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Studies on the Arterial Baroreceptor Reflex System
STUDIES STUD IES ON THE ARTERIAL BARORECEPTOR REFLEX REF LEX SYSTEM Sagawa, K., K. , Kumada, M. Schramm, Schra mm, L. L . P. P . and Shoukas, Shoukas , A. A. Department Depa rtment of Biomedical Biomedi ca l Engineering Eng inee ri ng The Johns Hopkins Hopki ns University Un iversity School Schoo l of Medicine Medici n e Baltimore, Ba lt imore , Maryland Mar y l and
The arterial reflex typical arteria l baroreceptor b aroreceptor ref l ex is a typ i ca l example of biological feed-biologica l control systems based on negative feed back.. It is also multi-input, back a l so an example examp l e of a multi - input , multimulti output, multi-level Both the carooutput , mu l ti - leve l control co ntrol system. mUltip l e components tid and aortic receptors sense multiple (1 , 2) of input pressure (1, The afferent signals via t h e two t wo nerves appear to converge into a common final the poo l and the individual reflex effe s ~fe neuron pool manner ' summed in an approximately additive manner' . efferen t s include control signals to the The reflex efferents heart (both rate and contractility), resistance and vesse l s , and some endocrine systems. sys t ems. Be capacity vessels, Beleve l s of the brain modifies side signals from higher levels l ex system. system . the performance of the ref reflex The purpose of this paper is to review a family of studies which viewpoint ", i.e., i.e. , have been made from "a systems viewpoint", tho se which evaluated the roles ro l es of various components those of the reflex system in a quantitative referrence to the goal of the reflex.
The reflex the cardiac ca r diac vagal motor neurons. neurons . ref l ex syssys tem now becomes a buffering regulator regu l ator which attenuattenuates a change in arterial pressure whether the change is initiated in the plant or at other parts of the brain. Since there cannot be a negative frequency, there must be some biasing discharge baro generated by the medullary neurons which the baroreceptor afferents inhibit in order to achieve the action . The actual arterial pressure buffering action. um between this pressor disdis then is an equilibri· equilibri·um barocharge and the depressor signals from the barol inearized open-loop open- loop receptors. Given the static linearized system , G , arterial pressure gain of the reflex system, c l osed- loop condit~on, condit~on, AP c , can be exex under the closed-loop pressed as
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immedi where AP max is the maximum pressure observed immediately after the inhibition by the baroreceptor e l iminated . man ifes afferents is totally eliminated. It is a manifestation of the pressor (biasing) discharge inherent medu ll ary center; AP max is at most 300 mm Hg to the medullary and rather unstable. This formula , although an simplification , is convenient to explain why over simplification, open- l oop ref l ex gain gai n has been bee n found to be 2 to the open-loop reflex r egion, and much 3 only in a very narrow pressure region, region . smaller outside this optimum region.
Goal of the Baroreceptor Reflex
interac t ion between physiology In the early phase of interaction theory , the reflex system was and classical control theory, often envisioned as a constant reference pressure 1 ) . The system thus servo control mechanism (Fig. 1). schematized attempts to equalize the actual arterial pressure with a desired pressure. Questions were r aised as to whether or not such a desired arterial raised gener pressure really exists,what neural structure generates it, where the comparator is, etc. If the reference signal were generated in the suprapontine structure , spura-pontine spura - pontine decerebration should result structure, fact , over all in a marked depressor response. In fact, ref l ex performance or the level of arterial pressure reflex changes only slightly after suprapontine de cerebration(5 , 6). 6) . Therefore, Therefore , the substantial part of the tion(5, reference signal generator in the above scheme must ponto - medul l ary reticular formbe assumed in the ponto-medullary ation . No investigator has been able to document ation. refer and define the neural representation of the reference pressure and error signal. At present it will be wiser to refrain from forcing the vaguely vague l y known part of the reflex system into such a technological Fig . 1. 1. scheme as shown in Fig.
Fig . 2 does not explicitly contain a The scheme in Fig. reference pressure. In many situations (arousal, exercise , etc.), etc . ) , signals from other neural strucexercise, tures impinge upon the common medullary neurons and shift arterial pressure. However, the scheme still implies that the reflex still contributes to the setting of arterial pressure level. There are two physiological findings which potentially rere concept . One is that quire modification of this concept. the receptors quickly (within 24 hours) adapt to hypoten the existing input pressure whether it is hypotensi ve or hypertensive(7, hypertensive (7, 8). 8) . This adaptive resettresett sive ing of the receptor renders the system floating buffer mechanism. The other finding is that in chronic dog preparations in which the sino-aortic re nerves were sectioned, mean arterial pressure reday(9 , 10). turned nearly to the control within a day(9, However, it fluctuated much more greatly than that animals . l atter finding raises a of normal animals. This latter conditions , too, too , the possibility that in normal conditions, reflex system may be operating merely as a buffer mecha having nothing to do with the level setting mechaHowever , since the reflex control of arterial nism. However, level , pressure is not reciprocal about the normal level, it is difficult to conceive the manner in which the reflex ref l ex can buffer pressure without affecting its dc level. It level . I t is easier to explain the absence of a
2) , which is less An alternative scheme (Fig. 2), differentiated from the standpoint of control theory, seems sufficient to explain the major performances imp l ied there is of the reflex system. The concept implied simply that the baroreceptor afferents inhibits the pontomedullary sympathetic neurons while activating These studies s t udies were supported suppo r ted by PHS Research Grant Nos. Nos . 14529 1 4529 & 15434. 15434 .
