressure was less variable than cardiac output in each subject. These findings are specific to the time span over which cardiovascular activity was measured, but are essentially in accord with the results of recent experiments in which cardiovascular function of instrumented animals was monitored directly and continuously. For example, it was observed that increases in cardiac output of conscious dogs subjected to volume loading with saline or blood were due to increases in heart rate, but stroke volume remained constant (15). When the same procedure was applied to anesthetized subjects, cardiac output increases were mediated by increases in stroke volume rather than by heart rate. The study found that in the well-trained, unanesthetized dog, heart rates tend to be low and stroke volume to be relatively high at rest, a hemodynamic condition not observed in the anesthetized preparation

(3).

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H438

ANDERSON,

YINGLING,

AND

SAGAWA

HEART RATE CARDIAC

OUTPUT

HEART RATE

HEART RATE

MEAN PRESSURE

TOTAL PERIPHEW\L RESISTANCE

CARDIAC

OUTPUT

FIG. 3. Frequency distributions of the 122 correlation coefficients calculated for 6 pairs of cardiovascular measures in terms of 1-min interval averages within 60-min periods of monitoring during rest sessions for the 7 dogs. Shaded areas indicate statistical significance beyond the 0.01 level.

HEART RATE

MEAN PRESSURE

STROKE VOLUME

lIInhlL 0

In another study (lo), mean blood pressure, cardiac output, and heart rate of instrumented dogs all oscillated in phase, whereas total peripheral resistance oscillated out of phase with the others. It was concluded that the variations in total peripheral resistance were in response to the variations in arterial pressure. Changes in heart rate will not sustain increases in cardiac output. It has been shown previously that electrical pacing of the myocardium of chronically instrumented dogs did not result in sustained and proportional changes in cardiac output (11). Rather, concurrent adjustments in the peripheral vasculature are also necessary for the maintenance of changes in cardiac output. It has been suggested that vasoconstriction in the splanchnit bed is a consistent correlate of sympathetically mediated increases in heart rate (13). It has also been shown that changes in blood flow to the skeletal muscles are consistently observed in the same direction as the change in heart rate and cardiac output of cats during confrontations with other animals (1). If the behavioral response is aggressive, increased cardiac output and increased blood flow to the skeletal muscles occur. If the behavioral

+l

response is immobilization, decreases in cardiac output occur, accompanied by decreases in blood flow to the skeletal muscles. These relationships support the view that cardiovascular adaptations of behaving animals occur in patterns, rather than as isolated independent events. The variability in arterial pressure observed in the present study was relatively smaller than that observed in cardiac output and total peripheral resistance. This relationship was observed previously in studies with dogs, showing that this relatively narrow range of variability depended on adequate function of the baroreceptor reflexes (5); in this-study, the coefficient of variation in intact dogs was about- lo%, compared with the mean value of 7% observed in the present experiments. The coefficients of variation for cardiac output were about twice the values of arterial pressure in both studies. In the present study, systolic and diastolic pressure variations were highly correlated under both conditions. A similar finding was reported in a previous study of anesthetized and unanesthetized man and laboratory animals under a variety of experimental conditions (6).

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COVARIATIONS

IN

CARDIOVASCULAR

H439

ACTIVITY

This previous report emphasized the lack of correlation between changes in arterial pressure-specifically, diaand changes in the state of the periphstolic pressureeral vasculature. The data from the present study also caution against extrapolations of this kind. However, the correlations between- changes in total peripheral resistance and the ratio of mean arterial pressure to heart rate were very high in the present study, suggesting that at least under some conditions it may be possible to estimate the direction of acute change in cardiac output and total nerinheral resistance on the basis of information aboutAarterial pressure and heart rate. It is well established that the cardiovascular system is capable of significant response to environmental stimulation and behavioral challenge (4). The data from the present study are consistent with the view that continuous input from the central nervous system tends to partially override the numerous autoregulatory reflexes

