Hemodynamic and metabolic adjustments exercise and shock avoidance in dogs ALAN
W. LANGER,
PAUL
A. OBRIST,
AND JAMES
during
A. McCUBBIN
Department of Psychiatry, School of Medicine, Division of Health Affairs, University of North Carolina, Chapel Hill, North Carolina 27514
cise response, this effect is associated with a reliable tachycardia. Unlike the exercise response, however, the metabolic significance of this phenomenon remains virH22SH230, 1979or Am. J. Physiol.: Heart Circ. Physiol. 5(2): tually unknown. Whether this represents a normal H225-H230, 1979.-The purpose of this study was to examine cardiac adjustment to an increased demand for oxygen, whether the hemodynamic and metabolic consequencesof a which is characteristic of the exercise response, has yet physical (treadmill exercise) and behavioral (signaled shockto be determined. Consequently, the purpose of the avoidance) stressor could be differentiated. To do this, direct is to examine the relationship becontinuous recordings of cardiac output, systolic and diastolic present experiment tween either cardiac output or heart rate and blood blood pressure, and discrete determinations of the arterial( (a-v)02 difference) during signaled mixed venous oxygen ((a-v)O,) content difference were ana- oxygen extraction lyzed in six dogsduring exposureto three grades of treadmill shock-avoidance stress in dogs to determine whether it exercise and when working on a shock-avoidance task. The is similar to or discrepant from the pattern elicited by results indicated that in five animals the relationship betwen treadmill exercise stress. A related aim is to evaluate cardiac output and the (a-v)Oe difference during shock-avoid- the blood pressure and total peripheral resistance ance conditioning was significantly different from the corre- changes that accompany these interventions. sponding.pattern observed during exercise. In four animals
LANGER, ALAN W., PAUL A. OBRIST, AND JAMES A. McCUBBIN. Hemodynamic and metabolic adjustments during exercise and shock avoidance in dogs. Am. J. Physiol. 236(2):
the data suggested that avoidance conditioning, relative to exercise stress, elicited overperfusion. Behavioral stress also produced reliable elevations in diastolic and systolic blood pressure. Theseresults suggestthat, when comparedto physical stress, behavioral stress can produce a dissociation of cardiovascular and metabolic processesin the presence of acute pressorresponses.
MATERIALS
AND METHODS
mongrel dogs weighing 11-15 kg obtained from the animal facility of the University of North Carolina at Chapel Hill. Throughout the course of the experiment all animals were maintained under ad libitum food and water. Apparatus. Subjects were run on a motor-driven cardiac output; heart rate; (a-v)O, differences; blood pressure; treadmill (Warren E. Collins) modified to provide paroverperfusion; stress tial restraint similar to a system described by Anderson et al. (2). This restraint system orients the animal toward the front of the apparatus where a translucent NUMEROUS STUDIES HAVE SHOWN thatphysicalexercise panel, 12 in. x 15 in., islocated. Both the illumination produces a reliable elevation in cardiac output that of this panel and the presentation of white noise comcovaries directly with the severity of the work load prise the discriminative stimulus for signaled shockimposed (4, 5, 13, 19, 26). Although this hemodynamic avoidance conditioning. A 1 kHz tone (Microtronics adjustment is primarily the result of a positive chronoCorp.) served as a warning signal or imperative stimutropic response, there is less consistent agreement re- lus associated with the delivery of a constant-current garding the extent to which stroke volume is responsishock (shock generator E6070B, Grayson-Stadler). The ble for this effect (4, 9, 12, 15, 18, 23, 25, 26, 28). presentation of the warning signal and delivery of shock Nonetheless, it is generally recognized that the rise in was programmed through a custom-designed, solidcardiac output that accompanies exercise typically cor- state logic system. responds to a predictable increase in blood oxygen The following parameters were continuously recorded extraction, i.e., widening of the (a-v)02 difference (4, 5, on a Beckman type RM Dynograph: 1) aortic blood flow 26). Such a relationship emphasizes the crucial role from an electromagnetic flowmeter (Carolina Medical perfusion plays in meeting the increased tissue demand Electronics) and 2 ) systolic and diastolic blood pressure for oxygen delivery during exercise stress. from either a strain gauge (MP-15 pressure transducer, Similarly, several recent investigations concerned Micron Instruments) and/or an implanted solid-state with the consequences of behavioral stress (aversive pressure transducer (model 6.5W, Konigsberg Instruconditioning) on the blood pressure responses of dogs ments). Parameters derived on the basis of recorded have reported significant increases in cardiac output signals included 1) total peripheral resistance obtained during episodes of signaled and unsignaled (Sidman) by dividing the estimated mean arterial pressure by the shock-avoidance conditioning (3, 20). As with the exer- corresponding cardiac output and 2 ) heart rate obtained 0363-6135/79/0000-0000$01.25
Copyright
0 1979 the American
Physiological
Subjects. The subjects were six male
Society
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H225
II226
LANGER,
OBRIST,
AND
McCUBBIN
by counting the number of cardiac cycles over a 10-s period followed by a period of 30-45 min when the period and multiplying the value by 6. animal was required to press an illuminated panel 10 s Finally, arterial and venous blood samples were col- after the onset of a 1 kHz tone. Failure to perform the lected in 2-ml oiled glass syringes connected to the criterion response resulted in the delivery of a ‘1.4-4.0 aortic and pulmonary arterial catheters by means of mA constant-current shock to the hindleg. A successful anesthesia extension sets. All samples were kept under response activated a relay that prevented the delivery refrigeration from l-3 h until they were analyzed for of shock, terminated the tone, which remained off for 20 oxygen content by means of an electronic oxygen ana- s, and initiated a new trial. Training the animal to lyzer (Lex-O&on M, Lexington Instruments). These panel press was accomplished by selectively reinforcing analyses were performed in duplicate and were required (withholding shock) successive approximations of the to check within 20.2 ~01%. desired response. Arterial and venous blood samples Surgery. Under aseptic sterile conditions all animals were collected at approximately 10,min intervals (10, were subjected to a left thoracotomy at the level of the 20, and 30 min) during the avoidance period and during third intercostal interspace while anesthetized with the 15-min rest (base line) when the animal was relasodium pentobarbital. For all dogs this procedure faciltively quiet. Also, these sessions incorporated three itated the implantation of I ) an electromagnetic flow bouts of exercise identical to that employed before probe (Carolina Medical Electronics or Zepeda Instrushock-avoidance training. These trials were separated ments) around the ascending aorta, 2) a pulmonary from the shock-avoidance episode by a 20-min rest arterial catheter, and 3 ) an aortic catheter and, for dogs interval. For these sessions (combined exercise and 3 and 4, a solid-state pressure transducer, implanted avoidance) the order of presentation of sh&k-avoidance directly in the descending aorta at the level of the aortic conditioning and treadmill exercise was counterbalcatheter. Catheters were introduced through the leff anced (the effect of order of presentation of the experiinternal thoracic artery and vein. The aortic catheter mental manipulations was controlled) across days, and was advanced through the left subclavian artery until any two sessions were separated by at least 1 day to it was localized in the descending aorta while the allow for recovery from the effects of blood sampling. pulmonary arterial catheter was routed through the In three dogs these procedures varied somewhat. For precava (cranial vena cava), the right atrium, and right dog 1 the first 4 days of shock-avoidance stress did not ventricle and then securely positioned in the pulmonary include exercise stress. Also, dog 2 received only 2 days artery. of exercise testing followed by 11 days of combined All catheters were constructed from modified anes- shock avoidance and exercise stress. thesia extension sets (Travenol Laboratories) and preData reduction. For all conditions (rest, exercise, and treated with a special heparin complex (tridodecylmethavoidance) all recorded and