355
sustained hypertension hyperte nsion by considering that some other compensatory mechanism mech a nism took t ook place, which is slower in action and buffered acute changes cha nge s much more poorly pocrly though tho ugh it set the average level of pressure. Taken together, togethe r, we regard the baroreceptor t or reflex as a short-term, sho rt-term, low-gain l ow- gain follower mechanism, the reference of which is undefined and subject to t o many modyfying signals. s ignals . 11.
Overall Ove rall Reflex Performance: Pe r formance:
pH, shallow anesthesia) in causing instability remains to be known. Scher and Young(16) pointed po inted out a frequency-depenfrequency-dep e ndent fall in ~ during the sinusoidal for of of the carotid sinus reflex. Levison et al. showed a reduction in the gain parameter pa rameter magnitude magnitUde p ulsati on was superimposed s uperimposed on the sinuswhen a 2-Hz pulsation oidally o idally changing c hang ing ISP. I SP . These and other o ther nonlinear phenomena are related, at least in part, pa rt, to t o the asymmetric rate sensitivity of the baroreceptor.
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Static and Dynamic
Under an open-loop ope n-loop condition, condi tion, the static relationship between betwee n the reflex input (intrasinus pressure, pressure , ISP) I SP) and the output. output, (AP) h~s been ~hown ~hown to t o be ~ (6, shaped and fitted wlth varlOUS emplrlcal emp lrl ca l formulas 11, 12). 1 2). We assumed that the static s tati c gain ga in is normally distributed around a r ound the peak gain region of input pressure, Thus for a given ISP, press ure, ISP I SPmax ' ISP ,
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stab ility of the closed-loop c l osed-l oop performance pe rfo rman ce of the The stability re flex system sys tem appears to t o be marginal. marginal . If one assumes reflex s tati c gain and dynamic performance pe rformance for a similar static baro r eceptor reflexes and also a l so both sino and aortic baroreceptor effects. a simply additive summation of both reflex effects, overal l reflex performance will wi ll lack stability. stability . the overall f l uctua t es In fact, mean arterial pressure often fluctuates dist'.lI'bances. spontaneously or in response to step dist'xrbances. ago , Guyton Guy t o n et e t al. (15) suspected suspec ted the t he barobaro Years ago, ref l ex as the cause of so-called so - ca lled spontaneous r eceptor reflex receptor va somotor waves (about 15 sec in period). However , vasomotor However, rrhage the dogs to these investigators needed to hemo hemorrhage provoke sustained blood The role of b l ood pressure waves. this additional procedure additiona l proce dure and other conditions (low
Both the carotid caro tid and aortic ao rti c receptors are rate sensensitive in an asymmetric fashion. A step increase of the input pressure in the ordinary ord in ary range causes cau ses a transient increment in crement in the receptor discharge, which is greater than the transient decrement in the discha rge caused by a step decrease of the input prespres charge sure. Therefore, Therefore , when the th e receptor was forced by a sinusodia l pressure, the number of impulse discharge sinusodial greate r than when the forcing per unit time is greater pressure is a nonpulsatile pressure at the same mean l sat i on of ISP in the ordinordinlevel. Consequently, pU pulsation ary pressure range results in a depressor response. However, as Landgren(18) showed years ago, ago , the magmag nitude and direction of this dynamic asymmetry is meI? level of input pressure. pressu r e . dependent on the meI~ a l. ( con firmed this recently. r ecent l y . Chr istensen et al. Christensen confirmed Stegman and Tibes(19) demonstrated that the above deppressor ressor response to pulsation pulsa tion turned tu rned into a pressor th e mean ISP was set se t above 170 mm Hg. Hg . response if the Cons idering this complex nonlinearity of the rec1~4) rec Considering ove rall reflex behavior, behavior , we tor property and the overall studied the cardiovascular cardi ovascu l ar reflex ref l ex response to 28 combina ti ons of mean levels, pulse p ulse pressures pressur es and combinations pulse rates of input ISP. The static gain of the mild l y with overall reflex was found to attenuate mildly pu l se pressure, pressure , whereas the th e effect of increases in pulse (Fig . 3). 3) . Angell Angel l changing pulse rate was minimum (Fig. DeB . Daly(3) Da ly(3) also obtained obta i ned similar findings. James and DeB.
