73

Influence of Heat Stress on Arterial Baroreflex Control ofHeart Rate in the Baboon

Andrew J. Gorman and Duane W. ProppeFrom the Department of Physiology, The University of Texas Health Science Center at San Antonio, and Southwest Foundation for

Research and Education, San Antonio, Texas

SUMMARY. The influence of environmental heat stress on the arterial baroreflex control of heartrate (HR) was studied in eight conscious, chronically instrumented baboons. Inflations of balloonoccluders around the inferior vena cava (IVC) and thoracic descending aorta (DA) were used toproduce acute, graded changes in mean arterial blood pressure (MABP) in 5 mm Hg intervalsranging from ±5 to ±25 mm Hg. After determination of the HR responses to changes in MABP inthe normothermic baboon (blood temperature <37.6°C), the animal was subjected to environmentalheating to produce hyperthermia. When blood temperature reached approximately 39.5°C, HRresponses to graded DA and IVC occlusions were again determined. During hyperthermia, the HRsensitivity (AHR/AMABP) to MABP changes was markedly diminished for reductions in MABP andsignificantly enhanced for increases in MABP. To determine whether these alterations in the HRresponse to changes in MABP were due to an alteration of the baroreflex control of HR, full,sigmoid-shaped HR-MABP curves for both the normothermic and hyperthermic states were con-structed and characterized by total HR range, estimated slope of the steep portion of the curve, andMABP at the midpoint of the HR range (BPM). During hyperthermia (1) the whole HR-MABP curveshifted significantly upward by 35-40 beats/min, (2) total HR range, the estimated slope, and BP50did not change, and (3) the control point (pre-occlusion HR-MABP value) shifted upward along thesteep portion of the HR-MABP curve. In six of the eight baboons, full HR-MABP curves were alsoconstructed during either /?-adrenergic blockade or cholinergic (Ch)-receptor blockade in thenormothermic and hyperthermic state. Similar to that seen for the unblocked heart, the whole HR-MABP curves were also shifted upward during hyperthermia in this group of baboons with noalteration in the total HR range, the estimated slope, or BPr,0. The upward shift in the HR-MABPcurve during Ch-receptor blockade, unlike during /S-receptor blockade, was much greater than thatwhich could be attributed only to the local effect of blood temperature. Although the control pointwas also shifted upward along the steep portion of the curve during /?- or Ch-receptor blockade, theupward shift observed during /S-adrenergic blockade was similar to that observed in the unblockedstate. Thus, a heat stress-induced hyperthermia produces a rise in HR without significantly alteringthe characteristics of the reflex control of HR by arterial baroreceptors. To rely solely on changes inHR sensitivity may lead to erroneous conclusions as to the effect of a particular stress on thebaroreceptor reflex control of HR. Further, these results indicate that: (1) the upward shift in theHR-MABP curve is mediated by both the local effect of blood temperature on HR and cardiacsympathetic efferent neurons which are independent of the baroreceptor reflex, and (2) the upwardshift in the control point is mediated predominantly by vagal withdrawal, probably as part of thecompensatory response to a heat-induced hypotension. (Ore Res 51: 73-82, 1982)

IN RESPONSE to changes in arterial blood pressure(ABP), the arterial baroreceptors initiate reflex cardiacand vasomotor responses in an attempt to return ABPto control level (Heymans and Neil, 1958). The reflexheart rate (HR) relationship to ABP is characterizedby an inverse S-shaped curve with normal ABP exist-ing somewhere on the steep portion of this relation-ship. Thus, HR changes are reflexly elicited bychanges in ABP on both sides of the normal level.One important question is whether various physio-logical stresses alter the characteristics of the reflexcontrol of HR by the arterial baroreceptors. Studieshave shown that hypoxia and hypercapnia are accom-panied by an alteration of heart interval (HI) sensitiv-ity to ABP changes and a shift of the characteristicHI-ABP curve (Guazzi et al., 1970; Korner et al.,1973a). During exercise, the characteristic HR-ABPcurve in man moves to a new position (upward and

to the right), but without any apparent changes in HRsensitivity to ABP changes (Robinson et al., 1966).However, if HI is analyzed rather than HR, a differentconclusion is reached—namely, a marked attenuationof the sensitivity of the HI response to changes inABP occurs during exercise (Bristow et al., 1971;Pickering et al., 1972).

Exposing man or animals to a hyperthermia-pro-ducing hot environment results in increases in skinblood flow to promote heat loss (Rowell et al., 1974;Proppe et al., 1976). Among the secondary cardiovas-cular adjustments during the development of hyper-thermia is a substantial gradual rise in HR (Rowell etal., 1974; Proppe et al., 1976). ABP either initially fallsand then recovers or changes very little during thistime in which HR is rising (Rowell et al., 1969; Proppeet al., 1976). These trends in HR and ABP suggest thatthe baroreflex control of HR may be altered during

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74 Circulation Research/Vo/. 51, No. 1, July 1982

the rise in internal temperature. Therefore, the objec-tive of this study was to determine whether hyper-thermia induced by environmental heat stress altersthe characteristics of the reflex HR responses to acuteABP changes in the unanesthetized, chronically in-strumented baboon. This was carried out by compar-ing the HR responses to graded occlusions of thedescending aorta and inferior vena cava in normo-thermic vs. hyperthermic states.