derived parameters were ylammonium chloride-heparin complex, Polysciences) averaged over a 10-s period that terminated when any to prevent the adhesion of any thrombi to the luminal given arterial and venous blood sample was obtained. surfaces of the catheters. Finally all leads were passed Thus, 10-s averages were computed for cardiac output subcutaneously to the back of the neck where they were (ml/min), systolic and diastolic blood pressure (mmHg), exteriorized and protected with ace bandage and tape. heart rate (beatslmin), and total peripheral resistance Training. Prior to thoracic surgery all animals were (peripheral resistance units (PRU) = mmHg/(ml/min)). initially trained for five daily. sessions to run on a These values were then used to calculate overall mean treadmill. These sessions incorporated a 15min rest levels by conditions for each individual animal. For dog period before exercise training to acclimate the dogs to 6 the cardiac output data were discarded on the basis of the apparatus and restraint system. After recovery from a defective flow probe.surgery the animals were exposed to five daily sessions Statistical analyses. Intercorrelations of heart rate of treadmill exercise the same as they received before with (a-v)On differences and of CO with (a-v)02 differsurgery. Each of these sessions consisted of a 15-mint ences were determined for avoidance and exercise stress rest period followed by three 3-min bouts of exercise for each individual animal. The corresponding slopes separated by 5-min time-out periods. The three exercise (regression coefficients) were determined by the method of least squares. This analysis, through the use of a periods represented three grades of exercise designated as light, intermediate, and heavy, which typically cor- general linear model, tested whether the slopes characresponded to treadmill speeds fixed at 1, 3, and 5 mph terizing the relationship between heart rate or cardiac output (the predictors) and the (a-v)02 difference (criterespectively. Arterial and venous blood samples were rion measure) were significantly different during exercollected at the end of the 3rd min of exercise stress and cise and avoidance. If they were not significantly differat a point during the 15-min rest period when the ent, the analysis tested whether the two conditions animal appeared relatively quiet and somatically inacwere associated with significantly different (a-v)02 levtive. To permit recovery from the effects of blood sampling, these sessions were separated by at least one els (main effect) when either predictor was statistically equilibrated across conditions (analysis of covariance). intervening day, during which the animals were not To assess the overall effect of the resting, exercise, subjected to the experimental protocols. After five sessions of treadmill exercise the dogs were and avoidance manipulations on total peripheral resistance and systolic and diastolic blood pressure, repeated shaped for 8 days on a signaled shock-avoidance task. Each of the these sessions started with a 15.min rest measures analyses of variance (treatment x subjects)
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HEMODYNAMICS
DURING
EXERCISE
AND SHOCK
AVOIDANCE
H227
output and the (a-v)02 difference, based on the exercise data, are both positive and significant (Table 2). In contrast, only two of the five subjects show evidence of a significant correlation among these variables during shock avoidance. Still, even when the correlations are significant for both conditions, those representing exercise stress are invariably larger. For all six subjects significant positive correlations were noted between heart rate and the (a-v)O* difference for exercise stress (Table 2), while only three animals gave evidence of a significant relationship between these parameters during avoidance. To better depict the difference in the relationship between cardiac output and the (a-v)O, difference during exercise and avoidance stress, the data from one RESULTS animal (dog 4 ) are presented in Fig. 1. The individual Exercise stress produced appreciable elevations in data points are the actual observations from this animal cardiac output, heart rate, and the (a-v)Oe difference during shock-avoidance conditioning. These values (Table 1). Th e magnitude of these effects varied as a have been superimposed over the line of best fit and the direct function of the severity of the exercise task. corresponding 95% prediction interval calculated from For the five dogs for which reliable cardiac output the data points obtained during exercise challenge. data are available, the correlations between cardiac Note that from a total of 21 observations during shock avoidance, more than 50% of these fall as outlyers below the lowest prediction band - a value that far exceeds the TABLE 1. Effects of rest, exercise, and shock expected frequency of only 2.5%. avoidance on cardiac output, heart rate, The reliability of such an effect was tested in four aitd (a-v)O, content difference dogs by analysis of covariance (Table 2, Main Effect). (a-v)02 DifferHeart Rate, Subj Condition For dogs 1,2, and 4 these analyses revealed that when beats/min ence, vol 96 cardiac output was statistically adjusted to comparable 1993&237 128210.1 5.220.24 Rest levels during exercise and avoidance stress, the corre6.020.28 Light 3060270 164t4.4 sponding (a-v)02 level was significantly lower during 177k7.9 7.1kO.30 Intermediate 37602163 avoidance. In one case (dog 5 ) this result was reversed, 20627.5 8.4t0.26 Heavy 4420t158 348Ok99 195t4.6 5.4t0.22 Avoidance i.e., at the same cardiac output levels the (a-v)02 difference was larger during shock avoidance. A differ1589k57 7522.1 4.4t0.15 Rest ent pattern emerged with dog 3. Here the slopes char125iz2.0 5.8kO.13 Light 2988t109 acterizing the cardiac output-(a-v)Oz relationship for 34242110 138d.5 6.4k0.15 Intermediate 3609t105 145k2.4 6.520.13 both conditions were significantly different (F = 8.90; Heavy 3219tllO 13224.2 5.6k0.14 Avoidance df = 1, 74; P c 0.01). This difference indicates that as cardiac output increases the discrepancy in (a-v)Oe 9Ok3.0 4.420.18 Rest 29772104 levels between conditions increases, with greater blood 15323.7 6.3t0.19 Light 57332153 oxygen extraction favoring the exercise task. Intermediate 62902127 165t3.4 8.520.21 195t3.2 10.220.26 Heavy 76282134 When this analysis was applied to the relationship 16024.7 6.320.31 Avoidance 52172127 between heart rate and (a-v)Oz differences, three subjects (dogs 1,2, and 4 ) gave evidence that when heart 14671r65 72k2.6 5.020.22 Rest rate was statistically equilibrated for both stressors, a 6.420.15 Light 2400t66 lllt3.9 Intermediate 2819255 131t4.0 7.1kO.20 significantly reduced (a-v)02 difference accompanied 3753270 17623.6 8.4kO.18 Heavy the shock avoidance stressor (Table 2, Main Effect). Avoidance 34762134 17026.3 6.520.36 Finally, of the remaining three animals, the data from two (dogs 3 and 6) showed significantly different slopes Rest 1867298 94t3.5 4.320.17 during exercise and avoidance, which in each case Light 31752132 148tl.4 6.5kO.17 Intermediate 36672205 15922.9 7.5t0.18 suggested that mathigher heart rates the (a-v)02 differHeavy 4301i1160 176k2.3 8.3kO.20 ence was lower during avoidance. 8.1kO.34 Avoidance 31832129 17725.1 Exercise stress and shock avoidance augmented both * -* diastolic and systolic blood pressure and attenuated 7722.4 4.820.13 Rest * * 14e3.0 7.1t0.18 Light total peripheral resistance for all subjects (Table. 3). A * * 16222.7 8.4kO.19 Intermediate repeated measures analysis of variance of diastolic * * 17723.6 9.2t0.41 Heavy pressure indicated a significant main effect for condi* * 146e5.5 8.120.25 Avoidance tions (F = 7.07; df = 4, 20; P c 0.002). Multiple Values are means t SE; n = 6 dogs. Light,. intermediate, and comparisons showed that heavy exercise and shock heavy refer to three increasing grades of treadmill exercise; avoidavoidance produced significant diastolic elevations over * Unavailable due to defective flow ance is shock avoidance. resting levels (Fig. 2). Also, only shock avoidance elicprobe. were performed on each of these measures. The purpose of these analyses was to compare to what extent these contingencies differentially altered arterial blood pressure and total peripheral resistance. A posteriori multiple pairwise comparisons were evaluated with Tukey’s HSD (honestly significant difference) test. This test provides a range statistic for a specified level of significance (CY= 0.05 in this case), which, when exceeded by a pairwise mean difference, indicates a reliable difference between the means. All analyses described were facilitated by the use of Statistical Analysis Systems (SAS) computer software (6).