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I t should be pointed po inted out that generally genera ll y the equilibIt rium arterial pressure AP c ' is not equal to ISP ISPm~x ' max iden tify a shift of ISP I SP Note also that one cannot identify cen t ral resetting unless unl ess AP relationship curve as a central e liminate any change in the plant p lant components. componen ts. he can eliminate Imether the vagi are intact or not was shown to al l the pa rameters in the above formula formu l a (13, (13,14). affect all parameters 14). Dynamic performance anal sis has been performed by severa l investigators(ll investi ga tors(ll in an ISP I SP region near AP ' several c studies , a small amplitude frequency reIn most studies, s p onse method was applied in a range from 1/200 to sponse 1/6 Hz. Hz . The findings agree in that the overall transfer function can be approximated by a linear second - order delay system (T::20 (T:; 20 sec) sec)with trans second-order wi th a transportation lag of about 2 sec.
The Ro Role l e of o f Rate Sensitivity of the Arterial Arte ri al Baroreceptor
re su lts lead to a number of interesting The above results pred i ct i ons. compe nsation of AP after predictions. For example, compensation hemorrhage by the baroreceptor reflex will be weaker rec epto r sees a falling ~ with unchanging when the receptor pu lse pressure p ressure than when the receptor receptor sees a nonnon pulse p ulsatile falling pressure. On the other hand, if pulsatile wel l as the pulse pressure decreases considerably as well fa lli ng ~, ~ , the reflex refl ex compensation compensa ti on may be equal to falling or This preo r greater than the(20yond case above. abo~e. pre dic ti on was tested diction by an experlment ln WhlCh hemor r hage was repeated r epea ted in the same individual individua l 20% hemorrhage c l osed-l oop condition dogs first under the natural closed-loop p ressure in the carotid and then with a depulsated pressure fal l ing AP of o f the dogs. sinuses which followed the falling The results showed no statistically significant (Fig . 4). We interpret difference in the fall of ~ (Fig. sensi ti vity to decrease in pulse p ulse that the receptor sensitivity pressu r e was not enough to t o augment the gain ga in of o f the pressure signifi can tly beyond the gain operative ope r ative with reflex significantly inpu t pressure depulsated input pressure.. IV IV
356
i bution of Reflex Controls Contro ls Relative Contr Contribution of the Heart, Hea rt. Capacity Vessels Vesse l s and Total Peripheral Per ipheral Resistance.
In order to incorporate the arterial baroreceptor reflex control in a model of overall circulatory mechanics, one must know the individual controls of the heart and systemic vascular components, not just the reflex effect on AP. Systematic information on these controls has been missing although fragmental knowledge on reflex controls of cardiac contractility, rate,and vascular resistance and capacity in some specific beds has been reported. Therefore, we analyzed in anesthetized dogs, the contribution of reflex changes in cardiac output (CO) and total peri~~3ra!4fesistance peri~~3ra!4fesistance (TPR) to the reflex chang~i?2~) , and to the posthemorrhage chang~i?2~) recovery of AP . Approximately 2/3 of the posthemorrhage recovery was by the reflex increase in TPR and about 1/3 was through reflex recovery of CO. It is worth mentioning that investigators who disturbed the carotid sinus reflex in subjects with intact vagal reflex observed little change in v1~~;o~~fed animals obCO, whil~ tho~e who used v1~~;o~~fed s~gn~f~cant changes served s~gn~f~cant .
other way, the central stimulation increased the peak open-loop gain of the reflex from 1.15 to 1.33 and ISP by 10 mm Hg. The stimulation also shifted the ~~ilibrium ~~ilibrium arterial pressures AP from 125 mm Hg during control period to 163 ~H9. The stimulation also increased the sensitivity of reflex control of renal, superior mesenteric and femoral arterial resistances. Between ISP's of 120 and 180 mm Hg the modulation of reflex sensitivity of the three resistances was greater in the renal (6.2 times of the control) and superior mesenteric (6.2 times) bed than in the femoral bed (2.3. times). The increase in reflex control of heart rate was much smaller (1.59 times of control) but no suppression was seen as op.~osed op.~gsed to the observation in man during exercise ( 5). ). For reasons discussed before, we feel that much more detailed and systematic experimental studies are needed regarding the modulation of the baroreceptor reflex by various neural structures before we can discuss the multi level control of the reflex system at a level comparable to that in control engineering.