MethodsEight adolescent male baboons (9-13 kg) of the Papio

anubis and Papio cynocephalus species were used in thisstudy. They were utilized following quarantine clearanceand adaptation to maintenance in a restraint chair.

Surgical PreparationEach animal was subjected to two aseptic surgeries, which

were performed under halothane anesthesia (0.5-5% in100% O2). By means of a left thoracotomy, the inferior venacava (IVC) and descending aorta (DA) were isolated 6-8 cmabove the diaphragm, and balloon occluders (In Vivo Met-ric) were positioned around these vessels. Also, the leftatrium was cannulated via its appendage with a Tygon(Norton Plastics) catheter for measurement of left atrialpressure (LAP). Each baboon was allowed to recover fullyfrom this thoracotomy (10-14 days) before the secondsurgery was performed. In the second surgery, the axillaryarteries were exposed bilaterally. A Tygon catheter wasinserted 10 cm into the left axillary artery so that its tip wasin or near the aortic arch for measurement of ABP. Into theright axillary artery was inserted a closed-tip catheter whichcontained a copper-constantan thermocouple (Bailey Instru-ments) for the measurement of arterial blood temperature(Tbi)- Thi was used as an index of internal temperature,since it is the primary determinant of temperature of thethermosensitive preoptic anterior hypothalamic region ofthe brain in the subhuman primate (Hayward and Baker,1968). The external jugular vein was also cannulated andused for drug infusion. All tubing from these two surgicalprocedures was passed subcutaneously to exit near theumbilicus.

After recovery from the second surgery, the baboon wasplaced in a restraint chair and maintained in a sound-attenuated chamber in which the ambient temperature (Ta)could be rapidly elevated and maintained at any level above25°C. Patency of all catheters was maintained by the con-tinuous infusion of heparinized saline (250 IU heparin in 50ml saline per day).

Measured VariablesLAP and ABP were measured by Statham P231D strain

gauge manometers. A cardiotachometer (Beckman Instru-ments), triggered by the ABP pulse, provided a continuousrecord of instantaneous HR. For the measurement of Tbi,the implanted copper-constantan thermocouple was con-nected to a digital thermometer (Bat-8C, Bailey Instruments)which also had an analogue output. All measurements werecontinuously recorded on a Beckman RM recorder. MeanABP (MABP) and mean LAP (MLAP) were also recordedby passing the pulsatile signals through low-pass filters inthe Beckman recorder.

Experimental ProtocolInitial experiments were conducted 2-3 weeks after the

thoracotomy. All experiments commenced early in the

morning while the baboon was sitting quietly in a thermo-neutral environment (25-27°C) and his Tb, was near thelowest level in its diurnal cycle (Tbi < 37.6°C). The firstprocedure consisted of performing graded DA and IVCocclusions through manual manipulation of saline-filledsyringes attached to the actuating tubing of the perivascularoccluders. Elevations and reductions in MABP were pro-duced in discrete intervals of ± 5-8, ± 9-12, ± 13-16, ±17-21, ± 22-27 mm Hg and maintained for 1.0-1.5 minute.After release of an occlusion, no subsequent occlusion wasperformed until HR and MABP had returned to their pre-occlusion levels. This usually entailed a 3- to 5-minuteperiod between occlusions. Preliminary experiments indi-cated that a series of consecutive DA occlusions tended tocause a gradual rise in the control (pre-occlusion) ABP level,while IVC occlusions had no effect on ABP. Therefore, DAand IVC occlusions were performed in a random sequencewhich was effective in maintaining a constant pre-occlusionABP level throughout a series of occlusions.

After a satisfactory series of ABP alterations had beenachieved at normothermic Tbi, Ta was elevated to 40-42°Cwhich caused Tbi to rise gradually. When Tbi reachedapproximately 39.6°C, elevations and reductions in ABPequivalent to the intervals produced in the normothermicstate were again produced. Following satisfactory manipu-lation of ABP in the hyperthermic state, environmentalheating was terminated.

In six of the eight baboons, in separate sessions ondifferent days, the same general protocol described abovewas again performed but during either jS-adrenergic orcholinergic (Ch)-receptor blockade.

To produce jS-adrenergic blockade, propranolol HCI (In-deral; Ayerst, Inc.) was infused intravenously at a rate of 10jug/kg per min following a bolus dose of 1 mg/kg. A priortest of the effectiveness of the yS-adrenergic blocking doseinvolved the intravenous infusion of the /S-adrenergic ago-nist isoproterenol (Isoprel; Vitarine Co., Inc.) at a maximumrate of 1.2 /ig/kg per min. The lack of a tachycardia at thisrate of isoproterenol infusion indicated that the above doseof propranolol was indeed an effective blocking dose. Atthe end of the experiment, the effectiveness of the /S-adren-ergic blockade was determined. While propranolol contin-ued to be infused, atropine sulfate was injected (see below),followed by maximal positive and negative changes in ABP(±35 mm Hg), inducing excessive excitement of the animal,or, in some cases, isoproterenol infusion (1.2 /ig/kg permin). If there was a lack of significant changes in HR duringeach of the above interventions, it was inferred that aneffective /8-adrenergic receptor blockade was present duringthe entire experimental period.