even when the individual is not in active behavioral interaction and that such variations occur in patterns. Clearly, relevant behavioral factors such as increased skeletal muscle tension (i.e., isometric exercise) can provide effects that alter the basic relationships observed in the present study (e.g., the inverse relationship between cardiac output and total peripheral resistance), and it remains the task of future research to disentangle these factors for a more complete understanding of behavioral influences on the circulation. The authors express their appreciation to Dr. Artin Shoukas and Dr. Hiroshi Hosomi for their expert assistance with this project and to Dr. Carl Rothe of the University of Indiana School of Medicine for his helpful advice regarding the statistical treatment of the data and structuring of the manuscript. This research was supported in part by National Heart, Lung, and Blood Institute Grant HL-17970. Received

13 October

1977; accepted

in final

form

24 October

1978.

REFERENCES 1. ADAMS, D. G., G. BACELLI, G. MANCIA, AND A. ZANCHETTI. Relation of cardiovascular changes in fighting to emotion and behavior. J. PhysioZ. London 212: 321-335, 1971. 2. ANDERSON, D. E., L. A. DALEY, J. D. FINDLEY, AND J. V. BRADY. A restraint system for psychophysiological study of the dog. Behau. Res. Methods Instrum. 2: 191-194, 1970. 3. BISHOP, V. S., AND F. D. PETERSON. Pathways regulating cardiovascular changes during volume loading in awake dogs. Am. J. PhysioZ. 231: 854-859, 1976. 4. COHEN, D. H., AND P. A. OBRIST. Interactions between behavior and the cardiovascular system. Circ. Res. 37: 693-706, 1975. 5. COWLEY, A. W., J. F. LIARD, AND A. C. GUYTON. Role of the baroreceptor reflex in daily control of arterial blood pressure and other variables in dogs. Circ. Res. 32: 564-576, 1973. 6. CULLEN, D. J. Interpretation of blood pressure measurements in anesthesia. Anesthesiology 40: 6-12, 1975. 7. DEWS, P. B., AND J. A. HERD. Behavioral activities and cardiovascular functions: effects of hexamethonium on cardiovascular changes during strong sustained static work in rhesus monkeys. J. PharmacoZ. Exp. Ther. 189: 12-23, 1974. 8. DONALD, K. W., A. R. LIND, G. W. MCNICHOL, P. W. HUMPHREYS,

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S. H. TAYLOR, AND H. P. STAUNTON. Cardiovascular responses to sustained (static) contractions. Circ. Res. 20-21, Suppl. 1: 15-30, 1967. GUILFORD, J. P. Psychometric Methods. New York: McGraw, 1954. LYNCH, J. J. Heart rate variability of dogs during classical conditioning. Psychol. Rec. 18: 101-106, 1968. NOBLE, M. I., D. TRENCHARD, AND A. Guz. Effect of changing heart rate on cardiovascular function in the unanesthetized dog. Circ. Res. 19: 206-213, 1966. RICHARDSON, D. W., A. J. HONOUR, G. W. FENTON, F. H. STOTT, AND G. W. PICKERING. Variation in arterial pressure throughout the day and night. CZin. Sci. 26: 445-454, 1964. ROWELL, L. B. Human cardiovascular adjustments to exercise and thermal stress. Physiol. Rev. 54: 75-159, 1974. SHIMADA, S. G., AND D. J. MARSH. Oscillations in mean arterial blood pressure of dogs. Federation Proc. (Abstract). 37: 223, 1978. SNEDECOR, G. W., AND W. G. COCHRAN. StatisticaL Methods. Ames, IA: Iowa Univ. Press, 1967. VATNER, S. F., AND D. H. BOETTSCHER. Regulation of cardiac output by stroke volume and heart rate in conscious dogs. Circ. Res. 42: 550-556, 1978.

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Minute-to-minute covariations in cardiovascular activity of conscious dogs.

Minute-to-minute covariations activity of conscious dogs in cardiovascular DAVID E. ANDERSON, JOHN E. YINGLING, AND KIICHI SAGAWA Departments of Psy...
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