The Effect of the Carotid Sinus Baroreceptor Reflex on Blood Flow …€¦ · ·...

274

The Effect of the Carotid Sinus BaroreceptorReflex on Blood Flow and Volume

Redistribution in the Total SystemicVascular Bed of the Dog

MARTHA J. BRUNNER, ARTIN A. SHOUKAS, AND CAROL L. MACANESPIE

SUMMARY To quantify the relative contribution of blood flow redistribution and active changes invascular capacity in the regulation of cardiac output, blood flow and volumes in two parallel vascularbeds were measured in response to varying carotid sinus pressures. In nine dogs, carotid sinuses wereisolated and intrasinus pressure was controlled. Two external reservoirs were placed between thecaval veins and the right heart to measure changes in vascular capacity in splanchnic and extra-splanchnic vascular beds. At intrasinus pressures of SO and 200 nun Hg, we have simultaneouslymeasured arterial resistances, compliances, changes in flows, and "unstressed vascular volume," andtime constants of venous drainage in the splanchnic and extrasplanchnic vascular beds. Compliancesand time constants of venous drainage were found to be nearly equal in the two beds. A decrease inintrasinus pressure from 200 to 50 mm Hg resulted in a small redistribution of blood flow (about 5% ofcardiac output) from the extraplanchnic compartment to the splanchnic vascular bed. Changes inreservoir volumes were found to be around 7.0 ml/kg. The splanchnic vascular bed was responsible fora greater change in reservoir volume for a given change in intrasinus pressure. With any change inintrasinus pressure, the change in arterial resistance in the extrasplanchnic vascular bed was greaterthan that of the splanchnic vascular bed. Blood flow redistribution was not found to be a significantfactor contributing to changes in reservoir volume. The changes in reservoir volume seen, must havebeen due to active changes in vascular capacity in the two channels chosen. Circ Res 48: 274-285, 1981

THE importance of changes in the capacitive prop-erty of the systemic vascular bed has been recog-nized for some time. For example, a decrease incapacity can increase the filling presure of the rightheart which, in turn, can increase cardiac output.Evidence that the carotid sinus baroreceptor reflexcontrols the systemic vascular capacity has beenpresented from several laboratories (Drees andRothe, 1974; Rashkind et al., 1953; Salzman, 1957;Shoukas and Sagawa 1973). The amount of bloodwhich can be mobilized from the entire systemicvascular bed by the reflex has also been quantified(Drees and Rothe, 1974; Rashkind et al., 1953;Shoukas and Sagawa, 1973). However, the exactmechanism and source of blood mobilization re-mains somewhat controversial (Caldini et al., 1974;Coleman et al., 1974; Green, 1975; Mitzner andGoldberg, 1975).

Using a dog preparation in which venous returnwas diverted into a reservoir while cardiac outputwas kept constant, Shoukas and Sagawa (1973)showed that significant shifts of blood between thedog and a reservoir occurred when carotid sinus

From the Department of Biomedical Engineering, The Johns HopkinsUniversity School of Medicine, Baltimore, Maryland.

This study was supported partly by U.S. Public Health Service GrantHL19039.

Address for reprints: Dr. Artin A. Shoukas, Department of BiomedicalEngineering, The Johns Hopkins School of Medicine, 720 Rutland Ave-nue, Baltimore, Maryland 21205.

Received June 2, 1980; accepted for publication September 5, 1980.

pressure was changed. They hypothesized that thereflex altered the "unstressed" vascular volume ofthe systemic veins based on the finding that thetotal systemic vascular compliance did not changesignificantly. A more recent work by Shoukas andBrunner (1980) indicated that the reflex affects thetotal compliance to a mild but significant degree.

Caldini et al. (1974) and Coleman et al. (1974)postulated an alternate mechanism to explain thechanges in reservoir volume. Caldini et al. (1974)used a preparation very similar to the one used byShoukas and Sagawa (1973) and found significantshifts of blood volume when epinephrine was in-fused into the dog. Based on a parallel channelmodel, Caldini et al. (1974) pointed out that aredistribution of blood flow from regions with largetime constants of venous drainage to regions withsmall time constants would result in passive shiftsof volume without any change in "unstressed" vas-cular volume and/or compliance. This explanationdoes not involve the active change of venous toneby adrenergic mechanisms.

In the present study, we attempted to test thehypothesis of Caldini et al. by dividing the systemicvascular bed into two parallel channels (splanchnicand extrasplanchnic) which were suspected bythese authors to have widely different time con-stants. We could measure the blood flow redistri-bution between the two channels, the time con-stants and compliances of the two channels, and

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BARORECEPTOR REFLEX CONTROL OF BLOOD FLOW AND VOLUME/Brunner et al. 275

blood volume shifts from the two channels associ-ated with the carotid sinus baroreceptor reflex. Inthe same dogs, we could repeat the previous exper-iments of Shoukas and Sagawa (1973) to check thereproducibility of the present data.

From these measurements, we conclude thatblood flow redistribution between the two parallelchannels chosen in our study is not the cause ofblood volume mobilization from the systemic vas-cular bed by the carotid sinus baroreceptor reflex.Therefore, active changes in venous tone by thereflex system remain important determinants ofblood volume mobilization.

Methods

Theoretical ConsiderationsFigure 1 shows a hydraulic analog of the systemic

vascular bed with three lumped elements. Asshown, the reflex can be assumed to change thearterial and venous compliances by changing thediameter and therefore the cross-sectional area ofboth chambers. The reflex system can also be as-sumed to alter the unstressed vascular volume ofboth of these chambers. Therefore, Figure 1 repre-sents a concept that the reflex system directly af-fects the capacity of the vascular system, thus al-tering the pressure-volume relationships of sys-temic arteries and veins. The net blood volumeshifts measured in the volume reservoir at constantvenous pressure are not a direct measure of thechanges in vascular capacity per se. The volumechanges are an algebraic sum of active changes inunstressed vascular volume and compliance andpassive changes in arterial and venous blood volumecaused by change in arterial pressure consequent toreflex changes in total peripheral resistance. A moredetailed consideration of the volume changes in areservoir has been published previously (Shoukasand Sagawa, 1973).