To produce Ch-receptor blockade, atropine sulfate (Vi-tarine Co., Inc.) was injected at a bolus dose of 0.15 mg/kgand followed by a constant infusion of 2 /^g/kg per min.Acute studies on two baboons indicated that the pro-nounced bradycardia in response to unilateral electricalstimulation of the right and left vagal nerve trunks wasblocked by atropine at the above dosage throughout a 3- to4-hour period. To determine the effectiveness of the Ch-receptor block at the end of an experiment in the consciousbaboon, large negative and positive changes in ABP wereproduced following a bolus injection of 1 mg/kg of pro-pranolol while atropine was continuing to be infused. Nosignificant changes in HR during maximal increases ordecreases in ABP (±35 mm Hg) indicated that an effectiveblock of the vagal influence on HR was present during theentire experimental period.

A potential criticism of the above protocol involving Ch-receptor blockade is whether the reported central excitatory

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Gorman and Proppe/Effect of Heating on Baroreflex Control of Heart Rate 75

effects of atropine sulfate (Donald et al., 1967) may haveinfluenced the results obtained. In two of the six baboonsundergoing autonomic blockade, therefore, the HR-MABPrelationship in the normothermic and hyperthermic states,the change in control HR, and the change in HR observedduring heat stress were compared for equivalent bolus doses(0.15 mg/kg) and infusion rates (2 ng/kg per min) ofatropine sulfate and atropine methylnitrate, a cholinergicantagonist that does not readily cross the blood-brain bar-rier (Innes and Nickerson, 1975). The data reported for Ch-receptor blockade (see Results) were not different in anymanner from those obtained during an infusion of atropinemethylnitrate in the two baboons studied.

Data Analysis

Our initial step in data analysis was the calculation of HRsensitivity to changes in ABP. HR sensitivity is the ratio ofthe change in HR (AHR) to a change in MABP (AMABP).HR sensitivity was calculated for each AMABP induced byIVC and DA occlusions. For equivalent changes in MABP,HR sensitivity values from the normothermic state werecompared with those obtained in the hyperthermic state.

To determine more fully the influence of hyperthermiaon the baroreceptor control of HR, we constructed full HR-MABP curves for both normothermic and hyperthermicstates. The average stimulus-response curve for a singlebaboon in a given state was constructed in the followingmanner: First, the average absolute MABP level achievedduring each interval change in MABP was determined froma number of experiments performed on separate days. Theaverage HR level elicited during a particular MABP changethen was determined in the same manner for each intervalchange in MABP. Then, the average HR was plotted againstthe average MABP which produced the characteristic sig-moid-shaped HR-MABP relationship (see Fig. 4).

To describe the HR-MABP relationship for the entiregroup of baboons, we computed the interanimal averageAHR for a given interval change in MABP by multiplyingthe interanimal average HR sensitivity value for each re-spective AMABP interval times the average value of eachAMABP interval, i.e., AHR = (AHR/AMABP) X AMABP.The absolute mean HR and MABP values were then derivedby adding the resulting AHR values and their correspondingAMABP to the mean absolute pre-occlusion HR and MABPlevels for all eight baboons. The resulting plot of HR vs.MABP depicts the HR-MABP relationship for all the ba-boons as a group.

The individual and group HR-MABP curves in the nor-mothermic and hyperthermic states were characterized byparameters similar to that introduced by Korner and col-leagues (1973a, 1979). These parameters are (1) total HRrange, (2) gain, i.e., slope of the steepest portion of thesigmoid curve, and (3) BPr*. The total HR range for eachanimal was obtained from the maximum plateau HR levelminus the minimum plateau HR level. The slope of thesteep portion of the HR-MABP curve was the regressioncoefficient derived from linear regression analysis of the 3-5 data points lying on this portion of the curve whichincluded the control (pre-occlusion) HR-MABP value andHR-MABP values that did not lie on the maximum andminimum plateau levels of the S-shaped curve. BP50 is theMABP level observed at one-half the HR range. Each curveparameter was determined for both the normothermic (con-trol) and hyperthermic Tbi states and compared.

Composite data from all animals are presented as mean± SEM. Significant differences between values from normo-thermic and hyperthermic states were determined by utiliz-ing the paired Student's f-test (Snedecor and Cochran,

1967). Changes were considered significant when P valueswere <0.05.

Results

During environmental heating, Thi was allowed torise from 36.9 ± 0.1°C to 39.5 ± 0.1°C before theABP manipulations were done at a hyperthermic Tbi •The time for Tbi to rise to this level ranged from 70to 110 minutes. During this rise in Tbi, HR rosegradually from 93 ± 8 to 144 ± 7 bpm (P < 0.001). Insome baboons, MABP changed very little during thewhole period of heating. In others, MABP declinedearly in the heating period, sometimes by as much as15 mm Hg, and then gradually returned to the controllevel as environmental heating was continued. For alleight baboons, MABP was 80.4 ± 4.3 mm Hg in thenormothermic control state and 84.8 ± 1.7 mm Hgwhen ABP manipulations commenced at hyperther-mic Tbi • During heat-stress, the changes in systolicand diastolic pressures were similar to the MABPchanges. Thus, the ABP manipulations in the hyper-thermic state were performed around the same ABPlevels as in the normothermic state, but the preocclu-sion HR levels were higher in the hyperthermic state.In four baboons in which MLAP measurements wereobtained, MLAP had declined by —1.6 ± 0.9 mm Hgby the end of heating, which was not statisticallydifferent from the normothermic MLAP level. Thichanged less than 0.3°C during any series of IVC andDA occlusions in both normothermic and hyperther-mic states.