Whether or not the reflex constriciton of capacity vessels importantly contributes to the reflex control of CO has also been controversial. We(23) determined the reflex change in the total systemic vascular compliance (6V/6P) and the reflex mobilization of blood from, or into, the systemic vascular bed. Although the reflex did not significantly alter the compliance, it mobilized about 4 ml/Kg body wt. of blood per 25 mm Hg change in ISP in the region of 135 ~ 12.5 mm Hg (Fig. 5). Combining this datum with the compliance value and Guy ton's early model,we estimate that a 25 mm Hg change in ISP can change cardiac output as much as 30% of the normal value solely through the reflex control of the vascular capacity. Exact contribution of the reflex changes in heart rate, contractility, venous filling pressure,and arterial afterload to an observed change in CO awaits further experimental analyses. Surprisingly enough, there has been no quantitative data even on the baroreceptor reflex control of cardiac output under well-controlled and extensive loading conditions.
When we started the analysis of the baroreceptor reflex system in 1964, we thought that we would be able to collect the minimal necessary experimental knowledge in about 10 years and able to begin constructing a model of the reflex which is compatible with a simplified cardiovascular plant model. Today we ~e not ready to start even the initial stage of the modeling, except for an anesthetized dog: REFERENCES 1.
2. 3. 4. 5.
V.
Modification of Carotid Sinus Baroreceptor Reflex Performance by Various Neural Systems 6.
A number of studies have shown that the carotid sinus baroreceptor reflex is subject to influences of various neural systems such ~~ the limbic forebrain area or the hypothalamus( ). From the control viewpoint, such modulations of reflex performances have been speculated as a result of change in the set point of the reflex system or an adaptive modulation of its gain. Though a tempting concept, resetting is not easily identified in biological feedback control system. We have recently observed in anesthetized, vagotomized dogs that the lateral hypothalamus altered both the operating range and gain of the carotid sinus baroreceptor reflex. Electrical stimulation of the lateral and posterior hypothalamus elicits a pattern of cardiovascular responses similar to the naturally elicited defense response. In our experiments the response to the hypothalamus stimulation markedly diminished with increases in ISP from 120 mm Hg to 180 and 240 mm Hg. Put in the
7. 8. 9. 10. 11.
12. 13. 14. 15. 16.
357
Christensen, B.N. et al.: In "Baroreceptor and Hypertension". Ed. by P. Kezdi, Pergamon Press, London, 1967, pp. 41-50. Ninomiya,I., and Irisawa,H.: Am. J. Physiol. 213: 1504-1511, 1967. Angell, James, J. E. and Daly, M. DeBurgh: J. Physiol. (London) 209: 257-293, 1970. Donald, D. E. and Edis, A. J.: J. Physiol. 215, 521-538, 1971. Katz, R. L. et al. In" Baroreceptor and Hypertension". Ed. by P. Kezdi, Pergamon Press, London, 1967, pp. 169-178. Kent, B. B. et al. Circulat.Res. 29: 534-541, 1971. McCubbin, J. W.: Circulation, 17: 791, 1958. Angell James, J. E.: Circulation Res. 32, 149, 1973. Pickering, G. "Hypertension" Williams & wilkins Baltimore, 1970, p. 8. Cowley, A. W. and Guy ton , A. C.: Federation Proc. 1972, 367 (abs) Scher, A. M. et al.: In "Physical Basis Circulatory Transport" Ed. by Reeve & Guy ton, Saunders, Phila. 1967, pp. 113-120. Korner, P. I. et al. Circulat. Res. 31: 637652, 1972. al. : Am. J. Physiol. 221: 480Schmidt, R.M. et al.: 487, 1971. al. : Am. J. Physiol. 223: 1-7 Schmidt, R.~. R.~. et al.: 1972. Guy ton, A.C. and Harris, J. W.: Am. J. Physiol. 165: 158-166, 1951. Scher, A.M. and Young, A.C.: Circulat. Res. 12: 152-162, 1963.
17.
21. Olmsted, Olmsted , F., et al.: Am. J. J . Physiol. Physio l. 219: 2 1 9: 1342-1346, 1966. 22. Constantine, J. J . W. et al.: al . : Am. J. Physiol. Phys i o l. 221: 1681-1685, 1 68 1-1 685, 1971. 1 971. 23. Shoukas, Sholikas , A. A. and Sagawa, Sagawa , K. Federation Proc. 31: 356 Abs., 1972. 24. Korner, Korner , P. I.: Physiol. Reviews. 51, 5 1, 2, 312-367, 1971 1 97 1
Levison, G. E. et al: Circulat. Res. Res . 18: 1 8: 673673 682, 682 , 1966. Landgren, S.: S . : Acta Ac t a Physiol.Scand. 26: 26 : 35-56, 1952. Stegemann, J. and Tibes, U.: Pflugers Pf lugers Arch., 305, 219-228, 2 1 9 - 228 , 1969. Kumada, M. et al.: Am.J. Physiol. 219: 13731379, 1970.