Shown in Figure 2A is a hydraulic analog of thesystemic vascular bed to illustrate the mechanismof passive blood volume mobilization caused by a

ARTERIAL

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FIGURE 1 Lumped three-compartmentmodel of the systemic vascular bed.

VOLUMERESERVOIR

series flow

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Volume Decrease of AV2

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FIGURE 2 A and B: Lumped three compartment par-allel flow model of the systemic vascular bed. See textfor details.

redistribution of blood flow. Each of the parallelflow channels is composed of arterial and venousresistances, represented by constrictions in the tubeand a capacity chamber between the resistances. Inthis representation, the capacity element in channel2 is made markedly larger in cross-sectional areathan that in channel 1, indicating that the compli-ance in channel 2 is greater than the compliance inchannel 1. For the purposes of this description, thearterial resistance in each channel is assumed to begreater than the venous resistance. We assume thevenous resistances to be equal, whereas the arterialresistances need not be equal in each channel. Totalnet vascular blood mobilization can be estimatedfrom a shift of blood between the systemic vascularbed and the volume reservoir shown in Figure 2B.Cardiac output is fixed by a pump, inserted betweenthe reservoir and right atrium, which perfuses thevascular channels at a constant flow rate. Centralvenous pressure can be maintained constant, evenwhen venous outflow changes, by adjusting theheight of the end of the tube which drains venousreturn into the reservoir. When carotid sinus baro-receptor pressure is changed, the consequentchange in reservoir volume reflects the net balancebetween the volume changes in both flow channelsof the systemic vascular bed. The mechanism (de-picted in Fig. 2B) proposed by Caldini et al. (1974)and Coleman et al. (1974) assumes that the reflexsystem increases the arterial resistance in channel



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276 CIRCULATION RESEARCH VOL.48, No.2, FEBRUARY 1981

2, Ra2, more than the arterial resistance in channel1, Rai. Since the total flow is maintained constant,this increase in resistance would then cause theflow in channel 1 to increase by an amount AF andthe flow in channel 2 to decrease by the sameamount. Thus, there would be an increase in thepressure of compliance capacity chamber 1 by anamount APci, and the decrease in the pressure ofcapacity chamber 2 by an amount APc2. If venouspressure, Pv, is maintained constant and the venousresistances, Rvi and Rv2, are equal, then thesechanges APci and APc2 will be equal but oppositein direction. Since the compliance of chamber 2 ismuch greater than that of chamber 1, the decreasein volume in chamber 2, AV2, will be much greaterthan the volume increase in chamber 1, AVi. Thenet difference in blood volumes, AV2 — AVi, willhave to come out of the animal and be measured asan increase in reservoir blood volume.

A very similar increase in reservoir blood volumewould occur if the compliances of chamber 1 andchamber 2 were equal but the venous resistance inchannel 2, Rv2, were much greater than that inchannel 1, Rvi. Under this condition, if there weresimilarly disproportionate increases in arterial re-sistances, which would decrease the flow in channel1, then the pressure decrease in chamber 2, APc2,would be greater than the pressure increase inchamber 1, APci. Since compliances Ci and C2 areassumed to be equal, the volume decrease in cham-ber 2, AV2, would be much larger than the volumeincrease in chamber 1, AVi. Again, this net differ-ence in chamber volumes, AV2 — AVi, would bemeasured as an increase in reservoir blood volume.Thus, the magnitude of the net volume shift de-pends upon the relative magnitudes of the compli-ances, Ci and C2, as well as the relative magnitudeof the venous resistances, Rvi and Rv2.

A convenient way to express the dependence ofa passive blood volume shift on the relative mag-nitude of Ci vs. C2 and/or Rvi vs. Rv2 is the productof venous resistance and compliance. Thus, if theproduct, Rv2 • C2 in channel 2 is much greater thanthe product, Rvi-Ci in channel 1 and there is aredistribution of flow away from the channel withthe larger Rv-C product (channel 2), then the netvolume measured in the external volume reservoirwill increase. The opposite is also true: that is, ifblood flow is redistributed toward the channel withthe larger Rv • C product, then reservoir volume willdecrease. The two parallel flow channel model sug-gests that significant shifts of blood volume mayoccur through changes in arteriolar tone alone with-out any neurally mediated changes in venous tone.

Two conditions must be met for this mechanismto be a valid explanation for blood mobilization inthe systemic vascular bed. First, there must be asignifcant difference in the Rv-C product betweenthe two channels of the vascular bed. Second, theblood flow must be redistributed by the reflex away

from the channel with the larger Rv-C product inresponse to lowering the carotid sinus pressure.

Figure 3 depicts a hydraulic analog which weconceived as representing the systemic vascularbed. It is identical to the model proposed by Caldiniet al (1974). In their experiment, Caldini measuredthe volume shifts in a single reservoir (see Fig. 2).However, to obtain accurate data on changes inindividual blood flows, as well as changes in thecapacities of the two channels, it is necessary to useseparate reservoirs for individual channels. The fol-lowing explanation is to clarify the methods usedfor measuring blood flows, volumes and compli-ances and determining Rv • C products. When intra-sinus pressure is changed, the steady state changesin blood flow can be measured directly at the out-flow of each channel going to the venous volumereservoir. Changes in total vascular capacity alsocan be determined by measuring the reservoir bloodvolume shifts in each of the channels. Measurementof these volume changes cannot allow one to distin-guish between active changes in vascular compli-ances and "unstressed" vascular volume changesand the passive volume changes caused by reflexredistribution of blood flow in the channels. Ittherefore is necessary to determine the vascularcompliances and Rv • C products in both channels.

An estimate of the vascular compliances can beobtained by simultaneously changing central ve-nous pressure for both channels by an equal amountand measuring the resultant steady state volumechange in each reservoir. For the case of a singleflow channel circuit through which flow is constant,the change in reservoir blood volume divided bythe change in venous pressure yields the compli-ances of the channel. However, it should be empha-sized that this conclusion is incorrect for the presentcircuit with two parallel flow channels. Using a two-port analysis technique which takes into accountthe dynamic and steady state properties (see Ap-pendix I), the steady state changes in volumes de-

CHANNEL2

FIGURE 3 Schematic representation of parallel flowmodel in order to determine the lumped vascular param-eters. See text for details.