HR Response to Changes in ABP—GeneralDescription

Representative original records obtained during DAand IVC occlusions in normothermic and hyperther-mic states are shown in Figures 1 and 2. In bothnormothermic and hyperthermic states, DA occlusionproduced a rapid rise in systolic and diastolic pres-sures, pulse pressure, and MABP (Fig. 1). MLAP was

A. Tb, = 37.2 T200 -i

B. Tbl = 39.7 °C

PulsatileArterialPressure{mm Hg)

MeanArterialPressure(mm Hg)

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FIGURE 1. Responses of pulsatile arterial blood pressure, meanarterial blood pressure (MABP), heart rate (HR) and left at rialpressure to partial occlusion of the descending aorta (between Onand Off) during normothermia (panel A) and hyperthermia (panelB). These data are from a single experiment.

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76 Circulation Research/Vo/. 51, No. 1, July 1982

A. Tb, = 37.5 °C B, = 39.7°C

PulsatileArterialPressure(mmHg)

MeanArterial

Pressure(mmHg)

HeartRate

(bpm)

2 0 0

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FiCURE 2. Responses of pulsatile arterialblood pressure, MABP, HR, and left atrialpressure to partial occlusion of the inferiorvena cava (between On and Off) duringnormothermia (panel A) and hyperther-mia (panel B). These data are from a singleexperiment.

also elevated slightly. In response to the elevation inABP, HR fell instantaneously and then either re-mained at that low level in the steady state or rose toa level in between the lowest and control level in thesteady state. The two-component HR response to DAocclusion was a common occurrence.

IVC occlusions resulted in a reduction in systolicand diastolic pressures, pulse pressure, MABP andMLAP (Fig. 2). The reflex tachycardia during an IVCocclusion was most often a two-component responsealso. HR rose gradually to reach its peak level inapproximately 15-25 seconds. Then, while the hypo-tensive stimulus was maintained, HR diminished toa steady state level which was about 10-20 beats/minless than the peak HR level.

In the following sections, HR levels designated as"peak HR" correspond to the maximum and mini-mum HR achieved during an IVC or DA occlusion,respectively, while "steady state HR" corresponds tothat steady level achieved 30-45 seconds after theonset of a given occlusion. Because one baboon wouldnot tolerate prolonged IVC and DA occlusions formore than 15-20 seconds, "steady state HR" data arefrom seven animals instead of eight.

HR Response to Changes in ABP in Normothermicvs. Hyperthermic States

For equivalent increases in MABP, a significantlygreater reduction in peak and steady state HR wasproduced in the hyperthermic than in the normother-mic state (Fig. 1). This enhancement of the reflexbradycardia was elicited in spite of the same elevationin MABP being accompanied by a smaller or equalincrease in pulse pressures and MLAP in the hyper-thermic state. On the other hand, the peak and steadystate reflex tachycardia in response to equivalent re-ductions in MABP was reduced in most baboons (Fig.2). For equivalent reductions in MABP, the reductionsin systolic and pulse pressures were not differentfrom the levels during normothermia. However,MLAP was reduced to a lesser degree during hyper-thermia.

The average changes in peak HR sensitivity forgiven MABP changes are shown in Figure 3. HRsensitivity to DA occlusions was significantly en-hanced for each equivalent MABP change at theelevated Tbi. The greatest enhancement in sensitivityoccurred for increases in MABP that were less than10 mm Hg. On the other hand, the HR sensitivity toreductions in MABP was significantly reduced in thehyperthermic state. The greatest reduction in HRsensitivity also occurred within 10 mm Hg of theinitial MABP. These same trends in HR sensitivitywere also observed for the steady state HR responses.

These changes in HR sensitivity to ABP changescan imply that the HR-MABP relationship is alteredat the hyperthermic Tbi. To determine whether thiswas true, the characteristic HR-MABP curves for eachanimal in normothermic and hyperthermic states wereconstructed. Figures 4 and 5 illustrate the peak andsteady state HR-MABP curves for one baboon and allthe baboons, respectively. The most pronounced re-sult is that the HR-MABP curve shifts upward in thehyperthermic state, while there appears to be verylittle, if any, change in the shape of the HR-MABPcurve.

• Normothermic Tw

Hyperthermic Tb!

A MABP (mm Hg)

FIGURE 3. Comparison of the interanimal average peak HR sensi-tivity values for each interval change in MABP (&MABP) in nor-mothermic and hyperthermic states. Values are mean ± sc of theindividual average HR sensitivities from eight baboons. * P < 0.05;f P < 0.01.

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Gorman and Proppe/Effect of Heating on Baroreflex Control of Heart Rate 77

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Mean Arterial Pressure (mm Hg)FIGURE 4. Comparison of the average peak (A) and steady state (B)HR-MABP relationships in the normothermic (0) vs. hyperthermic(O) states for a single baboon. The values are mean ± SE from sixexperiments performed on separate days. Also indicated is themean ± SE of the control HR-MABP level (control point) observedprior to each DA and IVC occlusion in the normothermic (Q) andhyperthermic f Q j states.