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HZ28 TABLE
LANGER,
AND McCUBBIN
2. Comparison of within-subject correlations and regression coeffzcients Avoidance
Exercise Subj
1
OBRIST,
=, Y
r
b
Avoidance
r
b
Difference
between
slopes
vs. Exercise Main
effect (analysis
of covariance)
0.48* 0.61t
o.oot3* 0.0266t
0.31 0.31
0.0066 0.0145
F = 0.06 F = 0.96
df= df=
1,41 1,41
F = 20.29t F = 42.51t
df = 1,41 df = 1,41
HR, (a-v)02
0.40* 0.46t
0.00049* 0.02405t
0.39* 0.23
0.00053* 0.0079
F = 0.02 F = 2.08
df= df=
1,70 1,70
F = 12.2w F = 12.3ot
df= df=
3
CO, (a-v)02 HR, (a-v)02
0.74t 0.68t
0.0014t 0.05519t
F = 8.90t F = 13.39t
df=1,74 df=1,74
4
CO, (a-v)O, HR, (a-v)O,
0.73t 0.62t
0.00124t 0.0211t
0.65t 0.44*
0.00178t 0.0259*
F = 1.82 F = 0.23
df = 1,67 df= 1,67
F = 35.59t F = 24.71t
df= df=
1,67 1,67
CO,
0.62t 0.58t
0.00082t 0.0401t
0.01 0.53t
0.00002 0.0362t
F = 2.92 F = 0.07
df=1,64 df= 1,64
F = 12.01t F = 0.24
df= df=
1,64 1,64
CO,
(a-v)02
HR, (a-v)O, 2
5
CO,
(a-v)Op
(a-v)02
HR, (a-v)02 6
CO,
-0.03 -0.03
-0.00008 -0.00222
I I
1,70 1,70 $ $
\
(a-v)O&
HR, (a-v)O, 0.7ot 0.05111t 0.56t 0.02563t F = 4.69* df= 1,60 $ I Values derived from measurements taken during treadmill exercise and shock avoidance; r, correlation coefficient; b, regression coefficient; CO, cardiac output; HR, heartrate. * P c 0.05. t P c 0.01. $ Not tested. 9 Unavailable due to defective flow probe.
sistance relative to resting levels. Furthermore, the drop in resistance found during heavy exercise was significantly greater than that accompanying light exercise, whereas the resistance values obtained during shock avoidance were reliably elevated over those levels determined for intermediate or heavy exercise stress.
IO
DISCUSSION
2000 CARDIAC
3000 OUTPUT
4000
5000
(milliliters/minute)
FIG. 1. Line of best fit and 95% prediction interval representing relationship between cardiac output and (a-v)02 difference determined on the basis of exercise stress for dog 4. Data points represent actual observations during shock avoidance.
ited significant increases in diastolic blood pressure above those levels reached during light or intermediate exercise stress. A comparable analysis of systolic blood pressure showed a reliable main effect for conditions (F = 19.23;df = 4, 20;P < 0.0001). Intermediate and heavy treadmill exercise as well as shock avoidance resulted in significant increases in systolic blood pressure over resting levels. Also, the systolic blood pressure level associated with shock avoidance was reliably greater than that found for either light or intermediate exercise stress (Fig. 2). Finally, the repeated measures analysis of variance of the total peripheral resistance data revealed a significant main effect for conditions (F = 72.81; df = 4, 16;P < 0.0001). Multiple pairwise comparisons indicated that all three levels of exercise and shock avoidance produced significant reductions in re-
Collectively, these data are not at variance with previous reports delineating the hemodynamic and metabolic correlates of the exercising dog (4, 5, 8, 9, 12, 13, 18,19). Therefore, using these data as a reference point, comparisons were made with those cardiovascular and metabolic adjustments evoked by signaled shock-avoidance conditioning. The most striking finding here was the fact that the relationship between cardiac output and the (a-v)Oz difference was significantly altered during avoidance. A comparable evaluation of the heart rate-( a-v)02 relationship indicated reliable differences between conditions for five dogs while only dog 5 showed no change between conditions. Although these findings are not invariant across subjects they nevertheless do demonstrate that behavioral stress can have a unique influence by producing a dissociation among cardiovascular and metabolic events relative to the exercise response. In four of the animals studied (dogs I, 2, 3, and 4 ), this pattern may be characterized in terms of overperfusion of the systemic circulation, i.e., the output appears relatively excessive for any given level of blood oxygen extraction during shock avoidance. Similarly, for three animals (dogs 1, 2, and 4) the heart rates encountered during avoidance stress appeared relatively exaggerated with respect to corresponding (a-v)02 levels, but for two other animals (dogs 3 and 6) this effect was only manifested at appreciably elevated heart rate levels. The relevance of these phenomena to blood pressure control is also apparent because the present findings show that only heavy exercise and avoidance produced significant elevations in diastolic blood pressure and that the largest change in systolic blood pressure typi-
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HEMODYNAMICS
DURING
EXERCISE
HZ9
AND SHOCK AVOIDANCE
TABLE 3.. Effects of rest, exercise, and shock avoidance on blood pressure and peripheral resistance Subj.