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BARORECEPTOR REFLEX CONTROL OF BLOOD FLOW AND VOLUME/Brunneretal. 277

termined by the change in venous pressures aregiven by

and

•AP0

where RT = Ra, + Ra2 + R,,, + RU2. The Rv-C prod-ucts of each channel can be obtained by measuringthe instantaneous volume changes in both channelsafter a step elevation of venous pressure, as is shownby Equation 5 in the Appendix. A semilog plot ofvolume versus time for each channel contains iden-tical information of the Rv-C products of bothchannels. Thus, the volume vs. time plot of eitherchannel should be curvilinear if the Rv • C productof that channel is different from that of the otherchannel, but if the Rv- C products of the two chan-nels were to be nearly equal, the plots would looklinear (see Appendix). Therefore, the single pertur-bation of simultaneously raising venous pressure forboth channels will yield estimates of the compliancevalues as well as information on the Rv • C products.

Experimental ProceduresNine mongrel dogs of both sexes, weighing be-

tween 22.0 and 27.0 kg (mean 24.8 ± 1.6 SD kg) wereanesthetized with sodium pentobarbital (30 mg/kg,iv). Heat cauterization and ligation of cut tissuemasses were used to minimize blood loss.

The left and right carotid bifurcation areas wereisolated from the rest of the circulatory system(Shoukas and Brunner, 1980). The pressure withinthe carotid sinus region was monitored via con-joined catheters placed in the left and right lingualarteries and connected to a pressure transducer(Statham P23AC). The cervical vagosympathetictrunks were exposed and cut to eliminate the buffer-ing effect of the aortic arch baroreceptor reflex andthe cardiopulmonary receptor reflexes. Intrasinuspressure was maintained at the desired level by aservo-controlled, non-pulsatile pressure-generatingsystem.

A right thoracotomy was performed at the 5thintercostal space under positive pressure ventilationusing room air. Figure 4 illustrates the surgicalpreparation and perfusion circuit used in these ex-periments. The right atrial appendage was cannu-lated first and connected to the outflow side ofperfusion pump no. 3 (Sarns, model 5M6002). Theinflow side of pump no. 3 was connected to thecommon reservoir no. 3. The perfusion circuit wasprimed with heparanized whole blood from anotherdog. The azygos vein was completely ligated. Thesuperior vena cava was then cannulated and blooddrained into reservoir 1. Perfusion pump 1 (Sarns,model 5M6002) pumped blood from reservoir 1 into

FIGURE 4 Experimental preparation. S.V.C. = supe-rior vena cava, I.V.C. = inferior vena cava, Az.V. =azygos vein, R.A. = right atrial appendage. Dashed linesindicate position of removable clamps, a and b. See textfor explanation of surgery.

reservoir 3. Perfusion started with an initial flow ofabout 35 ml/min per kg. Just prior to cannulatingthe inferior vena cava, we placed three large-borecannulae into the femoral veins; one toward theheart, and a pair toward the periphery. These can-nulae drained blood into reservoir no. 3 to preventan extremely low cardiac output and venous conges-tion in both the splanchnic and leg vascular bedsduring the cannulation of the inferior vena cava.The inferior vena cava then was cannulated andpump flows readjusted so that arterial pressure wasapproximately equal to the pressure before atrialcannulation. Total perfusion flow rate averaged 75.7± 7.5 (SD) ml/min per kg for the nine dogs.

To separate the systemic vascular bed into twoparallel flow channels which are thought to havewidely differing compliances and Rv • C products byCaldini et al. (1974) and Coleman et al. (1974), weperformed the following procedures: The femoralcannulae which drained blood from the peripheryof the hind limbs were connected to the superiorvena caval cannula. The femoral cannula insertedtoward the heart was clamped for the duration ofthe experiment. Thus the outflow from the inferiorvena cava represented venous outflow from intes-tine, liver, spleen, kidney, and abdominal wall. Thesuperior vena caval outflow contained venous out-flow from upper and lower limbs, head and neckskeletal muscles, skin, and brain. The flow fromeach great vein first passed through a reservoir(reservoir no. 1 or 2) and then through an adjustablespeed pump (pumps no. 1 or 2). The flow from thesuperior vena cava (extrasplanchnic flow) is termedchannel 1, and the inferior vena caval flow (splanch-nic flow) is termed channel 2. The two pump out-flows then passed into a common reservoir (reser-voir no. 3). The blood was then returned to theright atrium through a heat exchanger and an airtrap by a third constant flow pump (pump no. 3).

Central venous pressures in the two separate



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278 CIRCULATION RESEARCH VOL. 48, No. 2, FEBRUARY 1981

channels were measured within the superior andinferior venae cavae using pressure transducers(Statham, P23BB). Zero pressure reference was setat the junction of the inferior vena cava and theright heart under direct inspection. Venous pres-sures were controlled by changing the level of theends of the outflow tubes draining the inferior andsuperior vena cava.

Arterial pressure was measured in the ascendingaorta through a catheter inserted in the left com-mon carotid artery and connected to a pressuretransducer (Statham P23AC). Blood volumes inboth of the venous outflow reservoirs were moni-tored continuously by recording the hydrostaticpressures of the columns of blood with pressuretransducers (Beckman, model 807, 215071). Thesystem was calibrated by changing the reservoirblood volumes by a known amount and recordingthe corresponding pressure changes. The resolutionof the blood volume changes was 2.0 ml. Pumpsnos. 1 and 2 were equipped with tachometers whichproduced an electrical signal that was proportionalto the speed of each pump. The speeds were re-corded and calibrated against known flows, using astopwatch and graduated cylinder. All pressure,flow, and volume signals were smoothed by a low-pass filter with a time constant of 1 second andrecorded on an ink recorder (Brush, Mark 200). Alldata presented were normalized to individual bodyweights to allow comparison among the dogs.