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4. Figure 4. Time course of various hemodynamic variables after a 20 % haemorrhage in anesthetized anes th e tized dogs. dogs . q uick 20% quick In each ee times under dog the haemorrhage was repeated thr three differ e nt feedbacks of arterial arteria l ppressure ressure to the carocaro different tid sinuses. So lid circles circ l es represent data when the Solid only mean arterial arter i a l pressure was fed back to the sinuses and crosses when intrasinus pressure was fixed at the prehaemorrhage p rehaemorrhage level.
358
The arterial reflex typical arteria l baroreceptor b aroreceptor ref l ex is a typ i ca l example of biological feed-biologica l control systems based on negative feed back.. It is also multi-input, back a l so an example examp l e of a multi - input , multimulti output, multi-level Both the carooutput , mu l ti - leve l control co ntrol system. mUltip l e components tid and aortic receptors sense multiple (1 , 2) of input pressure (1, The afferent signals via t h e two t wo nerves appear to converge into a common final the poo l and the individual reflex effe s ~fe neuron pool manner ' summed in an approximately additive manner' . efferen t s include control signals to the The reflex efferents heart (both rate and contractility), resistance and vesse l s , and some endocrine systems. sys t ems. Be capacity vessels, Beleve l s of the brain modifies side signals from higher levels l ex system. system . the performance of the ref reflex The purpose of this paper is to review a family of studies which viewpoint ", i.e., i.e. , have been made from "a systems viewpoint", tho se which evaluated the roles ro l es of various components those of the reflex system in a quantitative referrence to the goal of the reflex.
The reflex the cardiac ca r diac vagal motor neurons. neurons . ref l ex syssys tem now becomes a buffering regulator regu l ator which attenuattenuates a change in arterial pressure whether the change is initiated in the plant or at other parts of the brain. Since there cannot be a negative frequency, there must be some biasing discharge baro generated by the medullary neurons which the baroreceptor afferents inhibit in order to achieve the action . The actual arterial pressure buffering action. um between this pressor disdis then is an equilibri· equilibri·um barocharge and the depressor signals from the barol inearized open-loop open- loop receptors. Given the static linearized system , G , arterial pressure gain of the reflex system, c l osed- loop condit~on, condit~on, AP c , can be exex under the closed-loop pressed as
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immedi where AP max is the maximum pressure observed immediately after the inhibition by the baroreceptor e l iminated . man ifes afferents is totally eliminated. It is a manifestation of the pressor (biasing) discharge inherent medu ll ary center; AP max is at most 300 mm Hg to the medullary and rather unstable. This formula , although an simplification , is convenient to explain why over simplification, open- l oop ref l ex gain gai n has been bee n found to be 2 to the open-loop reflex r egion, and much 3 only in a very narrow pressure region, region . smaller outside this optimum region.
Goal of the Baroreceptor Reflex
interac t ion between physiology In the early phase of interaction theory , the reflex system was and classical control theory, often envisioned as a constant reference pressure 1 ) . The system thus servo control mechanism (Fig. 1). schematized attempts to equalize the actual arterial pressure with a desired pressure. Questions were r aised as to whether or not such a desired arterial raised gener pressure really exists,what neural structure generates it, where the comparator is, etc. If the reference signal were generated in the suprapontine structure , spura-pontine spura - pontine decerebration should result structure, fact , over all in a marked depressor response. In fact, ref l ex performance or the level of arterial pressure reflex changes only slightly after suprapontine de cerebration(5 , 6). 6) . Therefore, Therefore , the substantial part of the tion(5, reference signal generator in the above scheme must ponto - medul l ary reticular formbe assumed in the ponto-medullary ation . No investigator has been able to document ation. refer and define the neural representation of the reference pressure and error signal. At present it will be wiser to refrain from forcing the vaguely vague l y known part of the reflex system into such a technological Fig . 1. 1. scheme as shown in Fig.
Fig . 2 does not explicitly contain a The scheme in Fig. reference pressure. In many situations (arousal, exercise , etc.), etc . ) , signals from other neural strucexercise, tures impinge upon the common medullary neurons and shift arterial pressure. However, the scheme still implies that the reflex still contributes to the setting of arterial pressure level. There are two physiological findings which potentially rere concept . One is that quire modification of this concept. the receptors quickly (within 24 hours) adapt to hypoten the existing input pressure whether it is hypotensi ve or hypertensive(7, hypertensive (7, 8). 8) . This adaptive resettresett sive ing of the receptor renders the system floating buffer mechanism. The other finding is that in chronic dog preparations in which the sino-aortic re nerves were sectioned, mean arterial pressure reday(9 , 10). turned nearly to the control within a day(9, However, it fluctuated much more greatly than that animals . l atter finding raises a of normal animals. This latter conditions , too, too , the possibility that in normal conditions, reflex system may be operating merely as a buffer mecha having nothing to do with the level setting mechaHowever , since the reflex control of arterial nism. However, level , pressure is not reciprocal about the normal level, it is difficult to conceive the manner in which the reflex ref l ex can buffer pressure without affecting its dc level. It level . I t is easier to explain the absence of a
2) , which is less An alternative scheme (Fig. 2), differentiated from the standpoint of control theory, seems sufficient to explain the major performances imp l ied there is of the reflex system. The concept implied simply that the baroreceptor afferents inhibits the pontomedullary sympathetic neurons while activating These studies s t udies were supported suppo r ted by PHS Research Grant Nos. Nos . 14529 1 4529 & 15434. 15434 .