Condition
Diastolic BP, mmHg
Total Peripheral Resistance, PRU
1
Rest
Light Intermediate Heavy Avoidance
53 55 61 67 66
t t 2 k 2
4.6 3.7 4.2 4.4 3.4
116 128 133 141 150
k t 2 t t
6.2 3.4 3.5 4.9 3.9
0.043 0.026 0.023 0.021 0.027
2 0.0045 AI 0.0007 + 0.0012 t 0.0011 t 0.0012
2
Rest Light Intermediate Heavy Avoidance
46 60 52 49 68
t t + t +
3.0 1.9 2.5 2.6 1.9
91 110 109 109 124
t t f. ,t t
3.6 1.9 3.0 3.2 2.5
0.040 0.026 0.021 0.019 0.028
k 0.0028 of 0.0012 St 0.0011 t'0.0009 A 0.0008
3
Rest Light Intermediate Heavy Avoidance
58 69 77 92 88
2 t t t k
2.1 -2.1 2.6 2.5 3.3
100 113 121 144 137
t 2.9 k 2.8 t 3.1 ,+ 3.3 t 3.5
0.025 0.015 0.015 0.015 0.020
t It 2 k 2
0.0014 0.0005 0.0005 0.0004 0.0006
4
Rest Light Intermediate Heavy Avoidance
60 60 69 90 107
t 2.6 k 2.6 in 2.9 t 3.8 k 3.5
122 120 129 149 175
f 3.0 2 2.7 2 3.6 t 3.9 -e 4.9
0.056 0.034 0.031 0.029 0.038
t t 2 t +
0.0036 0.0012 0.0011 0.0011 0.0011
Rest Light Intermediate Heavy Avoidance
67 77 69 72 83
+ 2.0 k 2.7 k 2.1 t 9.5 ~fr2.0
113 130 131 129 145
in & k k t
0.046 0.031 0.028 0.021 0.034
t t t t k
0.0023 0.0016 0.0020 0.0018 0.0029
5
2.3 2.2 9.9 9.5 2.5
* Rest 49 + 1.8 103 & 1.4 * Light 56 2 1.7 112 k 2.3 t Intermediate 54 t 3.2 120 2 4.1 * Heavy 57 t 2.7 123 k 5.3 * Avoidance 59 t 1.7 128 2 2.9 Values are means t SE; n = 6 dogs. PRU, peripheral ance units. * Unavailable due to defective flow probe. 6
* * * * * resist-
tally occurred during avoidance stress. These data, then, replicate in most respects, as well as extend, the findings previously reported by Anderson and Tosheff (3) and Lawler et al. (20). These authors reported that behavioral stress in the form of shockavoidance conditioning produced appreciable increases in cardiac output, heart rate, and arterial blood pressure in chronic dogs. The present study not only confirms these observations, but also points out that the augmentation in cardiac output during avoidance is not always metabolically warranted, but rather can be disproportionate to comparable adjustments made during physical exercise. Thus, the cardiovascular and metabolic patterns found during physical and behavioral stress are not always comparable or equivalent: a point fundamental to the advancement of any cardiovascular-based “psychosomatic” hypothesis. Equally important is the fact that the present results (for four dogs) conform to the expectations of the socalled autoregulation theory of essential hypertension (10, 17, 21); that is, behavioral stress, unlike exercise, precipitates episodes, of over-perfusion, which according to the autoregulation theory is a necessary precursor to the development of compensatory increases in arteriolar resistance. The fact that the effects observed in the present study were transient and that long-term resist-
60
BASELINE
SLOW
MEDIUM
FAST AVOIDANCE
FIG. 2. Average systolic and diastolic blood pressure responses of 6 dogs during rest, 3 grades of treadmill exercise, and shockavoidance stress.
ante changes were not evaluated does not rule out the possibility that protracted behavioral stress (several months or longer) could elicit a sustained overperfusion, which might trigger resistance-mediated increases in arterial pressure. Although the results of this study do not directly address the problem of neurogenic mediation some interesting data with a direct bearing on this issue are available. In this connection, Anderson and Brady (1) have recently shown that beta-adrenergic receptor blockade (propranolol) significantly attenuates the tachycardia typically elicited by shock avoidance in dogs. Furthermore, such a reduction in heart rate implies a concomitant decrease in cardiac output, an effectthat has been demonstrated during beta-adrenergic blockade in dogs exposed to short~term classical aversive conditioning (8) and in rhesus monkeys subject to Sidman avoidance stress (14). Also, beta-adrenergic blockade can effectively reduce myocardial contractility in both rhesus monkeys (24) and chronic dogs (22) during classical aversive conditioning. In addition, a recent report indicates that cardiospecific beta-adrenergic blockade can reduce the elevation in cardiac output, left ventricular dP/&, and heart rate during 2-min episodes of signaled shock avoidance in dogs (16). Collectively, these observations tend to support the speculation that the relative dissociation of either cardiac output and/or heart rate with the (a-v)Oz differences seen in the present study might be imputed to increased sympathetic activity. If the effects reported here were a function of marked sympathetic tone on the heart, they would show some remarkable parallels with the symptomatology associated with labile hypertension.
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H230
LANGEI&
The authors express their appreciation to Dr. Lloyd R. Yonce of the Department of Physiology, School of Medicine, Division of Health Affairs, University of North Carolina at Chapel Hill, for his extensive help and comments on this manuscript. The research reported in this article was supported by National Institute of Mental Health Grants MH-07995 and MH-14269, National Institute of Heart, Lung, and Blood Grant HL-18976, and
OBRIST,
AND McCUBBIN
North Carolina Heart Association Grant 1975-76 AO14. Address reprint requests to: Dr. Alan W. Langer, .Department of Psychiatry, School of Medicine, Division of Health mairs, University of North Carolina, Chapel Hill, North Carolina 27514. Received 8 May 1978; accepted in final form 8 September 1978.
REFERENCES 1. ANDERSON, D. E., AND J. V. BRADY. Cardiovascular responses TV avoidance conditioning in the dog: effects of beta adrenergic blockade. Psychosom. Med. 38: 181-189,1976. 2. ANDERSON, D. E., L. E. DALEY, J. D. FINDLEY, AND J. V. BRADY. A restraint system for the psychophysiological study of dogs. Behav. Res. Methods & Instrum. 2: 191-194, 1970. 3. ANDERSON, D. E., AND J. G. TOSHEFF. Cardiac output and total peripheral resistance changes during preavoidance periods in the dog. J. Appl. Physiol. 34: 650-654,1973. 4. BAILIE, M. D., S. ROBINSON, H. H. ROSTORFER, *AND J. L. NEWTON. Eflects of exercise on heart output of the dog. J. Appl. Physiol. 16: 107-111,1961, 5. BARGER, A. C., V. RICHARDS, 3. METCALF, AND B. GUNTHER. Regulation of the circulation during exercise: cardiac output (direct Fick) and metabolic adjustments in the normal dog. Am. J. Physiol. 184: 613-623,1956. 6. BARR, A. J., J. H. GOODNIGHT, J. P. SALL, AND J. T. HELW~G. A User’s Guide to SAS 76. Raleigh, NC: SAS Institute, 1977. 7. BASSENGE, E., M. KUCHARCZYK, J. HOLTZ, AND D. STOIAN. Treadmill exercise in dogs under beta adrenergic blockade: adaptation of coronary and systemic hemodynamics. Pfzuegers Arch. 332: 40-55, 1972. 8. BERGAMASCHI, M., AND A. M. LONCONI. Cardiovascular events in anxiety: experimental studies in the conscious dog. Am. Heart J. 86: 385-394,1973. 9. CERRETELLI, P., J. PIIPER, F. MANGILI, F. CUITICA,~ AND B. RICCI. Circulation in exercising dogs. J. AppZ. Physiol. 19: 2932,1964. 10. COLEMAN, T. G., H. J. GRANGER, AND A. C. GUYTON. Wholebody circulatory autoregulation and hypertension. Circ. Res. 28-29: 76-87, 1971. 11. EHRLICH, W., F. V. SCHRIJEN, D. T. KRAUSMAN, P. CALDINI, AND J. V. BRADY. The effect of beta-blockade on coronary and systemic circulation in dogs at rest and during adaptation to exercise. Arch. Int. Pharmacodyn. Ther. 204: 213-227, 1973. 12. ERICKSON, H. H., V. S. BISHOP, M. B. KAIUXIN, AND L. D. HORWITZ. Left ventricular internal diameter and cardiac function during exercise. J. AppZ. Physiol. 80: 473-478, 1971. 13. FIXLER, D, E.,, J. M. ATKINS, J. H. MITCHELL, AND L. D. HORWITZ. Blood flow to respiratory, cardiac, and limb muscles in dogs during graded exercise. Am. J. Physiol. 231: 1515-1519, 1976. 14. FORSYTH, R. P. Effect of propranolol on stress-induced hemodynamic changes in monkeys. In: Beta-Adrenoceptor Blocking