Initially, intrasinus pressure (ISP) was set at 200mg Hg. By adjusting the heights of the two outflowtubes, we set venous pressures in both channel 1and 2 at 3 mm Hg. The outflow pumps which drainthe two reservoirs into the common reservoir wereset to a speed at which the fluid levels in the tworeservoirs remained constant. Initially, the sum oftwo pump flows was exactly equal to the venousoutflow. Mean arterial and venous pressures, res-ervoir volumes, and the two venous outflows wererecorded. The total resistance of each channel wascalculated as the difference in arterial and venouspressures divided by the corresponding steady stateflow.

At an intrasinus pressure of 200 mm Hg, venouspressures in the two channels were raised simulta-neously and quickly (approximately 1 second) byan equal amount. This increase amounted to ap-proximately 5 mm Hg. This sudden increase invenous pressures caused concomitant decreases inreservoir blood volumes. The transient changes inblood volumes were used to obtain the Rv • C prod-ucts in each channel. The ratios of the steady statechanges in reservoir blood volumes to the changesin venous pressures were also determined to obtaina measure of the vascular compliances. Venouspressures were decreased to the control value andthe measurements were repeated.

Intrasinus pressure was decreased from 200 to 50mm Hg while keeping venous pressures constant.Following this change, the blood volume in reservoir

2 usually increased, indicating that the venous out-flow (inflow to the reservoir) increased with respectto the constant flow removed from reservoir 2 bypump 2. Conversely, reservoir 1 blood volume usu-ally decreased, indicating that the flow in channel1 decreased with respect to the constant flow out ofreservoir 1 by pump 1. Five minutes after thechange in intrasinus pressure, the slopes of theblood volume changes with respect to time gave ameasure of the changes in flows in each channelwhich resulted from changing intrasinus pressure.The shift in flow from one compartment to anotherfollowing changes in carotid sinus pressure rangedfrom 50 to 200 ml/min. The speeds of the twooutflow pumps 1 and 2 then were readjusted toequal the new venous outflows.

Blood volume shifts into each reservoir also weremeasured. An increase in reservoir blood volumecorrected for changes in blood flow redistributionwould indicate a decrease in vascular capacity foreach channel.

At an intrasinus pressure of 50 mm Hg, theresistances were calculated and the determinationsof transient and steady state volume changes wererepeated.

Intrasinus pressure was increased from 50 to 200mm Hg, keeping venous pressures constant. Theoutflows changed in directions opposite to thosepreviously described for a decrease in intrasinuspressure. The changes in reservoir volumes weremeasured again.

To correlate the data obtained in this study usingseparate channels with previous studies on the en-tire systemic vascular bed, the two separate venouschannels were joined into a single outflow. A clampwas switched from position A to B to divert allblood flow to a single reservoir (see Fig. 4). Thus,all the venous return from channel 1 was divertedinto channel 2 and single reservoir 2. This systemwas analogous to the method used by Shoukas andSagawa (1973).

At an intrasinus pressure of 200 mm Hg, and withthe single reservoir system, the total systemic vas-cular compliance was measured (Shoukas and Sa-gawa, 1973). The height of the outflow tube (andthus the venous pressure) was raised causing asteady state reservoir volume change. The ratio ofthe steady state volume change to the change invenous pressure is the total systemic vascular com-pliance. The total peripheral resistance of the entirevascular bed was also calculated by the differencein arterial and venous pressures divided by totalflow.

Intrasinus pressure then was decreased from 200to 50 mm Hg while keeping venous pressure con-stant at 3 mm Hg. The blood volume change in thesingle reservoir was monitored continuously. Thisblood volume shift should equal the sum of theblood volume shifts of the previous separate chan-nel reservoirs. At an intrasinus pressure of 50 mmHg, the total peripheral resistance and total sys-



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BARORECEPTOR REFLEX CONTROL OF BLOOD FLOW AND VOIMME/Brunner et al. 279

temic vascular compliance were again determined.Intrasinus pressure then was increased from 50 to200 mm Hg, maintaining a constant venous pres-sure, and the reservoir blood volume change wasmeasured again.

All data are reported as the mean ± SEM. (n =9). Paired t-tests were performed for data at ISP =50 and 200 mm Hg. Significance levels were set atP values of <0.05.

Results

FlowIn the nine dogs studied, the total perfusion flow

ranged from 1675 to 2010 ml/min. The mean valueswere 75.8 ± 7.5 ml/min per kg. At an intrasinuspressure of 200 mm Hg, the mean flow in channel1 (extrasplanchnic) was 30.69 ± 5.33 ml/min per kg,while the mean flow in channel 2 (splanchnic) was47.79 ± 6.84 ml/min per kg. When intrasinus pres-sure was 50 mm Hg, the mean flow in channel 1(extrasplanchnic) averaged 31.42 ± 6.34 ml/min perkg and in channel 2 (splanchnic) was 47.01 ±9.11ml/min per kg.

The upper panel of Figure 5 shows the changesin flow for each dog resulting from decreasing intra-sinus pressure from 200 to 50 mm Hg. In the ninedogs, an average decrease in flow of channel 1(extrasplanchnic) was 1.11 ± .81 ml/min per kg,whereas the flow in channel 2 (splanchnic) in-creased by an average of 1.51 ± 2.92 ml/min per kg.The decrease in flow in channel 1 and increase inflow in channel 2 were seen in seven of the ninedogs. Two dogs gave an opposite response. In theseven dogs, the mean decrease in flow in channel 1was 2.11 ± .59 ml/min per kg and the mean increasein channel 2 flow was 2.71 ± 0.67 ml/min per kg.The lower panel of Figure 5 shows the response toincreasing intrasinus pressure from 50 to 200 mmHg. For the nine dogs, the flow in channel 1 in-creased by 1.41 ± 0.97 ml/min per kg and the flowin channel 2 decreased by 2.18 ± 1.12 ml/min perkg. In the same seven of nine dogs, channel 1 flowincreased an average of 2.55 ± 0.79 ml/min per kgand channel 2 flow decreased 3.43 ± 0.93 ml/minper kg, with the increase in intrasinus pressure. Thechanges in blood flow distribution were small andwere always less than 5% of total perfusion flow inany dog.

