1. Bhick (liaKraminatic illushation of the arterial haroreeeptor control of the .... value of 1-9 ml/mm Hg per kg body wt. immediately after infusing or with- drawing ...
AJEBAK 51 (Pt. 1) 33-52 (1973)
A SYSTEMS APPROACH TO BARORECEPTOR REFLEX CONTROL OF THE CIRCULATION liy K. SAGAWA, M. KUMADA AM. A. SHOUKAS (From tilt' Department of Biomcdiciil Engim-rrinf;, School cif Mrdicinc, Tlu- Johns Hopkins University, Balliniorc. Maryhiml 21205 U.S.A.) Given at a Symposium on 'Circulatory Control' at the Regional Meeting, International Union of Physiological Sciences, Sydney, August, 1972.
The main stream of physiology has recently developed tn\vard.s biophysics and biochemistry, searching underlying mechanisms among Iwjttomless microscopic details where all the life processes are eventually to he described in terms (if moh-enlar (or even snhmolecnlar) physics and chemistry. Along this exciting path toward depth, medically-oriented researchers oiten e.viXTJeneed a friLStration that there remain, and will continue to remain, so many gaps of knowledge becatise thnse(|uent falls or rises in arterial pressure (JSAP^, ^ISAPi, or ^lSAPr4.i) were determined 2 min after changes in ISP. The sum uf individual responses (JSAPr + /:1SAPi) wiis coth ISFs were elianged sinniltaneously (JSAPrM). The plot in Fig. 2a shows this comparison; data points were scattt^ed on Ixith sides of the line of identity hut within the range of 1-25 > zlSAP,+,/(zlSAP, 4- JSAP,) > 0-8. On the basis of this finding, we concluded that the overall refle.v sigiiiils from the individual side carotid sinuses were sununed in a simply additive manner as long as the input ISP changes were small and the reflex system was operating in its linear range.
BAROREFLEX AND CIRCULATION
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Fig. 2a. Comparison of the changes in s>stcinic iirteriul pressure caused by combined stimulation of biluteral carotid sinuses (JSAF^^ ,) against thi- sum of arteriul pressure changes eaiLsed hy individually stimulating the right and left carotid sinu.';es (, |SAP^ + .ISAP,). Different syml>ols represent tbe effec-ts of dilferent input sinus pressures. Reproduced from Sagawa and Watanahe [ 10&5) with the permission of the publisber. A 10 mm Hg (Single step), • 20 mm Hg (Single step). O 40 mm Hg (Single step), • Vagi cut. 50
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Fig. 2b. Comparison of the percent changes in total systemic resistance caused by combined stimulations of the carotid sinas and aortic arch reflrxes ..IR,.,_i_na (ordinate). against iht- sum of the effecLs of individual stimulations of these reflexes. JR,., + JJI^BIC Plotted from the data reported by Angell James and DeBurtjh Daly (1970). See also the fimtnote of the next page.
36
K. SAGAWA, M. KUMADA AND A. SHOUKAS
Wiing and Borrison (1947) studied the convergence of bilateral carotid sinus receptt)r sigiuiLs and concluded an "occlusive" summation of them in the spinal centre. Their cotichislon was based on tlje observations made by raising ISP from 0 to 200 mm Hg. Undou!)tedl\'. saturation must be taking place at various levels of the reflex are and this could easily mislead to a conclusion of inhibitor\' summation. Slegetnann and Miiller-Butow (1966) also studied the summation in somewhat more detail, and concluded that even in the normal operating range the stimmation was slightly inhibitory, tliough the differenee between (. ISAP^ 4.lSAP,) and ISAP,,, was small. Martin, Levy and Zieske (1969) analyzed the summation of the bilateral carotid reflex conti'ol of left ventricular wntraetility wliieh was determined in terms of the peak systolic pressure in an isovoluniically contracting dog \entricle. The conclusiou was that tlie bilatc-ral signals snnimated in an approximately additive manner. However, the detailed analysis revealed that the summation was slightly facilitatory when ISP's were changed in subuonnal range and slightly inhibitory when ISP's were in supranormal range. The conclusion of Martin et al. (1969) is in agreement with ours as long as the normal operating range of ISP is concerned. Tliere is no exact information at tlie moment concerning the summation of the carotid sinus and aortic arch baroreceptor reflex signals. Angell James and DeBurgh Daly (1970) de\L'!oped a pr60
E 2.0
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Fig. 5. EUctfs of inlrasimis pressure (absfis.sa) mi total s>-sten)ic- ^•ast•ular compliance (,JV7_1P) plotted ill tlif Irfl puiiul and on the Mood volunic of a reservoir iitserted hetween the oaval vein and a pcrftision pump which in turn pt-rfiised a constant volume How into the right heart. .IV,,, plotletl in the- rinht panel. Both data were obtained in identical (loys but in separate experimental runs. Circles represent mean value's friHn 13 vagotomized dogs and bars the standard errors uf the inemi %alues.