Agents, edited by P. R. Smena and R. P. Forsyth. Amsterdam: North-Holland, p. 317-322, 1976. 15. FRANKIJN, D. L., R. M. ELLIS, AND R. F. RUSHMER. Aortic blood flow in dogs during treadmill exercise. J. AppZ. Physiol. 14: 809812,1959. 16. GRIGNOLO, A., K. C. LIGHT, AND P. A. OBRI~T. Cardiac betaadrenergic responses during behavioral stress in the dog (Abstract). Fe&ration Proc. 37: 701,1978. 17. GUYTON, A. C., T. G. COLEUN, J. D. BOWER, AND H. J. GRANOER. Circulatory control in hypertension. Circ. Res. 26-27, Suppl. 2: 135-137, 1970. 18. HORWITZ, L. D., J. M. ATKINS, ANb S. J. LESHIN. Role of the Frank-Starling mechanism in exercise. Circ. Res. 31: 868875, 1972. 19. KHOURI, E. M., D. E. GREGG, AND C. R. RAYFORD. Effect of exercise on cardiac output, lefi coronary flow, and myocardial metabolism in the unanesthetized dog. Circ. Res. 17: 427437, 1965. 20. LAWLER, J. E., P. A. OBRIST, AND K. A. LAWLER. Cardiovascular f&&ion during preavoidance, avoidance, and postavoidance in dogs. Psychophysiology 12: 4-11,1975. 21. LEDINGHAM, J. M., AND R. D. COHEN. Role of the heart in the pathogenesis of renal hypertension. Lancet 2: 979-981,1963. 22. OBRIST, P. A., J. L. HOWARD, J. E. LAWLER, J. R. SIJTIXRER, K. W. SMITHSON, AND P. L. MARTIN. Alterations in cardiac contractility during classical aversive conditioning in dogs: methodological and theoretical implications. Psychophysiology 9: 246-261, 1972. 23. PIIPER, J., P. CERRETELLI, F. CUTTICA, AND F. MANGILI. Energy metabolism and circulation in dogs exercising in hypoxia. J. AppZ. Physiol. 21: 1143-1149,1966. 24. RANDALL, D. C., AND 0. A. SMITH. Ventricular contracility during controlled exercise and emotion in the primate. Am. J. PhysioZ. 226: 1051-1059,1974. 25. RUSHMER, R. F. Constancy of stroke volume in ventricular response TV exertion. Am. J. Physiol. 196: 745-750,1959. 26. SMULYAN, H., R. P. CUDDY, W. A. VINCENT, U. KASHEMASANT, AND R. H. EICH. Initial hemodynamic responses to mild exercise in trained dogs. J. AppZ. Physiol. 20: 437-442,1965. 27. VAN CITTER~, R. L., AND D. L. FRAN-. Cardiovascular performance of Alaska sled dogs during exercise. Gin:. Res. 24: 33-42,1969. 28. WILSON, M. F. Left ventricular diameter, posture, and exercise Circ. Res. 11: 3342, 1962.
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W. LANGER,
PAUL
A. OBRIST,
AND JAMES
during
A. McCUBBIN
Department of Psychiatry, School of Medicine, Division of Health Affairs, University of North Carolina, Chapel Hill, North Carolina 27514
cise response, this effect is associated with a reliable tachycardia. Unlike the exercise response, however, the metabolic significance of this phenomenon remains virH22SH230, 1979or Am. J. Physiol.: Heart Circ. Physiol. 5(2): tually unknown. Whether this represents a normal H225-H230, 1979.-The purpose of this study was to examine cardiac adjustment to an increased demand for oxygen, whether the hemodynamic and metabolic consequencesof a which is characteristic of the exercise response, has yet physical (treadmill exercise) and behavioral (signaled shockto be determined. Consequently, the purpose of the avoidance) stressor could be differentiated. To do this, direct is to examine the relationship becontinuous recordings of cardiac output, systolic and diastolic present experiment tween either cardiac output or heart rate and blood blood pressure, and discrete determinations of the arterial( (a-v)02 difference) during signaled mixed venous oxygen ((a-v)O,) content difference were ana- oxygen extraction lyzed in six dogsduring exposureto three grades of treadmill shock-avoidance stress in dogs to determine whether it exercise and when working on a shock-avoidance task. The is similar to or discrepant from the pattern elicited by results indicated that in five animals the relationship betwen treadmill exercise stress. A related aim is to evaluate cardiac output and the (a-v)Oe difference during shock-avoid- the blood pressure and total peripheral resistance ance conditioning was significantly different from the corre- changes that accompany these interventions. sponding.pattern observed during exercise. In four animals
LANGER, ALAN W., PAUL A. OBRIST, AND JAMES A. McCUBBIN. Hemodynamic and metabolic adjustments during exercise and shock avoidance in dogs. Am. J. Physiol. 236(2):
the data suggested that avoidance conditioning, relative to exercise stress, elicited overperfusion. Behavioral stress also produced reliable elevations in diastolic and systolic blood pressure. Theseresults suggestthat, when comparedto physical stress, behavioral stress can produce a dissociation of cardiovascular and metabolic processesin the presence of acute pressorresponses.
MATERIALS
AND METHODS
mongrel dogs weighing 11-15 kg obtained from the animal facility of the University of North Carolina at Chapel Hill. Throughout the course of the experiment all animals were maintained under ad libitum food and water. Apparatus. Subjects were run on a motor-driven cardiac output; heart rate; (a-v)O, differences; blood pressure; treadmill (Warren E. Collins) modified to provide paroverperfusion; stress tial restraint similar to a system described by Anderson et al. (2). This restraint system orients the animal toward the front of the apparatus where a translucent NUMEROUS STUDIES HAVE SHOWN thatphysicalexercise panel, 12 in. x 15 in., islocated. Both the illumination produces a reliable elevation in cardiac output that of this panel and the presentation of white noise comcovaries directly with the severity of the work load prise the discriminative stimulus for signaled shockimposed (4, 5, 13, 19, 26). Although this hemodynamic avoidance conditioning. A 1 kHz tone (Microtronics adjustment is primarily the result of a positive chronoCorp.) served as a warning signal or imperative stimutropic response, there is less consistent agreement re- lus associated with the delivery of a constant-current garding the extent to which stroke volume is responsishock (shock generator E6070B, Grayson-Stadler). The ble for this effect (4, 9, 12, 15, 18, 23, 25, 26, 28). presentation of the warning signal and delivery of shock Nonetheless, it is generally recognized that the rise in was programmed through a custom-designed, solidcardiac output that accompanies exercise typically cor- state logic system. responds to a predictable increase in blood oxygen The following parameters were continuously recorded extraction, i.e., widening of the (a-v)02 difference (4, 5, on a Beckman type RM Dynograph: 1) aortic blood flow 26). Such a relationship emphasizes the crucial role from an electromagnetic flowmeter (Carolina Medical perfusion plays in meeting the increased tissue demand Electronics) and 2 ) systolic and diastolic blood pressure for oxygen delivery during exercise stress. from either a strain gauge (MP-15 pressure transducer, Similarly, several recent investigations concerned Micron Instruments) and/or an implanted solid-state with the consequences of behavioral stress (aversive pressure transducer (model 6.5W, Konigsberg Instruconditioning) on the blood pressure responses of dogs ments). Parameters derived on the basis of recorded have reported significant increases in cardiac output signals included 1) total peripheral resistance obtained during episodes of signaled and unsignaled (Sidman) by dividing the estimated mean arterial pressure by the shock-avoidance conditioning (3, 20). As with the exer- corresponding cardiac output and 2 ) heart rate obtained 0363-6135/79/0000-0000$01.25
Copyright
0 1979 the American
Physiological
Subjects. The subjects were six male
Society
Downloaded from www.physiology.org/journal/ajpheart at Macquarie Univ (137.111.162.020) on February 15, 2019.