ResistanceShown in Figure 6 are the resistances of channel

1 (extrasplanchnic) and channel 2 (splanchnic), aswell as the total peripheral resistances of the singlereservoir experiments for intrasinus pressures of 50and 200 mm Hg. At an intrasinus pressure of 50 mmHg, the mean resistance was 0.0059 ± 0.0022 mmHg(ml/min per kg) for channel 1 and 0.0041 ±0.0021 mm Hg/(ml/min per kg) for channel 2 in thenine dogs. Total peripheral resistance was calcu-lated from the average resistances of the parallel

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flow channels, using the equation for parallel resist-ances. This calculated value was 0.0023 mm Hg/(ml/min per kg) which was nearly equal to thevalue 0.0022 ± 0.0001 mm Hg/(ml/min per kg)obtained in the independent studies with a singlereservoir. Paired i-test of the difference betweenthe values calculated from two channel resistancevalues and the values obtained from the singlereservoir experiment showed no statistical signifi-cance.

Similar analysis and calculations were done forthe resistances at an intrasinus pressure of 200 mmHg. At this intrasinus pressure, the mean resistancefor channel 1 (extrasplanchnic) was 0.039 ± 0.005mm Hg/(ml/min per kg) and for channel 2(splanchnic) was 0.0024 ± 0.0008 mm Hg/(ml/minper kg). The calculated total peripheral resistance0.0015 mm Hg/(ml/min per kg) was again equal tothe value of 0.0015 mm Hg/(ml/min per kg) fromthe independent single reservoir experiment. Pairedt-test showed no statistically significant difference.The resistance values at intrasinus pressures of 50



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FIGURE 6 Resistances at the two levels of intrasinus pressure. Left: resistance in the extrasplanchnic channel (1).Center: resistance in the splanchnic channel (2). Right: total peripheral resistance. See text for details.

and 200 mm Hg showed significant differences (P< 0.05) for channel 1, channel 2, and the totalperipheral resistance as shown in Figure 6.

Volume-to-Pressure RatioFigure 7 shows the ratio of the steady state

volume to the step change in venous pressure in thetwo-channel experiment as well as the ratio in thesingle reservoir experiment for each dog. The ex-treme right panel of Figure 7 shows the ratio of thevolume change to pressure change which is the totalsystemic vascular compliance (see theoretical con-siderations). The mean value for all nine dogs was1.34 ± 0.15 ml/mm Hg per kg at an intrasinuspressure of 200 mm Hg and was 1.23 ± 0.12 ml/mmHg per kg at 50 mm Hg. Paired t-test showed a

statistically significant difference between values at200 and 50 mm Hg. For channel 1 (extrasplanchnic),the average ratios of volume change to presurechange at intrasinus pressures of 50 and 200 mm Hgare 0.46 ± 0.04 and 0.45 ± 0.03 ml/mm Hg per kg,respectively. The volume-to-pressure ratios forchannel 2 (splanchnic) were significantly largerthan those for channel 1, being 0.81 ± 0.11 and 0.69± 0.09 ml/mm Hg per kg for intrasinus pressures of50 and 200, respectively. There was no statisticallysignificant difference by paired £-test between thetwo ratios values at the two intrasinus pressures foreither channel. At an intrasinus pressure of 50 mmHg, the sum of the average ratio values from thetwo channels, (namely, 0.46 + 0.81) ml/mm Hg perkg was 1.27 ml/mm Hg per kg, as compared to thetotal systemic vascular compliance obtained inde-

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FIGURE 7 Volume changes following changes in venous pressure. Changes in reservoir volumes divided by venouspressure changes measured at the two levels of intrasinus pressure. Left: AVi/A P for the extrasplanchnic channel (1).Center: AVj/AP for the splanchnic channel (2). Right: total systemic vascular compliance.



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pendently in the single reservoir experiment, i.e.,1.23 ml/mm Hg per kg. At an intrasinus pressure of200 mm Hg, the sum from both channels was 1.14ml/mm Hg per kg as compared to 1.34 ml/mm Hgper kg for the total systemic vascular compliance.Paired t-test of the individual differences in eachdog between the sum of AVi/AP + AV2/AP and thetotal systemic vascular compliance show significantdifferences in the values (P < 0.025; n — 9) at bothlevels of intrasinus pressure (see Appendix).

Volume Time CourseThe time courses of the volume changes in both

channels were monitored when the venous pres-sures were simultaneously increased or decreasedin a stepwise fashion. For each channel, the log ofthe volume change was plotted against time in orderto obtain the time constant. Figure 8 shows theseplots from two different dogs. The left panel showsboth channels as straight lines, whereas the rightpanel shows both channels as curvilinear lines. Theplot would be a straight line if the volume changewas a single exponential function of time. However,if the plots were curvilinear, then two or moreexponential functions could be fitted. If the plotwas found to be linear, a time constant was mea-sured. This straight line behavior occurred in ap-proximately 50% of the cases studied. At the intra-sinus pressure of 50 mm Hg, the mean time con-stants were 11.17 ± 1.69 and 4.75 ± 0.63 seconds forchannel 1 (extrasplanchnic) and channel 2 (splanch-nic), respectively. At the intrasinus pressure of 200mm Hg, the mean time constants were 8.53 ± 1.82and 8.03 ± 1.27 seconds for channels 1 and 2,respectively.

Volume Shifts

The changes in reservoir volume for the parallelchannel and single reservoir experiments when in-trasinus pressure was decreased from 200 to 50 mmHg, are shown in Figure 9. In all the dogs, reservoirblood volume increased in the single reservoir ex-periments. The mean increase in reservoir volumewas 4.83 ± 1.03 ml/kg. In channel 2 (splanchnic),reservoir volume increased by 6.60 ± 1.41 ml/kg forall the dogs. For channel 1 (extrasplanchnic), themean value of the reservoir volume showed anincrease of 1.02 ± 0.051 ml/kg despite the fact that

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J2.0

I 1-0

\ \

0 20 40 60 80TIME sec.