The data from analysis of the HR-MABP curves areshown in Table 1. Two things demonstrate that theshape of the HR-MABP curve did not change duringhyperthermia. First, the total HR range over the sameMABP range of ±25 mm Hg was not altered byhyperthermia. Second, the estimated slope of thesteep portion of the HR-MABP curve showed noconsistent difference between the normothermic andhyperthermic states. Also, BPso was unaltered by hy-perthermia. On the other hand, both the maximumand minimum reflex HR levels increased markedlyduring hyperthermia. Thus, a major influence of hy-perthermia is to shift the HR-MABP curve upwardwithout significantly changing the characteristics ofthe curve or shifting it horizontally.

Hyperthermia was accompanied also by a signifi-cant upward shift of the control point (i.e., the HR-MABP level prior to occlusions) along the steep por-tion of the curve (Figs. 4 and 5; Table 1). The peakand steady state reflex bradycardia portion of the

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FIGURE 5. Interanimal average peak (A) and steady state (B) HR-MABP relationships in the normothermic (O) and hyperthermic(O) states. These data are from eight and seven baboons, respec-tively. Also indicated on each of the curves is the mean ± SE of thecontrol HR-MABP level (®, B).

curve significantly increased from 24 ± 2% to 40% ±3% in the hyperthermic state and the reflex tachycar-dia portion decreased by the same amount.

Normothermic and Hyperthermic HR-MABPRelationship during Cholinergic and /}-AdrenergicReceptor Blockade

In six of the eight baboons, separate experimentswere performed on different days to determine theinfluence of heat stress on the HR-MABP relationshipwith only the cardiac vagal influence on HR intact(/J-receptor blockade) or with only the sympatheticefferent influence on HR intact (Ch-receptor block-ade). Before DA and IVC occlusions were performedin the hyperthermic state, Tbi was elevated by 2.2 ±0.1 °C during environmental heating.

From a normothermic level of 92 ± 6 beats/min,/8-receptor blockade decreased HR by 11 ± 2 beats/min (P < 0.05) while Ch-receptor blockade increasedHR by 44 ± 4 beats/min (P < 0.05). MABP was notsignificantly altered from its control level of 83 ± 3mm Hg during either receptor block.

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TABLE 1Peak (n = 8) and Steady State (n = 7) HR-MABP Curve Analysis in Normothermic and Hyperthermic

States

Maximum HR (beats/min)Minimum HR (beats/min)Total HR range (beats/min)Maximum reflex bradycardia

(beats/min)Maximum reflex tachycardia

(beats/min)Estimated slope (beats/min per

mm Hg)BP™ (mm Hg)

Peak HR

N

177 ± 1062 ± 5

112 ± 7-27 ± 2

86 ± 8

8.1 ± 1.0

80 ± 3

response

H

215 ± 10f103 ± 7]115 ± 8-45 ± 2*

73 ± 9

8.4 ± 1.0

84 + 2

Steady state

N

168 ± 1070 ± 897 ± 10

-19 ± 2

71 ± 8

5.2 ± 0.7

84 ± 4

HR response

H

192 ± 9\109 + 7f84 ± 4

-33 ± 2f

55 ± 6f

5.0 ± 0.6

86 ± 2

Values are mean ± SE. N = normothermic state; H = hyperthermic state.* 0.05 > P > 0.01; f P < 0.01.

In the normothermic state, the maximum peak andsteady state reflex bradycardia (—27 ± 3 and —21 ±2 beats/min, respectively) were not significantly al-tered during y8-receptor blockade. In contrast, Ch-receptor blockade completely abolished the initial,peak reflex bradycardia and significantly reduced themagnitude of the steady state bradycardia by 59 ±4%. In addition, the rate of reduction of HR in re-sponse to an elevation in ABP was noticeably atten-uated during Ch-receptor blockade. Whereas the un-blocked, peak bradycardia occurred within the first2-5 seconds of the ABP elevation, the Ch-blockedheart required approximately 20-30 seconds before itachieved its lowest HR level, which is equivalent tothe time when the steady state HR level was analyzed.Therefore, in order to make quantitative comparisonsof the HR-MABP relationship during /?- or Ch-recep-tor blockade, only the steady state HR-MABP curvesare presented.

At the normothermic Tbi, the maximum peak andsteady state reflex tachycardia in response to de-creases in ABP (+86 ± 7 and +72 ± 8 beats/min,respectively) were consistently attenuated duringeither /?- or Ch-receptor blockade. The magnitude ofthe steady state reflex tachycardia was reduced by anaverage of 57 ± 4% (P < 0.01) during yS-receptor and48 ± 9% (P< 0.01) during Ch-receptor blockade.

Figure 6 shows the interanimal average steady stateHR-MABP curves during Ch-receptor blockade in thenormothermic and hyperthermic states. The HR-MABP curve demonstrated an upward shift duringhyperthermia, similar to what was observed in theunblocked animals (Fig. 5). Both the maximum andminimum plateau HR levels were significantly ele-vated (Table 2). However, there were no significantalterations in the total HR range, BP50, or the estimatedslope (Table 2). Because the steady state reflex brady-cardia was slightly enhanced during hyperthermiawith only the sympathetic influence on HR intact, andthe HR-MABP curve showed no change in the totalHR range, the control HR-MABP level (control point)was found to be shifted upward along the interanimal

HR-MABP curve by an average of +9 ± 4 beats/min.This upward shift in the control point was not sig-nificantly different from the magnitude observed inthe unblocked, hyperthermic state.