H225
II226
LANGER,
OBRIST,
AND
McCUBBIN
by counting the number of cardiac cycles over a 10-s period followed by a period of 30-45 min when the period and multiplying the value by 6. animal was required to press an illuminated panel 10 s Finally, arterial and venous blood samples were col- after the onset of a 1 kHz tone. Failure to perform the lected in 2-ml oiled glass syringes connected to the criterion response resulted in the delivery of a ‘1.4-4.0 aortic and pulmonary arterial catheters by means of mA constant-current shock to the hindleg. A successful anesthesia extension sets. All samples were kept under response activated a relay that prevented the delivery refrigeration from l-3 h until they were analyzed for of shock, terminated the tone, which remained off for 20 oxygen content by means of an electronic oxygen ana- s, and initiated a new trial. Training the animal to lyzer (Lex-O&on M, Lexington Instruments). These panel press was accomplished by selectively reinforcing analyses were performed in duplicate and were required (withholding shock) successive approximations of the to check within 20.2 ~01%. desired response. Arterial and venous blood samples Surgery. Under aseptic sterile conditions all animals were collected at approximately 10,min intervals (10, were subjected to a left thoracotomy at the level of the 20, and 30 min) during the avoidance period and during third intercostal interspace while anesthetized with the 15-min rest (base line) when the animal was relasodium pentobarbital. For all dogs this procedure faciltively quiet. Also, these sessions incorporated three itated the implantation of I ) an electromagnetic flow bouts of exercise identical to that employed before probe (Carolina Medical Electronics or Zepeda Instrushock-avoidance training. These trials were separated ments) around the ascending aorta, 2) a pulmonary from the shock-avoidance episode by a 20-min rest arterial catheter, and 3 ) an aortic catheter and, for dogs interval. For these sessions (combined exercise and 3 and 4, a solid-state pressure transducer, implanted avoidance) the order of presentation of sh&k-avoidance directly in the descending aorta at the level of the aortic conditioning and treadmill exercise was counterbalcatheter. Catheters were introduced through the leff anced (the effect of order of presentation of the experiinternal thoracic artery and vein. The aortic catheter mental manipulations was controlled) across days, and was advanced through the left subclavian artery until any two sessions were separated by at least 1 day to it was localized in the descending aorta while the allow for recovery from the effects of blood sampling. pulmonary arterial catheter was routed through the In three dogs these procedures varied somewhat. For precava (cranial vena cava), the right atrium, and right dog 1 the first 4 days of shock-avoidance stress did not ventricle and then securely positioned in the pulmonary include exercise stress. Also, dog 2 received only 2 days artery. of exercise testing followed by 11 days of combined All catheters were constructed from modified anes- shock avoidance and exercise stress. thesia extension sets (Travenol Laboratories) and preData reduction. For all conditions (rest, exercise, and treated with a special heparin complex (tridodecylmethavoidance) all recorded and derived parameters were ylammonium chloride-heparin complex, Polysciences) averaged over a 10-s period that terminated when any to prevent the adhesion of any thrombi to the luminal given arterial and venous blood sample was obtained. surfaces of the catheters. Finally all leads were passed Thus, 10-s averages were computed for cardiac output subcutaneously to the back of the neck where they were (ml/min), systolic and diastolic blood pressure (mmHg), exteriorized and protected with ace bandage and tape. heart rate (beatslmin), and total peripheral resistance Training. Prior to thoracic surgery all animals were (peripheral resistance units (PRU) = mmHg/(ml/min)). initially trained for five daily. sessions to run on a These values were then used to calculate overall mean treadmill. These sessions incorporated a 15min rest levels by conditions for each individual animal. For dog period before exercise training to acclimate the dogs to 6 the cardiac output data were discarded on the basis of the apparatus and restraint system. After recovery from a defective flow probe.surgery the animals were exposed to five daily sessions Statistical analyses. Intercorrelations of heart rate of treadmill exercise the same as they received before with (a-v)On differences and of CO with (a-v)02 differsurgery. Each of these sessions consisted of a 15-mint ences were determined for avoidance and exercise stress rest period followed by three 3-min bouts of exercise for each individual animal. The corresponding slopes separated by 5-min time-out periods. The three exercise (regression coefficients) were determined by the method of least squares. This analysis, through the use of a periods represented three grades of exercise designated as light, intermediate, and heavy, which typically cor- general linear model, tested whether the slopes characresponded to treadmill speeds fixed at 1, 3, and 5 mph terizing the relationship between heart rate or cardiac output (the predictors) and the (a-v)02 difference (criterespectively. Arterial and venous blood samples were rion measure) were significantly different during exercollected at the end of the 3rd min of exercise stress and cise and avoidance. If they were not significantly differat a point during the 15-min rest period when the ent, the analysis tested whether the two conditions animal appeared relatively quiet and somatically inacwere associated with significantly different (a-v)02 levtive. To permit recovery from the effects of blood sampling, these sessions were separated by at least one els (main effect) when either predictor was statistically equilibrated across conditions (analysis of covariance). intervening day, during which the animals were not To assess the overall effect of the resting, exercise, subjected to the experimental protocols. After five sessions of treadmill exercise the dogs were and avoidance manipulations on total peripheral resistance and systolic and diastolic blood pressure, repeated shaped for 8 days on a signaled shock-avoidance task. Each of the these sessions started with a 15.min rest measures analyses of variance (treatment x subjects)
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HEMODYNAMICS
DURING
EXERCISE
AND SHOCK
AVOIDANCE
H227