•Channel 1o Channel 2

20 40 60 80TIME sec.

FIGURE 8 Plots of the log of volume versus time for twodifferent dogs. See text for details.

CHANNEL 1

O

E 4if)in

<r? o

SINGLERESERVOIR

200 50 200 50 200 50

INTRASINUS PRESSURE mmHg

FIGURE 9 Reservoir volume changes for decreasing in-trasinus pressure. See text for details.

three of the nine dogs showed a decrease in volume.In each of the dogs, the change in reservoir volumewas always greater in channel 2 than in channel 1.For each individual dog, the algebraic sum of thevolume shifts from the two channels was nearlyequal to the change observed in the single reservoirexperiment.

The reservoir volume changes in response toincreasing intrasinus pressure are shown in Figure10. The right panel shows the changes in volumefor the single reservoir experiments. Reservoir vol-ume always decreased in response to increasingintrasinus pressure from 50 to 200 mm Hg in alldogs. The average decrease was 6.43 ± 0.85 ml/kg.The center and left panel of Figure 10 shows thevolume changes in channel 2 (splanchnic) and chan-nel 1 (extrasplanchnic). In response to the increasein intrasinus pressure, channel 2 volume decreasedin all dogs by an average of 8.42 ± 1.32 ml/kg. Theaverage volume change in channel 1 for all the dogswas an increase of 2.28 ± 1.32 ml/kg. In the sevencases where the reservoir volume in channel 1 in-creased, there was always a large decrease in chan-nel 2 reservoir volume. Therefore, the algebraic sum

INCREASING INTRASINUS PRESSURECHANNEL 1 CHANNEL 2 SINGLE

RESERVOIR

> °a:

o -8<io

200 50 200 SO

INTRASINUS PRESSURE mmHg200

FIGURE 10 Reservoir volume changes for increasingintrasinus pressure. See text for details.



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of the two channels, 6.14 ml/kg, showed a decreaseand was nearly equal to the volume decrease of 6.43ml/kg in the single reservoir experiment.

DiscussionThis experimental preparation demonstrates

that the carotid sinus baroreceptor reflex exertscontrol of both resistive and capacitive propertiesof the systemic vascular bed. The magnitude ofreflex change in arterial resistance is indeed differ-ent between the two parallel flow channels studied.The direction of the blood flow redistribution is ofspecial interest. When intrasinus pressure was de-creased from 200 to 50 mm Hg, the extrasplanchnicchannel flow decreased while the splanchnic chan-nel flow increased. This direction of flow redistri-bution is opposite to that hypothesized by Caldiniet al. (1974) and Coleman et al. (1974). As wasdiscussed previously, for a net increase in bloodvolume to occur in the reservoir, it would be nec-essary that blood flow decreases in an area of largeRv • C product. We found no significant differencesin the time constant of either channel with changesin intrasinus pressure, and the ratio of the changein volume to the change in venous pressure of thesplanchnic channel was nearly twice that of theextrasplanchnic channel. When intrasinus pressurewas decreased, the blood flow in the splanchnicchannel increased. Since the time constants of thetwo channels were nearly equal, no change in thereservoir volume can be attributed to the flow re-distribution mechanism. In fact, we always mea-sured an increase in reservoir volume in responseto decreases in intrasinus pressure. Therefore, wewould conclude that the increase in reservoir vol-ume following a decrease in intrasinus pressure islikely to be caused by active changes in vascularcapacity. Caldini et al. (1974) have also suggestedthat there must be active changes in venous tonewhich alter the unstressed vascular volume duringepinephrine infusion.

To examine whether the systemic vascular bedresponds differently to epinephrine and the baro-receptor reflex, we performed an additional experi-ment in three of the dogs tested. In these dogs,epinephrine was infused at constant rates of ap-proximately 2 jug/min per kg while either keepingintrasinus pressure fixed or allowing it to follow theincrease in arterial pressure. Regardless of the in-trasinus pressure conditions, infusion of epineph-rine always produced a decrease in flow in theextrasplanchnic channel and an increase in flow inthe splanchnic channel. The reservoir blood vol-umes in both channels increased; however, the vol-ume increase in the extrasplanchnic channel waslarger. Although the number of observations issmall, we probably can consider that the overallresponses to epinephrine are similar to those ofdecreasing intrasinus pressure.

Our experiments show no significant differencesin time constants in the two channels and that the

blood flow redistribution was opposite to the direc-tion hypothesized by Caldini et al. (1974) and Cole-man et al. (1974). However, this need not com-pletely negate the significance of the proposedmechanism. It may simply be that the particulardivision of the systemic vascular bed we chose didnot demonstrate the mechanism, but some otherdivision(s) can have appropriately different timeconstants and exhibit appropriate redistribution bythe baroreceptor reflex. Mitzner et al. (1975) dividedthe systemic vascular bed into three parallel flowchannels: the superior vena caval channel, the he-patic venous channel (splanchnic flow), and thechannel draining below the hepatic vein. Theyfound that epinephrine infusion caused no changesin superior vena caval flow, an increase in splanch-nic flow of 8%, and a decrease in flow below theliver of 8%. The combination of splanchnic flow andflow below the liver minus the femoral flow wouldbe comparable to channel 2 flow in the presentexperiments. Mitzner's data indicate no change inflow in that combination of vascular beds. However,a small blood flow redistribution was seen in thepresent study. The differences could very well bedue to the reflex control of skeletal muscle vascularbeds drained through the femoral veins.

The results of our study are consistent with thoseof Mitzner and Goldberg (1975) and Green (1975),who found nearly equal compliances in experimentsusing parallel channels. Mitzner and Goldberg(1975) found nearly identical compliance values forflow channels similar to those chosen in our exper-iments. In addition, the value of the total systemicvascular compliance decreased by approximately10% when intrasinus pressure was decreased from200 to 50 mm Hg. The finding is consistent with,but slightly smaller than, the results of a recentstudy by Shoukas and Brunner (1980) in whichvascular compliance decreased approximately 22%for the same magnitude of change in intrasinuspressure.