Figure 7 shows the interanimal average steady stateHR-MABP curves during /S-receptor blockade in boththe normothermic and hyperthermic states. Again,the HR-MABP curve shifted upward during hyper-thermia in a manner similar to what was seen in theunblocked and Ch-blocked baboon. The absolutemaximum and minimum plateau HR levels were sig-nificantly elevated while the total HR range and BP50were not altered (Table 2). Although the mean valuesof the estimated slopes suggests a trend towards areduction in the hyperthermic state, this reductiondid not prove to be statistically significant. There wasalso a +14 ± 3 beats/min upward shift in the controlpoint along the HR-MABP curve in the hyperthermicstate during /S-receptor blockade. Again, there was nodifference in the magnitude of this upward shift of

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FIGURE 6. Interanimal average steady state HR-MABP relationshipsduring cholinergic-receptor blockade in the normothermic (O) andhyperthermic (A) states. These data are from six baboons. Alsoindicated on each curve is the mean of the control HR-MABP level(Q).

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_ 170-1

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FIGURE 7. Interanimal average steady state HR-MABP relationshipsduring fi-adrenergic receptor blockade in the normothermic (O)and hyperthermic states (A). These data are from six baboons.Also indicated on each of the curves is the mean of the controlHR-MABP level (Q).

the control point compared to the unblocked or Ch-receptor blocked, hyperthermic state.

Discussion

The results of this investigation demonstrate that:(1) the reflex bradycardia in response to acute arterialhypertension is enhanced and the reflex tachycardiain response to arterial hypotension is attenuated dur-ing hyperthermia induced by environmental heatstress, and (2) the HR-MABP relationship is shiftedupward during heat stress without pronouncedchanges in the characteristics of the baroreflex controlof HR. This investigation provides the first detailedstudy of the influence of environmental heat stress onthe baroreceptor reflex control of HR. It should beemphasized that the data was obtained only at Tbilevels that were the lowest of the diurnal cycle(<37.6°C) and the highest that could be comfortablytolerated by the baboons (39.6°C). What alterations,if any, occur within this range of Tbi is unknown sinceHR-MABP reflex data were not obtained during thedevelopment of hyperthermia.

In this study, a given series of DA and IVC occlu-sions producing elevations and reductions in ABPwere accompanied by similar directional changes in

systolic pressure, pulse pressure, and MABP. Previousinvestigations have shown that pulse pressure andpulse frequency may influence discharge patternsfrom arterial baroreceptors and the magnitude of thereflex vasomotor responses (Ead et al., 1952; Angell-James and Daly, 1970). However, we chose to considerMABP as the predominant baroreceptor stimulus forthe following two reasons. First, Korner et al. (1972)have shown that the stimulus-response curves derivedfrom single (MABP only) and multiple (MABP, PP,and RAP) regression functions during IVC and DAocclusions were very similar, which indicates that thesingle regression function based only on MABPchanges is a reasonable index of the complex pressurefunction generated during balloon inflation. Second,in the technical sense, a given change in MABP wasconsistently and easily established during each occlu-sion, which permitted the analysis of the HR-ABPrelationship to be performed with greater accuracy.Therefore, the analysis of the baroreflex control ofHR and the conclusions presented were based solelyupon the relationship of HR to MABP.

Since blood gases and ventilatory rates were notmeasured in the present study, it is difficult to assesstheir potential influence on the results observed dur-ing hyperthermia in the conscious baboon. However,Hales et al. (1979) have reported that, in the consciousbaboon, arterial Po-2, PC02, and pH are unchangedfrom control (normothermic) periods during mild,moderate, or servere hyperthermia. As in humans,essentially all heat loss in the baboon is through theskin (i.e., thermoregulatory sweating) and not throughpanting (Hales et al., 1977). However, hyperventila-tion has been shown to occur frequently in baboons(Funkhouser et al., 1967) and humans (Baltrip, 1954;Gaudio and Abramson, 1968; Rowell et al., 1969)during whole body heating with increases in minutevolume of 1-2 liters/min. Evidence from the con-scious dog indicates that lung inflation receptors havea substantial influence in modulating the reflex re-sponses to carotid chemoreceptor stimulation (Vatnerand Rutherford, 1981). Results of a study on theconscious rabbit by Korner et al. (1973b) suggest thathyperventilation may slow the heart rate withoutexerting a significant influence on the shape of the

TABLE 2

Steady State HR-MABP Curve Analysis in the Normothermic and Hyperthermic States duringCholinergic and /3-Adrenergic Receptor Blockade (n = 6)

Maximum HR (bcats/min)Minimum HR (beats/min)Total HR range (beats/min)Estimated slope (beats/min per

mm Hg)BPa, (mm Hg)

Cholinergic

N

172 ± 12125 ± 447 ± 93.1 ± 0.4

86 ± 2

blockade

H

197 + 8*144 ± 5*52 ± 63.9 ± 0.5

88 ± 2

/^-Blockade

N

111 ± 563 ± 448 ± 32.9 ± 0.4

82 ± 4

H

129 ± 2*88 ± 8*42 ± 51.8 ± 0.2

81 ± 2

Values are mean ± SE. N = normothermic state; H = hyperthermic state.* P< 0.01.