output and the (a-v)02 difference, based on the exercise data, are both positive and significant (Table 2). In contrast, only two of the five subjects show evidence of a significant correlation among these variables during shock avoidance. Still, even when the correlations are significant for both conditions, those representing exercise stress are invariably larger. For all six subjects significant positive correlations were noted between heart rate and the (a-v)O* difference for exercise stress (Table 2), while only three animals gave evidence of a significant relationship between these parameters during avoidance. To better depict the difference in the relationship between cardiac output and the (a-v)O, difference during exercise and avoidance stress, the data from one RESULTS animal (dog 4 ) are presented in Fig. 1. The individual Exercise stress produced appreciable elevations in data points are the actual observations from this animal cardiac output, heart rate, and the (a-v)Oe difference during shock-avoidance conditioning. These values (Table 1). Th e magnitude of these effects varied as a have been superimposed over the line of best fit and the direct function of the severity of the exercise task. corresponding 95% prediction interval calculated from For the five dogs for which reliable cardiac output the data points obtained during exercise challenge. data are available, the correlations between cardiac Note that from a total of 21 observations during shock avoidance, more than 50% of these fall as outlyers below the lowest prediction band - a value that far exceeds the TABLE 1. Effects of rest, exercise, and shock expected frequency of only 2.5%. avoidance on cardiac output, heart rate, The reliability of such an effect was tested in four aitd (a-v)O, content difference dogs by analysis of covariance (Table 2, Main Effect). (a-v)02 DifferHeart Rate, Subj Condition For dogs 1,2, and 4 these analyses revealed that when beats/min ence, vol 96 cardiac output was statistically adjusted to comparable 1993&237 128210.1 5.220.24 Rest levels during exercise and avoidance stress, the corre6.020.28 Light 3060270 164t4.4 sponding (a-v)02 level was significantly lower during 177k7.9 7.1kO.30 Intermediate 37602163 avoidance. In one case (dog 5 ) this result was reversed, 20627.5 8.4t0.26 Heavy 4420t158 348Ok99 195t4.6 5.4t0.22 Avoidance i.e., at the same cardiac output levels the (a-v)02 difference was larger during shock avoidance. A differ1589k57 7522.1 4.4t0.15 Rest ent pattern emerged with dog 3. Here the slopes char125iz2.0 5.8kO.13 Light 2988t109 acterizing the cardiac output-(a-v)Oz relationship for 34242110 138d.5 6.4k0.15 Intermediate 3609t105 145k2.4 6.520.13 both conditions were significantly different (F = 8.90; Heavy 3219tllO 13224.2 5.6k0.14 Avoidance df = 1, 74; P c 0.01). This difference indicates that as cardiac output increases the discrepancy in (a-v)Oe 9Ok3.0 4.420.18 Rest 29772104 levels between conditions increases, with greater blood 15323.7 6.3t0.19 Light 57332153 oxygen extraction favoring the exercise task. Intermediate 62902127 165t3.4 8.520.21 195t3.2 10.220.26 Heavy 76282134 When this analysis was applied to the relationship 16024.7 6.320.31 Avoidance 52172127 between heart rate and (a-v)Oz differences, three subjects (dogs 1,2, and 4 ) gave evidence that when heart 14671r65 72k2.6 5.020.22 Rest rate was statistically equilibrated for both stressors, a 6.420.15 Light 2400t66 lllt3.9 Intermediate 2819255 131t4.0 7.1kO.20 significantly reduced (a-v)02 difference accompanied 3753270 17623.6 8.4kO.18 Heavy the shock avoidance stressor (Table 2, Main Effect). Avoidance 34762134 17026.3 6.520.36 Finally, of the remaining three animals, the data from two (dogs 3 and 6) showed significantly different slopes Rest 1867298 94t3.5 4.320.17 during exercise and avoidance, which in each case Light 31752132 148tl.4 6.5kO.17 Intermediate 36672205 15922.9 7.5t0.18 suggested that mathigher heart rates the (a-v)02 differHeavy 4301i1160 176k2.3 8.3kO.20 ence was lower during avoidance. 8.1kO.34 Avoidance 31832129 17725.1 Exercise stress and shock avoidance augmented both * -* diastolic and systolic blood pressure and attenuated 7722.4 4.820.13 Rest * * 14e3.0 7.1t0.18 Light total peripheral resistance for all subjects (Table. 3). A * * 16222.7 8.4kO.19 Intermediate repeated measures analysis of variance of diastolic * * 17723.6 9.2t0.41 Heavy pressure indicated a significant main effect for condi* * 146e5.5 8.120.25 Avoidance tions (F = 7.07; df = 4, 20; P c 0.002). Multiple Values are means t SE; n = 6 dogs. Light,. intermediate, and comparisons showed that heavy exercise and shock heavy refer to three increasing grades of treadmill exercise; avoidavoidance produced significant diastolic elevations over * Unavailable due to defective flow ance is shock avoidance. resting levels (Fig. 2). Also, only shock avoidance elicprobe. were performed on each of these measures. The purpose of these analyses was to compare to what extent these contingencies differentially altered arterial blood pressure and total peripheral resistance. A posteriori multiple pairwise comparisons were evaluated with Tukey’s HSD (honestly significant difference) test. This test provides a range statistic for a specified level of significance (CY= 0.05 in this case), which, when exceeded by a pairwise mean difference, indicates a reliable difference between the means. All analyses described were facilitated by the use of Statistical Analysis Systems (SAS) computer software (6).
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HZ28 TABLE
LANGER,
AND McCUBBIN
2. Comparison of within-subject correlations and regression coeffzcients Avoidance
Exercise Subj
1
OBRIST,
=, Y
r
b
Avoidance
r
b
Difference
between
slopes
vs. Exercise Main
effect (analysis
of covariance)
0.48* 0.61t
o.oot3* 0.0266t
0.31 0.31
0.0066 0.0145
F = 0.06 F = 0.96
df= df=
1,41 1,41
F = 20.29t F = 42.51t
df = 1,41 df = 1,41
HR, (a-v)02
0.40* 0.46t
0.00049* 0.02405t
0.39* 0.23
0.00053* 0.0079
F = 0.02 F = 2.08
df= df=
1,70 1,70
F = 12.2w F = 12.3ot
df= df=
3
CO, (a-v)02 HR, (a-v)02
0.74t 0.68t
0.0014t 0.05519t
F = 8.90t F = 13.39t
df=1,74 df=1,74
4
CO, (a-v)O, HR, (a-v)O,
0.73t 0.62t
0.00124t 0.0211t
0.65t 0.44*
0.00178t 0.0259*
F = 1.82 F = 0.23
df = 1,67 df= 1,67
F = 35.59t F = 24.71t
df= df=
1,67 1,67
CO,
0.62t 0.58t
0.00082t 0.0401t
0.01 0.53t
0.00002 0.0362t
F = 2.92 F = 0.07
df=1,64 df= 1,64
F = 12.01t F = 0.24
df= df=
1,64 1,64
CO,
(a-v)02
HR, (a-v)O, 2
5
CO,
(a-v)Op
(a-v)02
HR, (a-v)02 6
CO,
-0.03 -0.03
-0.00008 -0.00222
I I
1,70 1,70 $ $
\
(a-v)O&
HR, (a-v)O, 0.7ot 0.05111t 0.56t 0.02563t F = 4.69* df= 1,60 $ I Values derived from measurements taken during treadmill exercise and shock avoidance; r, correlation coefficient; b, regression coefficient; CO, cardiac output; HR, heartrate. * P c 0.05. t P c 0.01. $ Not tested. 9 Unavailable due to defective flow probe.
sistance relative to resting levels. Furthermore, the drop in resistance found during heavy exercise was significantly greater than that accompanying light exercise, whereas the resistance values obtained during shock avoidance were reliably elevated over those levels determined for intermediate or heavy exercise stress.
IO
DISCUSSION
2000 CARDIAC
3000 OUTPUT
4000
5000
(milliliters/minute)
FIG. 1. Line of best fit and 95% prediction interval representing relationship between cardiac output and (a-v)02 difference determined on the basis of exercise stress for dog 4. Data points represent actual observations during shock avoidance.