to the iiniinal. Note that these two shifts arc opix)sitc in the dhoction and therefore we can oliserve only the net alj^ehraic effect if both effects occur. Thirdly, if the reflex altered pressure distributions among various regions of the systemic venous bed. this wotild also alter the volume distribution iu the systemic rcgi()n.s in the absi;nce ol auy change in the capacity of those regional vessels. The la.st factor is very difficult to mcastire or itssess, and we inchided it as part of the cliange in unstressed vascular volume in our determination. Our data in the right panel of Fig. 5 shows that the Ciirotid sintis reflex indeed mobilized blood from or into the vascular bed. The niiixinium gain of mobilization (JV per ..JISP of 25 mm Hgl WAS found tcj be 3-4 ml/kg on au average from 13 dogs in the region of ISP l>et\vecn 125 and 150 mm Hg in which the reflex changed total peripheral resistance most intensely. When we c-orrected the ma.sking effect of changed arterial prcsstire on the blood volume shift, the gain value became almost twice as large. The next ([uestion worth ct>nsidering is whether or not thLs much mobilization of blood is (juantitatively important for overall circnlat()ry regulation. As Guyton and his associates (Guyton, 1960) clearly demonstrated through a number of publications, the siguificance of control of vascnlar capacity lies in its ability to modify the filling pressure of the heart. This means that w-hether or not an obser\ed change in vascular capacity is great depends on if it alters cardiac filling pressure to a significant degree. We can examine this as follows.
40
K. SAGAWA, M. KUMADA AND A. SHOUKAS
Suppose that ISP was raised from 125 to 150 mm Hg in a 20 kg dog. This would result in a 68 ml increase in the total systemic vascnlar capacity. Considering tlie total vascular compliance valne of 2-0 ml/mm Hg/kg or 40 ml/mm Ilg in this dog, the filling pressure for the right heart .sliould decrease by about 1-7 mm Hg, with all other factors (eardiac contractility, venotis resistance, etc.) assumed to remain unaltered. This fall in filling pressure is quite important if one remembers how sensitive the right heart is to a change in right atrial pressure. The data from our laboratory indicate that cardiac outptit from the heart-lting preparation changes as mucli as 80!f in response to 2 mm Hg cliange in right atrial presstire. Kumada, Okai and Gunji (1971) measured the rcHex change In mt'an systemic filling pressure- in dogs. The study showed that a change of 1 to 2 mm Hg accompanied common carotid occhision. Browse, Donald and Shepherd (1966) obtained a set of data on the reflex control of capacity vessels similar to ottr data. As yet, their interpretation of the (jtiantitative importance of the reflex change is opposite to ours. We believe that their conclusion derived partly from the laek of consideration of the tremendous sensitiviy of the right cardiac ptimp to a small change in its filling pressure. Our conclusion that the reHex controls total vascular capacity to a significant degree relative to the sensitivity of right cardiac pump does not ncce.ssari1y mean tliat the stimulation of tlie sinus nerve in intact animals should cause a reduction in cardiac output or that occhision of common carotid arteries should increase cardiac output. There are many otlier faetors to be considered simultaneously, and eonsideration of these multiple faetors in a ([uantitative manner is precisely what systems analyses intend to achieve. To this end, liowever, we had to start from some basic knowledge, and we are not yet ready for this type of overall analysis. lM)Uu OF GARDIAG OUTPUT IN REFLEX CONTROL OF ARTERIAL PRESSURE. There is no doubt that the baroreceptor reflex eontrols heart rate and cardiac contractility as part of its control of arterial pressure. The reflex control of cardiae output still remains somewhat controversial today. In anaesthetized dogs with vagi intact, occlusion of common carotid arteries causes sometimes an increiise in cardiac output, sometimes a decrease and some other times no significant change. Iriuchijima, Souisliy and Wilson (196S) showed that, although cardiac sympathetic impulses were always tliere to enhance; contractility and heart rate, cardiac (nitput did not increase beeause of tbe simnltaneonsly increased arterial pressure afterload. W'e also studied relative importance (jf changes in cardiac outpnt and total peripheral resistance when the carotid sinns reflex cx)ntrols arterial presstire (Schmidt, Kumada and Sagawa, 1971). We found that the reflex significantly changed both variables in the range from 80 to 160 mm Hg in anaesthetized closed-chest dogs. However, the reflex control of cardiac otitpiit was far more marked after vag(jtomy than before vagotomy (Fig. 6). Reflex control of total pcripiieral resistance was much less dependent on the presence