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80 Circulation Research/Vo/. 51, No. 1, July 1982

curve relating HR and MABP. However, due to thelack of direct evidence from man or the consciousbaboon, the possible influence of hyperventilation onthe baroreflex control of HR during heat stress re-mains open to question.

A major effect of elevated Tbi on the baroreflexcontrol of HR was a reduction in HR sensitivity (AHR/AMABP) in the tachycardia response and an increasein HR sensitivity in the bradycardia response forequivalent reductions and elevations in MABP.Changes in HR sensitivity have been utilized in otherinvestigations as an index of the influence of stress,such as exercise and hypoxia, on the baroreflex con-trol of HR (Bevegard and Shepherd, 1966; Robinsonet al., 1966; Guazzi et al., 1970). In this approach, it isgenerally believed that changes in sensitivity, as de-fined above, indicate an interaction between the stressbeing imposed and the baroreceptor reflex, whereas,no changes in sensitivity indicate that the stress andthe baroreceptor reflex influence a cardiovascular var-iable in a noninteractive or additive manner. Appli-cation of this reasoning to the present study wouldindicate that heat stress does alter the baroreflexcontrol of HR because HR sensitivity to ABP changesis altered during heat stress.

However, caution is required when inferring inter-action between a stress and baroreceptor control ofHR based solely on changes in HR "sensitivity." It istheoretically possible that during a stress the HR-MABP control point may merely shift to a differentposition on the curve describing the baroreceptor-mediated HR-MABP relationship. For example, if thestress was accompanied by an upward shift in theHR-MABP control point on the HR-MABP curvewithout changing the characteristics of the HR-MABPrelationship, it would be expected that HR sensitivityto hypotensive stimuli would diminish and the HRsensitivity to hypertensive stimuli would increase. Inthis case, it would be incorrect to conclude that thecharacteristics of the baroreflex control of HR wasaltered by the stress just because HR sensitivities toABP changes were altered.

Therefore, to determine more fully the effects ofhyperthermia on the baroreceptor-mediated HR re-sponse in unanesthetized baboons, full HR-MABPcurves were constructed for the normothermic andhyperthermic states and analyzed similar to themethod of Korner et al. (1973a, 1973b, 1979). Theirrationale is that if the inputs characteristic of a partic-ular disturbance (e.g., heat stress) influence the bar-oreflex control of HR, the parameters which charac-terize the baroreceptor-mediated HR-MABP curvewill be altered from the values observed during con-trol conditions. On the other hand, if only the meanlevel of HR is altered by the disturbance, causing anupward or downward shift, then the disturbance doesnot exert a significant direct influence on the barore-ceptor control of HR.

Thus, the most notable finding of this present studywas that the HR-MABP curves shifted upward inresponse to an elevation in Tbi without significant

changes in the HR range, estimated slope, and BP50 ofthe HR-MABP relationship. These results imply thatexternal heat stress elicits a rise in HR independent ofthe mechanisms of control by the arterial barorecep-tors with no alteration in the characteristics of thebaroreflex control of HR. This conclusion is similarto that of Korner et al. (1973b) with regard to theinfluence of artificial hyperventilation on the barore-flex control of HR in the conscious rabbit. Theyhypothesized that the fibers from lung inflation re-ceptors project to part of the cardiac motoneuron poolwhich does not receive projections from any circula-tory baroreceptors. Perhaps the neuronal pool acti-vated by environmental heat stress also does notproject to cardiac motoneurons that are connected tobaroreceptors.

A major cause of the upward elevation in the HR-MABP relationship during heat stress must be thedirect, local influence of temperature on the sinoatrialnode. Jose et al. (1970) have shown that the localtemperature effect elevates HR about 7-9 beats/minper °C rise in Tbi. In this study, the maximum andminimum HR levels of the HR-MABP relationshipwere displaced by 35-40 beats/min following an av-erage 2.6°C rise in Tbi. Thus, with the local effectbeing 7-9 beats/min per °C, about 18-23 beats/minof the upward shift of the HR-MABP curve can beattributed to the local effect of Tbi on the sinoatrialnode. However, since the upward shift in the HR-MABP curve is larger than predicted from the localinfluence of Tbi on HR, other mechanisms, presum-ably neural, must also be involved. The HR-MABPrelationship during either /?- or Ch-receptor blockadewas also shifted upward during hyperthermia with nosignificant alterations in total HR range, BP50, or slope.The magnitudes of the upward shift in the maximumand minimum plateau levels were as large or largerthan that predicted for the local effect of Tbi. During/S-receptor blockade, the plateau levels of the HR-MABP curve were elevated by 22 beats/min for a2.2°C rise in Tbi. During Ch-receptor blockade, theupward displacement was approxiamtely a 28 beats/min increase for a 2.2°C rise in Tbi. The local effectof Tbi (+9 beats/min per °C) in these two instanceswould be predicted to cause a 20 beats/min increasein the plateau levels, which is similar to the upwarddisplacement observed during /S-receptor blockade.Therefore, these data would indicate that, in additionto the local effect of Thi, cardiac efferent sympatheticneurons, independent of the arterial baroreflex, maybe involved in producing the upward shift in thebaroreceptor-mediated HR-MABP relationship dur-ing hyperthermia.