355
sustained hypertension hyperte nsion by considering that some other compensatory mechanism mech a nism took t ook place, which is slower in action and buffered acute changes cha nge s much more poorly pocrly though tho ugh it set the average level of pressure. Taken together, togethe r, we regard the baroreceptor t or reflex as a short-term, sho rt-term, low-gain l ow- gain follower mechanism, the reference of which is undefined and subject to t o many modyfying signals. s ignals . 11.
Overall Ove rall Reflex Performance: Pe r formance:
pH, shallow anesthesia) in causing instability remains to be known. Scher and Young(16) pointed po inted out a frequency-depenfrequency-dep e ndent fall in ~ during the sinusoidal for of of the carotid sinus reflex. Levison et al. showed a reduction in the gain parameter pa rameter magnitude magnitUde p ulsati on was superimposed s uperimposed on the sinuswhen a 2-Hz pulsation oidally o idally changing c hang ing ISP. I SP . These and other o ther nonlinear phenomena are related, at least in part, pa rt, to t o the asymmetric rate sensitivity of the baroreceptor.
1i91
Static and Dynamic
Under an open-loop ope n-loop condition, condi tion, the static relationship between betwee n the reflex input (intrasinus pressure, pressure , ISP) I SP) and the output. output, (AP) h~s been ~hown ~hown to t o be ~ (6, shaped and fitted wlth varlOUS emplrlcal emp lrl ca l formulas 11, 12). 1 2). We assumed that the static s tati c gain ga in is normally distributed around a r ound the peak gain region of input pressure, Thus for a given ISP, press ure, ISP I SPmax ' ISP ,
2
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1
stab ility of the closed-loop c l osed-l oop performance pe rfo rman ce of the The stability re flex system sys tem appears to t o be marginal. marginal . If one assumes reflex s tati c gain and dynamic performance pe rformance for a similar static baro r eceptor reflexes and also a l so both sino and aortic baroreceptor effects. a simply additive summation of both reflex effects, overal l reflex performance will wi ll lack stability. stability . the overall f l uctua t es In fact, mean arterial pressure often fluctuates dist'.lI'bances. spontaneously or in response to step dist'xrbances. ago , Guyton Guy t o n et e t al. (15) suspected suspec ted the t he barobaro Years ago, ref l ex as the cause of so-called so - ca lled spontaneous r eceptor reflex receptor va somotor waves (about 15 sec in period). However , vasomotor However, rrhage the dogs to these investigators needed to hemo hemorrhage provoke sustained blood The role of b l ood pressure waves. this additional procedure additiona l proce dure and other conditions (low
Both the carotid caro tid and aortic ao rti c receptors are rate sensensitive in an asymmetric fashion. A step increase of the input pressure in the ordinary ord in ary range causes cau ses a transient increment in crement in the receptor discharge, which is greater than the transient decrement in the discha rge caused by a step decrease of the input prespres charge sure. Therefore, Therefore , when the th e receptor was forced by a sinusodia l pressure, the number of impulse discharge sinusodial greate r than when the forcing per unit time is greater pressure is a nonpulsatile pressure at the same mean l sat i on of ISP in the ordinordinlevel. Consequently, pU pulsation ary pressure range results in a depressor response. However, as Landgren(18) showed years ago, ago , the magmag nitude and direction of this dynamic asymmetry is meI? level of input pressure. pressu r e . dependent on the meI~ a l. ( con firmed this recently. r ecent l y . Chr istensen et al. Christensen confirmed Stegman and Tibes(19) demonstrated that the above deppressor ressor response to pulsation pulsa tion turned tu rned into a pressor th e mean ISP was set se t above 170 mm Hg. Hg . response if the Cons idering this complex nonlinearity of the rec1~4) rec Considering ove rall reflex behavior, behavior , we tor property and the overall studied the cardiovascular cardi ovascu l ar reflex ref l ex response to 28 combina ti ons of mean levels, pulse p ulse pressures pressur es and combinations pulse rates of input ISP. The static gain of the mild l y with overall reflex was found to attenuate mildly pu l se pressure, pressure , whereas the th e effect of increases in pulse (Fig . 3). 3) . Angell Angel l changing pulse rate was minimum (Fig. DeB . Daly(3) Da ly(3) also obtained obta i ned similar findings. James and DeB.