There is evidence in the literature to support theobservation that blood flow in the splanchnic chan-nel increases when intrasinus pressure is decreased.In particular, Bagshaw and Cox (1977), Polosa andRossi (1961), and Vatner et al. (1970) all found thatmuscle vascular resistance can change much morethan can visceral vascular resistance. Thus, for agiven decrease in intrasinus pressure, there is anunequal vasoconstriction in the two vascular beds.Therefore, with a constant cardiac output, splanch-nic blood flow would increase and extrasplanchnicflow would decrease in equal amount. In a moreintact animal, with varying cardiac output, it is alsopossible that similar changes in vascular resistancemay or may not occur.

The nearly 7 ml/kg increase in single reservoirvolume following a decrease in intrasinus pressureis in agreement with previously reported studies ofShoukas and Sagawa (1973). This volume changerepresents the net amount of volume that the reflex



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can mobilize. However, as Shoukas and Sagawa(1973) have shown, if arterial pressure is controlled,a much larger increase in reservoir volume is seen.This volume change can be twice as large as thatseen under the uncontrolled arterial pressure in thisstudy. As was mentioned previously, capacity canchange by an alteration in compliance, an alterationin "unstressed" vascular volume, or passive volumeshifts caused by changes in intravascular pressure.The 10% change in compliance seen can only ac-count for changes in volume of approximately 1.5ml/kg. Since there were no large changes in flowdistribution and the time constants of both channelswere nearly equal, volume changes by this mecha-nism would be small. Therefore, the decrease incapacity of the vascular bed must have been causedby decreases in "unstressed" vascular volume whenintrasinus pressure was decreased. In this study,the splanchnic channel was found to exhibit greaterchanges in vascular capacity than the extrasplanch-nic channel. We thought that one source of thisdifference in volume responses is likely to be theactive participation of the spleen. In two dogs, weperformed splenectomies after all data had beentaken. This attenuated the volume response in thesplanchnic channel. Our calculation indicated thatthe spleen was responsible for approximately 30%of the change in splanchnic reservoir volume. Thus,other organs or vascular beds were responsible forthe major change in vascular capacity in thesplanchnic channel.

One very interesting result is that changes invascular capacity seem to be highly dependent uponthe direction of the intrasinus pressure changes.Decreasing intrasinus pressure caused each channelto decrease its capacity and increase reservoir bloodvolume. Increasing intrasinus pressure caused thesplanchnic channel to increase capacity and de-crease reservoir volume, whereas the extrasplanch-nic channel decreased capacity and increased res-ervoir blood volume. The changes in total vascularcapacity in single reservoir experiments showed anincrease in reservoir volume when intrasinus pres-sure was decreased and a similar magnitude ofdecrease when intrasinus pressure was increased.However, the relative contributions of the twochannels are very different, depending on the direc-tion of the intrasinus pressure change. Two possi-bilities do exist that need further investigation.First, Shoukas and Brunner (1980) have shownrecently that the static overall open loop gain of thebaroreceptor reflex is smaller for increasing intra-sinus pressure than for decreasing mean intrasinuspressure. Second, there is evidence by Mitzner andGoldberg (1975) that venous resistances can in-crease with infusion of epinephrine. Since changesin venous resistances could not be reliably obtainedin the physiological experiments, the sensitivity ofthe system to changes in venous resistances wastested in a computer simulation. We found thatdisproportionate changes in venous resistance could

change not only the magnitude of blood flows andvolume in the two channels but also the directionof flow shift. Taken together with the notion thatthere are differences in static open loop gain of thereflex between increasing and decreasing directions,it is not unlikely to see the reversal of direction inthe change in reservoir volume of the extrasplanch-nic channel. Therefore, changes in venous resist-ances are potentially important in determining res-ervoir volume changes and need further investiga-tion.

Although passive blood volume changes causedby flow redistribution by the reflex could not ac-count for the changes in reservoir blood volumeseen in the two channels chosen here or in singlereservoir experiments, we must emphasize that thisfinding does not totally negate the potential valueof the Caldini-Coleman hypothesis for other physi-ological stimuli. We conclude, however, that thecarotid sinus baroreceptor reflex is likely to exhibitcontrol over changes in vascular capacity primarilythrough concomitant reflex changes in venous tone.

AppendixSteady State Compliance Analysis

For the model shown in Figure 3, the correspond-ing two-port transfer equations for the two channelsare:

Fai(S)-Fv,(S)

1A

R v '+~C- 1

"as

- 1

RC SS j

fPa(S) 1LPV,(S)J

and

r F.1(S)iL-FV2(S)J

where

1B

, ^ lV2 T c 2 s

-

-lot-l e t

- 1C2S

Rv' + c7- l

- lC2S

Ra2 + c 2 s j

- 1

s "c^s

rp.(S)iLPv,(S)J '

and

B = det

- 1C2S C2S

c 2 s a2 c2sPa and Pv are arterial and venous pressures and Faand Fv are the arterial and venous flows.