At a normothermic Tbi, the HR-MABP controlpoint on the HR-MABP curve is located at the lowerportion of the HR-MABP curve. At the hyperthermicTbi level, the HR-MABP control point was shiftedupward on the HR-MABP curve. In the context of nochanges in HR range or slope during hyperthermia,this upward shift in the HR-MABP control pointwould explain why the maximum reflex bradycardia

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Gorman and Proppe/Ef feet of Heating on Baroreflex Control of Heart Rate 81

and tachycardia were significantly increased and re-duced, respectively, during hyperthermia. It was ob-served in this study, as well as by others studyinghumans (Rowell et al., 1971), that ABP tends to fallduring the early phase of heating. Perhaps, the arterialbaroreceptor reflex is attempting to compensate forthis fall in ABP, with part of the compensation beinga reflex tachycardia accompanied by an upward shiftof the control point on the stimulus-response curve.

The efferent mechanisms mediating the heat-in-duced "compensatory" reflex tachycardia and thusthe upward shift of the control point on the HR-MABP curve may be determined by analyzing therelative changes in the control point for the unblockedheart and during either /?- or Ch-receptor blockadeduring hyperthermia. Heart rate was elevated 52beats/min for a +2.6°C change in Tbi which is 12-17beats/min greater than the increase in the plateaulevels. Since no significant change in the total HRrange occurred in the unblocked heart and the con-trolled hyperthermic MABP level was not alteredfrom its normothermic level, the result was an average14 beats/min increase in the control point along thesteep portion of the unblocked, hyperthermic HR-MABP curve. During Ch- or /^-receptor blockade,MABP and the total HR range of the HR-MABPcurves also were not significantly altered during hy-perthermia. Thus, the control point increased by 9beats/min during Ch-receptor blockade and 15 beats/min during /S-receptor blockade. This indicates thatboth the cardiac efferent sympathetics and vagus,respectively, may be involved in mediating a"compensatory" elevation in HR during hyperthermiain response to the heat stress-induced hypotensionsometimes observed in baboons (Proppe, 1980; thisstudy) and man (Rowell et al., 1969; Rowell et al.,1971). However, the magnitude of the elevation of thecontrol point observed during /8-receptor blockade(i.e., with only the vagal influence on HR intact) isequivalent to the 14 beats/min increase seen for theunblocked-hyperthermic state. The fact that the com-pensatory reflex rise in HR due to sympathetic acti-vation or vagal withdrawal are not additive in naturemay reflect the dominant influence of vagal tone indetermining the control, resting HR level in the con-scious animal (Levy and Zieske, 1969).

Although in the present study the baroreflex con-trol of HR was unaltered with hyperthermia, it shouldbe emphasized that a similar preservation of the bar-oreflex control of vascular resistance is not impliedby the authors. In humans, Heistad et al. (1973)reported that heating one hand abolished the cuta-neous vasoconstrictor response of the opposite handto lower body negative pressure (LBNP) but did notsignificantly affect the reflex tachycardia. In contrast,Crossley et al. (1966) and Johnson et al. (1973) dem-onstrated in humans exposed to whole body heatingthat the cutaneous bed still retained the ability tovasoconstrict in response to LBNP but was not capableof overriding the heat-induced vasodilation (Johnsonet al., 1973). Whether the present findings would be

observed for cold stress is uncertain although thereflex tachycardia during LBNP has been shown inhumans to be significantly attenuated with cold ther-mal stimuli of one hand (Heistad et al., 1973). It isdifficult, however, to project whether the above re-sults do indeed indicate an influence of thermal stim-uli on the baroreflex control of vascular resistance orHR, since full stimulus-response curves were notconstructed. As demonstrated in the present study, torely solely on alterations in reflex responses, i.e., HRsensitivity or changes in vascular resistance, withoutthe construction of full stimulus-response curves maylead to erroneous conclusions as to the influence of aphysiological stress on a baroreceptor reflex.

We wish to thank William Church and Paul Comeaux for theexcellent technical assistance in these studies. Also, we thank LindaShimerda and Ruth Cozette for their skillful preparation of thismanuscript.

Supported by Grants HL-21451 and HL-27504 from the NationalHeart, Lung, and Blood Institute.

Address for reprints: Duane W. Proppe, Ph.D., Department ofPhysiology, The University of Texas Health Science Center at SanAntonio, 7703 Floyd Curl Drive, San Antonio, Texas 78284.

Received August 20, 1981; accepted for publication April 15,1982.

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INDEX TERMS: Primate • Baroreceptor reflex • Thermalstress • Heart rate sensitivity • Curveanalysis • Cholinergic blockade • fi-ad-renergic blockade

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A J Gorman and D W ProppeInfluence of heat stress on arterial baroreflex control of heart rate in the baboon.

Print ISSN: 0009-7330. Online ISSN: 1524-4571 Copyright © 1982 American Heart Association, Inc. All rights reserved.is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation Research

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