1£4)
I t should be pointed po inted out that generally genera ll y the equilibIt rium arterial pressure AP c ' is not equal to ISP ISPm~x ' max iden tify a shift of ISP I SP Note also that one cannot identify cen t ral resetting unless unl ess AP relationship curve as a central e liminate any change in the plant p lant components. componen ts. he can eliminate Imether the vagi are intact or not was shown to al l the pa rameters in the above formula formu l a (13, (13,14). affect all parameters 14). Dynamic performance anal sis has been performed by severa l investigators(ll investi ga tors(ll in an ISP I SP region near AP ' several c studies , a small amplitude frequency reIn most studies, s p onse method was applied in a range from 1/200 to sponse 1/6 Hz. Hz . The findings agree in that the overall transfer function can be approximated by a linear second - order delay system (T::20 (T:; 20 sec) sec)with trans second-order wi th a transportation lag of about 2 sec.
The Ro Role l e of o f Rate Sensitivity of the Arterial Arte ri al Baroreceptor
re su lts lead to a number of interesting The above results pred i ct i ons. compe nsation of AP after predictions. For example, compensation hemorrhage by the baroreceptor reflex will be weaker rec epto r sees a falling ~ with unchanging when the receptor pu lse pressure p ressure than when the receptor receptor sees a nonnon pulse p ulsatile falling pressure. On the other hand, if pulsatile wel l as the pulse pressure decreases considerably as well fa lli ng ~, ~ , the reflex refl ex compensation compensa ti on may be equal to falling or This preo r greater than the(20yond case above. abo~e. pre dic ti on was tested diction by an experlment ln WhlCh hemor r hage was repeated r epea ted in the same individual individua l 20% hemorrhage c l osed-l oop condition dogs first under the natural closed-loop p ressure in the carotid and then with a depulsated pressure fal l ing AP of o f the dogs. sinuses which followed the falling The results showed no statistically significant (Fig . 4). We interpret difference in the fall of ~ (Fig. sensi ti vity to decrease in pulse p ulse that the receptor sensitivity pressu r e was not enough to t o augment the gain ga in of o f the pressure signifi can tly beyond the gain operative ope r ative with reflex significantly inpu t pressure depulsated input pressure.. IV IV
356
i bution of Reflex Controls Contro ls Relative Contr Contribution of the Heart, Hea rt. Capacity Vessels Vesse l s and Total Peripheral Per ipheral Resistance.
In order to incorporate the arterial baroreceptor reflex control in a model of overall circulatory mechanics, one must know the individual controls of the heart and systemic vascular components, not just the reflex effect on AP. Systematic information on these controls has been missing although fragmental knowledge on reflex controls of cardiac contractility, rate,and vascular resistance and capacity in some specific beds has been reported. Therefore, we analyzed in anesthetized dogs, the contribution of reflex changes in cardiac output (CO) and total peri~~3ra!4fesistance peri~~3ra!4fesistance (TPR) to the reflex chang~i?2~) , and to the posthemorrhage chang~i?2~) recovery of AP . Approximately 2/3 of the posthemorrhage recovery was by the reflex increase in TPR and about 1/3 was through reflex recovery of CO. It is worth mentioning that investigators who disturbed the carotid sinus reflex in subjects with intact vagal reflex observed little change in v1~~;o~~fed animals obCO, whil~ tho~e who used v1~~;o~~fed s~gn~f~cant changes served s~gn~f~cant .
other way, the central stimulation increased the peak open-loop gain of the reflex from 1.15 to 1.33 and ISP by 10 mm Hg. The stimulation also shifted the ~~ilibrium ~~ilibrium arterial pressures AP from 125 mm Hg during control period to 163 ~H9. The stimulation also increased the sensitivity of reflex control of renal, superior mesenteric and femoral arterial resistances. Between ISP's of 120 and 180 mm Hg the modulation of reflex sensitivity of the three resistances was greater in the renal (6.2 times of the control) and superior mesenteric (6.2 times) bed than in the femoral bed (2.3. times). The increase in reflex control of heart rate was much smaller (1.59 times of control) but no suppression was seen as op.~osed op.~gsed to the observation in man during exercise ( 5). ). For reasons discussed before, we feel that much more detailed and systematic experimental studies are needed regarding the modulation of the baroreceptor reflex by various neural structures before we can discuss the multi level control of the reflex system at a level comparable to that in control engineering.
Whether or not the reflex constriciton of capacity vessels importantly contributes to the reflex control of CO has also been controversial. We(23) determined the reflex change in the total systemic vascular compliance (6V/6P) and the reflex mobilization of blood from, or into, the systemic vascular bed. Although the reflex did not significantly alter the compliance, it mobilized about 4 ml/Kg body wt. of blood per 25 mm Hg change in ISP in the region of 135 ~ 12.5 mm Hg (Fig. 5). Combining this datum with the compliance value and Guy ton's early model,we estimate that a 25 mm Hg change in ISP can change cardiac output as much as 30% of the normal value solely through the reflex control of the vascular capacity. Exact contribution of the reflex changes in heart rate, contractility, venous filling pressure,and arterial afterload to an observed change in CO awaits further experimental analyses. Surprisingly enough, there has been no quantitative data even on the baroreceptor reflex control of cardiac output under well-controlled and extensive loading conditions.