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Since the total inflow is the sum of Fa, and Fa2and is held constant, these sets of equations can besolved for venous flows Fv, and FV2 in terms of theirrespective venous pressures Pv, and Pv2. This solu-tion yields:

and

-Fv,(S)

S ^ O t . , + Ra2)CiS(R., + Ra2 + Rv2) + C2SRy2

+ R ) + S{T(R ' Vl1

RV))}i 2

Ra2 + RV2) + T2(Ra]Ra, + Ra2 + Rv, + Rv2

and

-FV 2(S)

C1C2S RVl(Ra, + Ra2)+ C2S(Ra, + Ra2 + RV|) -• Pv2(S)

S2T,T2(Ra, + Ra2) + S{TI(R.,

+ Ra2 + Rv2) + T2(Ra, + Ra2 + Rv,)}+ Ra, + Ra2 + Rv, + Rv2

where TI = Rv,Ci and T2 = RV2C2.In our experimental preparation, the changes in

reservoir volumes AVi and AV2 are the time inte-grals of the changes in venous flows after equalmagnitude step changes in venous pressure

P PPv,(S) = -^ and PV2(S) = -^. Therefore, we can in-tegrate the above two venous flow equations toobtain the volume changes caused by the venouspressure change. Thus:

CiC2SR(,2(Ra, + Ra2)AV,(S)_ + d ( R a , + Ra2 + Rv2) + C2RV

Pv S2TlT2(Ra, + Ra2) H-SiT^Ra,+ Ra2 + Rv2) + T2(Ra, + Ra2 + Rv,)}

+ Ra, + Ra, + Rv, + Rv,

(1)

and

AV2(S) C2(Ra, + Ra

Ra2)

Pv S2TlT2(Ra, + Ra2) + S{T,(Ra,+ Ra2 + Rv2) + T2(Ra, + Ra2 + Rv,)}

+ Ra, + Ra2 + Rv, + Rv2

(2)

We can apply the final value theorem to the abovetwo equations to yield the steady state solutions to

AVi AV2the ratios — - and -r^-- This results in the respec-ZAx v Zix v

tive solutions:

r-Ci-Ra, + Ra2 + Rv2

APV Ra, + Ra2 + Rv, + Rv2

+ C2

(3)

AV2 Ra, + Ra2 + Rv,

Ra,

+ C,

Rv, + Rv2

Rv

(4)

Ra, + Ra2 + Rv, + Rv2

As can be seen from Equations 3 and 4, the ratiosof AVi/APv and AV2/APV are not the compliancesCi and C2 of the individual channels, but a combi-nation of Ci and C2, each of which is weighted bythe ratio of arterial and venous resistances. For thisreason we are reluctant to call AVi/APv and AV2/APV the compliances, Ci and C2, of the individualchannels. Furthermore, since we know that arterialresistance and possibly venous resistance wouldchange during changes in intrasinus pressure, theratios of the resistances are not constant in Equa-tions 3 and 4. Therefore, using the ratios of AVi/APV and AV2/APV as Ci and C2 could lead to theerroneous conclusion that Ci and C2 are changingwhen indeed only the ratios of the resistances arechanging.

Although the ratios of AVj/APv and AV2/APV arenot individual compliances Ci and C2, the ratio oftotal volume change divided by APV is the total

AVsystemic vascular compliance, C = ——- = Ci + C2.

Transient Analysis of Volume ChangeFrom Equations 1 or 2, the volume transient to

a step change in venous pressure is of the form

- r2)

( K(r2 - a)

r2(ri - r2)

(5)

Ra, + Ra2 + Rv, + Rv2

where ri and r2 are the roots of the polynomial poleand K and a contain the compliances and resist-ances of the model. As can be seen from Equations1 and 2, the polynomial pole equations for bothchannels (i.e., the denominators) are equal. How-ever, the zeros (the numerators) of both equationsare markedly different. The coefficients of bothexponentials in Equation 5 depend upon the rootsand primarily the zeros. These coefficients wouldbe markedly different for a given channel. In chan-nel 1, the coefficient [K(a — ri)]/[ri(ri — r2)] is muchgreater than the coefficient [K(r2 — a)]/[r2(ri —r2)], whereas, in channel 2, the coefficient [K(r2 —a)]/[r2(ri — r2)] is much greater than the coefficient[K(a — ri)]/[ri(r! — r2)] for an arterial-to-venousresistance ratio of approximately 4 to 1. The largerthis arterial-to-venous resistance ratio, the greaterthe differences in the coefficients. Therefore, al-though the volume transients from each channelcontain two exponentials, only one of the exponen-tial terms will predominate.



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AcknowledgmentsWe wish to express our thanks to Dr. Kiichi Sagawa for his

helpful assistance during the course of these experiments and toJanet Marie Allred for her typing assistance.

ReferencesBagshaw RJ, Cox RH (1977) Baroreceptor control of regional

hemodynamics during halothane anesthesia in the dog. Br JAnesth 49: 535-544

Caldini P, Permutt S, Wadell JA, Riley RL (1974) Effect ofepinephrine on pressure, flow and volume relationships in thesystemic circulation of dogs. Circ Res 34: 606-623

Coleman T, Manning R, Norman R, Guyton A (1974) Control ofcardiac output by regional blood flow distribution. AnnBiomed Eng 2: 149-163

Drees J, Rothe C (1974) Reflex venoconstriction and capacityvessel pressure-volume relationships in dogs. Circ Res 34:360-373

Green JF (1975) Pressure-flow and volume-flow relationships of

the systemic circulation of the dog. Am J Physiol 229: 761-769

Mitzner W, Goldberg H (1975) Effects of epinephrine on resistiveand compliant properties of the canine vasculature. J ApplPhysiol 39: 272-280

Polosa C, Rossi G (1961) Cardiac output and peripheral bloodflow during occlusion of carotid arteries. Am J Physiol 200:1185-1190Rashkind W, Lewis D, Henderson J, Heiman D, Dietrick R(1953) Venous return as affected by cardiac output and totalperipheral resistance. Am J Physiol 175: 415-423

Salzman E (1957) Reflex peripheral venoconstriction induced bycarotid occlusion. Circ Res 5: 149-152

Shoukas AA, Sagawa K (1973) Carotid sinus baroreceptor reflexcontrol of total systemic vascular capacity. Circ Res 33: 22-33

Shoukas AA, Brunner MJ (1980) Epinephrine and the carotidsinus baroreceptor reflex control of capacitive and resistiveproperties of the total systemic vascular bed of the dog. CircRes 47: 249-257

Vatner S, Franklin D, VanCitters R, Braunwald E (1970) Effectsof carotid sinus nerve stimulation on blood flow distributionin conscious dogs at rest and during exercise. Circ Res 27:495-503



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M J Brunner, A A Shoukas and C L MacAnespiein the total systemic vascular bed of the dog.

The effect of the carotid sinus baroreceptor reflex on blood flow and volume redistribution

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