ited significant increases in diastolic blood pressure above those levels reached during light or intermediate exercise stress. A comparable analysis of systolic blood pressure showed a reliable main effect for conditions (F = 19.23;df = 4, 20;P < 0.0001). Intermediate and heavy treadmill exercise as well as shock avoidance resulted in significant increases in systolic blood pressure over resting levels. Also, the systolic blood pressure level associated with shock avoidance was reliably greater than that found for either light or intermediate exercise stress (Fig. 2). Finally, the repeated measures analysis of variance of the total peripheral resistance data revealed a significant main effect for conditions (F = 72.81; df = 4, 16;P < 0.0001). Multiple pairwise comparisons indicated that all three levels of exercise and shock avoidance produced significant reductions in re-
Collectively, these data are not at variance with previous reports delineating the hemodynamic and metabolic correlates of the exercising dog (4, 5, 8, 9, 12, 13, 18,19). Therefore, using these data as a reference point, comparisons were made with those cardiovascular and metabolic adjustments evoked by signaled shock-avoidance conditioning. The most striking finding here was the fact that the relationship between cardiac output and the (a-v)Oz difference was significantly altered during avoidance. A comparable evaluation of the heart rate-( a-v)02 relationship indicated reliable differences between conditions for five dogs while only dog 5 showed no change between conditions. Although these findings are not invariant across subjects they nevertheless do demonstrate that behavioral stress can have a unique influence by producing a dissociation among cardiovascular and metabolic events relative to the exercise response. In four of the animals studied (dogs I, 2, 3, and 4 ), this pattern may be characterized in terms of overperfusion of the systemic circulation, i.e., the output appears relatively excessive for any given level of blood oxygen extraction during shock avoidance. Similarly, for three animals (dogs 1, 2, and 4) the heart rates encountered during avoidance stress appeared relatively exaggerated with respect to corresponding (a-v)02 levels, but for two other animals (dogs 3 and 6) this effect was only manifested at appreciably elevated heart rate levels. The relevance of these phenomena to blood pressure control is also apparent because the present findings show that only heavy exercise and avoidance produced significant elevations in diastolic blood pressure and that the largest change in systolic blood pressure typi-
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HEMODYNAMICS
DURING
EXERCISE
HZ9
AND SHOCK AVOIDANCE
TABLE 3.. Effects of rest, exercise, and shock avoidance on blood pressure and peripheral resistance Subj.
Condition
Diastolic BP, mmHg
Total Peripheral Resistance, PRU
1
Rest
Light Intermediate Heavy Avoidance
53 55 61 67 66
t t 2 k 2
4.6 3.7 4.2 4.4 3.4
116 128 133 141 150
k t 2 t t
6.2 3.4 3.5 4.9 3.9
0.043 0.026 0.023 0.021 0.027
2 0.0045 AI 0.0007 + 0.0012 t 0.0011 t 0.0012
2
Rest Light Intermediate Heavy Avoidance
46 60 52 49 68
t t + t +
3.0 1.9 2.5 2.6 1.9
91 110 109 109 124
t t f. ,t t
3.6 1.9 3.0 3.2 2.5
0.040 0.026 0.021 0.019 0.028
k 0.0028 of 0.0012 St 0.0011 t'0.0009 A 0.0008
3
Rest Light Intermediate Heavy Avoidance
58 69 77 92 88
2 t t t k
2.1 -2.1 2.6 2.5 3.3
100 113 121 144 137
t 2.9 k 2.8 t 3.1 ,+ 3.3 t 3.5
0.025 0.015 0.015 0.015 0.020
t It 2 k 2
0.0014 0.0005 0.0005 0.0004 0.0006
4
Rest Light Intermediate Heavy Avoidance
60 60 69 90 107
t 2.6 k 2.6 in 2.9 t 3.8 k 3.5
122 120 129 149 175
f 3.0 2 2.7 2 3.6 t 3.9 -e 4.9
0.056 0.034 0.031 0.029 0.038
t t 2 t +
0.0036 0.0012 0.0011 0.0011 0.0011
Rest Light Intermediate Heavy Avoidance
67 77 69 72 83
+ 2.0 k 2.7 k 2.1 t 9.5 ~fr2.0
113 130 131 129 145
in & k k t
0.046 0.031 0.028 0.021 0.034
t t t t k
0.0023 0.0016 0.0020 0.0018 0.0029
5
2.3 2.2 9.9 9.5 2.5
* Rest 49 + 1.8 103 & 1.4 * Light 56 2 1.7 112 k 2.3 t Intermediate 54 t 3.2 120 2 4.1 * Heavy 57 t 2.7 123 k 5.3 * Avoidance 59 t 1.7 128 2 2.9 Values are means t SE; n = 6 dogs. PRU, peripheral ance units. * Unavailable due to defective flow probe. 6
* * * * * resist-
tally occurred during avoidance stress. These data, then, replicate in most respects, as well as extend, the findings previously reported by Anderson and Tosheff (3) and Lawler et al. (20). These authors reported that behavioral stress in the form of shockavoidance conditioning produced appreciable increases in cardiac output, heart rate, and arterial blood pressure in chronic dogs. The present study not only confirms these observations, but also points out that the augmentation in cardiac output during avoidance is not always metabolically warranted, but rather can be disproportionate to comparable adjustments made during physical exercise. Thus, the cardiovascular and metabolic patterns found during physical and behavioral stress are not always comparable or equivalent: a point fundamental to the advancement of any cardiovascular-based “psychosomatic” hypothesis. Equally important is the fact that the present results (for four dogs) conform to the expectations of the socalled autoregulation theory of essential hypertension (10, 17, 21); that is, behavioral stress, unlike exercise, precipitates episodes, of over-perfusion, which according to the autoregulation theory is a necessary precursor to the development of compensatory increases in arteriolar resistance. The fact that the effects observed in the present study were transient and that long-term resist-
60
BASELINE
SLOW
MEDIUM
FAST AVOIDANCE
FIG. 2. Average systolic and diastolic blood pressure responses of 6 dogs during rest, 3 grades of treadmill exercise, and shockavoidance stress.
ante changes were not evaluated does not rule out the possibility that protracted behavioral stress (several months or longer) could elicit a sustained overperfusion, which might trigger resistance-mediated increases in arterial pressure. Although the results of this study do not directly address the problem of neurogenic mediation some interesting data with a direct bearing on this issue are available. In this connection, Anderson and Brady (1) have recently shown that beta-adrenergic receptor blockade (propranolol) significantly attenuates the tachycardia typically elicited by shock avoidance in dogs. Furthermore, such a reduction in heart rate implies a concomitant decrease in cardiac output, an effectthat has been demonstrated during beta-adrenergic blockade in dogs exposed to short~term classical aversive conditioning (8) and in rhesus monkeys subject to Sidman avoidance stress (14). Also, beta-adrenergic blockade can effectively reduce myocardial contractility in both rhesus monkeys (24) and chronic dogs (22) during classical aversive conditioning. In addition, a recent report indicates that cardiospecific beta-adrenergic blockade can reduce the elevation in cardiac output, left ventricular dP/&, and heart rate during 2-min episodes of signaled shock avoidance in dogs (16). Collectively, these observations tend to support the speculation that the relative dissociation of either cardiac output and/or heart rate with the (a-v)Oz differences seen in the present study might be imputed to increased sympathetic activity. If the effects reported here were a function of marked sympathetic tone on the heart, they would show some remarkable parallels with the symptomatology associated with labile hypertension.
Downloaded from www.physiology.org/journal/ajpheart at Macquarie Univ (137.111.162.020) on February 15, 2019.
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LANGEI&
The authors express their appreciation to Dr. Lloyd R. Yonce of the Department of Physiology, School of Medicine, Division of Health Affairs, University of North Carolina at Chapel Hill, for his extensive help and comments on this manuscript. The research reported in this article was supported by National Institute of Mental Health Grants MH-07995 and MH-14269, National Institute of Heart, Lung, and Blood Grant HL-18976, and
OBRIST,
AND McCUBBIN
North Carolina Heart Association Grant 1975-76 AO14. Address reprint requests to: Dr. Alan W. Langer, .Department of Psychiatry, School of Medicine, Division of Health mairs, University of North Carolina, Chapel Hill, North Carolina 27514. Received 8 May 1978; accepted in final form 8 September 1978.
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