When we started the analysis of the baroreceptor reflex system in 1964, we thought that we would be able to collect the minimal necessary experimental knowledge in about 10 years and able to begin constructing a model of the reflex which is compatible with a simplified cardiovascular plant model. Today we ~e not ready to start even the initial stage of the modeling, except for an anesthetized dog: REFERENCES 1.
2. 3. 4. 5.
V.
Modification of Carotid Sinus Baroreceptor Reflex Performance by Various Neural Systems 6.
A number of studies have shown that the carotid sinus baroreceptor reflex is subject to influences of various neural systems such ~~ the limbic forebrain area or the hypothalamus( ). From the control viewpoint, such modulations of reflex performances have been speculated as a result of change in the set point of the reflex system or an adaptive modulation of its gain. Though a tempting concept, resetting is not easily identified in biological feedback control system. We have recently observed in anesthetized, vagotomized dogs that the lateral hypothalamus altered both the operating range and gain of the carotid sinus baroreceptor reflex. Electrical stimulation of the lateral and posterior hypothalamus elicits a pattern of cardiovascular responses similar to the naturally elicited defense response. In our experiments the response to the hypothalamus stimulation markedly diminished with increases in ISP from 120 mm Hg to 180 and 240 mm Hg. Put in the
7. 8. 9. 10. 11.
12. 13. 14. 15. 16.
357
Christensen, B.N. et al.: In "Baroreceptor and Hypertension". Ed. by P. Kezdi, Pergamon Press, London, 1967, pp. 41-50. Ninomiya,I., and Irisawa,H.: Am. J. Physiol. 213: 1504-1511, 1967. Angell, James, J. E. and Daly, M. DeBurgh: J. Physiol. (London) 209: 257-293, 1970. Donald, D. E. and Edis, A. J.: J. Physiol. 215, 521-538, 1971. Katz, R. L. et al. In" Baroreceptor and Hypertension". Ed. by P. Kezdi, Pergamon Press, London, 1967, pp. 169-178. Kent, B. B. et al. Circulat.Res. 29: 534-541, 1971. McCubbin, J. W.: Circulation, 17: 791, 1958. Angell James, J. E.: Circulation Res. 32, 149, 1973. Pickering, G. "Hypertension" Williams & wilkins Baltimore, 1970, p. 8. Cowley, A. W. and Guy ton , A. C.: Federation Proc. 1972, 367 (abs) Scher, A. M. et al.: In "Physical Basis Circulatory Transport" Ed. by Reeve & Guy ton, Saunders, Phila. 1967, pp. 113-120. Korner, P. I. et al. Circulat. Res. 31: 637652, 1972. al. : Am. J. Physiol. 221: 480Schmidt, R.M. et al.: 487, 1971. al. : Am. J. Physiol. 223: 1-7 Schmidt, R.~. R.~. et al.: 1972. Guy ton, A.C. and Harris, J. W.: Am. J. Physiol. 165: 158-166, 1951. Scher, A.M. and Young, A.C.: Circulat. Res. 12: 152-162, 1963.
17.
21. Olmsted, Olmsted , F., et al.: Am. J. J . Physiol. Physio l. 219: 2 1 9: 1342-1346, 1966. 22. Constantine, J. J . W. et al.: al . : Am. J. Physiol. Phys i o l. 221: 1681-1685, 1 68 1-1 685, 1971. 1 971. 23. Shoukas, Sholikas , A. A. and Sagawa, Sagawa , K. Federation Proc. 31: 356 Abs., 1972. 24. Korner, Korner , P. I.: Physiol. Reviews. 51, 5 1, 2, 312-367, 1971 1 97 1
Levison, G. E. et al: Circulat. Res. Res . 18: 1 8: 673673 682, 682 , 1966. Landgren, S.: S . : Acta Ac t a Physiol.Scand. 26: 26 : 35-56, 1952. Stegemann, J. and Tibes, U.: Pflugers Pf lugers Arch., 305, 219-228, 2 1 9 - 228 , 1969. Kumada, M. et al.: Am.J. Physiol. 219: 13731379, 1970.
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4. Figure 4. Time course of various hemodynamic variables after a 20 % haemorrhage in anesthetized anes th e tized dogs. dogs . q uick 20% quick In each ee times under dog the haemorrhage was repeated thr three differ e nt feedbacks of arterial arteria l ppressure ressure to the carocaro different tid sinuses. So lid circles circ l es represent data when the Solid only mean arterial arter i a l pressure was fed back to the sinuses and crosses when intrasinus pressure was fixed at the prehaemorrhage p rehaemorrhage level.
358