BAROREFLEX AND CIRCULATION or alwencf of the vagus nerves. Another new finding from this study was that the cardiac output contml was observed nwre evenly over a wider range of ISP whih' the eontrol of total periphenil rcsistancv was concentrated on a narrower range of ISP from UK) to 150 mm Hg. However, there w;is COILS iderahle variation from dog to dog of the relative magnitude of cardiac output and total peripheral resistance factors. 150 140 130
CARDIAC OUTPUT •" [cc/m!n/kg) ,,(, IOO 90 SO 50 75 IOO 125 ISO 175 IOO INTRASINUS PRESSURE [mm Hg) 22S
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FiK- 6 . E l l e c t of inlmsiiiiLs p r e s s u r e o n eardiiu- o u t p u t ( a ) , tola! iH-ripluTul rcsi-staiii-e ( b ) a n d ini-aii s y s t e m i c a r t e r i a l prcs.snre ( c ) b. Hepn>duc-(Hl from S t h i i i i d i , K u n u i d a arxl Satcawii I 1 9 7 I t w i t h llu- |>enni.vston of t h e publisher. — • — X'agal n e n e s i n t a c t . - - ^ - - X'afial n e n m s e v e r e d .
Itegarding this individual variation. Olmsted, Mcdibhin and Page {1966) found in unanai-sthetized, vagotomized dogs that aninmis with relatively low C"ardiae ontpnt under the control condition increased e-ardiac ontpnt ri-Iati\ely more than total pi-ripheral resLstanct' in ri'spimse to comiixin carotid occlusion. A similar tendency could Ix" oljserved in our study. Tliis suggests that the strategy of the reflex system involves nse of those effector organs with the greatest reser\T for ehange under a given eonditioti. To confirm this jiossibility, mueh more detailed and aecnrate measurements of cardiac outpnt innst he made under a variety of conditions. This is another example of ([iicstioiis that systems aiuil)'.ses shonid be pursuing.
K. SAGAWA, M. KUMADA AND A. SHOUKAS
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Conceriiiiig the direct mechanical loading effoct ni artrrial presstire on cardiac otitptit, there stiJl is a conflict of concepts among investigators. A group ol investigators believe that any increase in arterial pressure red\ices cardiac output by its afterload efFect, as exemplified by t!ie view of Iriuchijima et al. (1968). Other researchers regard the heart as a relatively cf)nstant How pump on the basis of "homeometrie autoregiilation" origirtally reported by Sarnoff, Mitciiell, Clihnore and Remensnyder (1960). Our stndies {Sagawa, U)67a; Herndon and Sagawa. 1969) indicate that the pressnre afterload characteristics of the heart depend on tin- level of preload and on the reHex control of contractility (Fig. 7). We need more information eoncerning the interactive effects of the reHe\- and preloaded venotis pressnre on the relationship between afterload arterial pressure and cardiac ontptit before we can (iuantitati\eiy predict cardiac output responses to various disturbances in intact animals and man.
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MEAN AORTIC PRESSURE (mm Hg) Fig. 7. i'^llftt ()£ mean aortic pressure of pulsation superimposed on fimr different mean pressures (75, KK), I2.5 ami 150 mm Hg) on mean arterial pressure (left panel), cardiac output (centre panel) and total peripheral resistance I riKht panel). The amplitude of pulsation was fixwl at 5(t mm HK peak to peak. FreV
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MEAN CAROTID SINUS PRESSURE {mm Hg) Fig. lOu. Clonihined efFefts of mean intrasinus pressure and its piil.se pressure on mean arterial pressure, heforc (solid line) and after (broken line) vagotiiniy in ctoKs. Fig. 10a was reprtKlucetl from Stluuidt, Kumada and Sagawa (1972) witli tlie permission of tlu publisher.
BAROREFLEX AND CIRCULATION We attempted to extend the knowledj^e on the effect of pulsatile forcing on the reflex controls of arterial pressure, eardiac output and total peripheral resistance (Schmidt, Kumada and Sagawa, 1972). In anaesthetized dogs carotid sinus pressure was set at 75, 100, 125 and 150 mm Hg and then pulsated sinusoidally with frequencies of 1, 2. 3 and 4 Hz and peak-to-peak amplitude of 25, 50 and 75 mm Hg. The study was repeated before and after vagotomy. As shown by the plot in Fig. S of mean values fnnn 6 to 10 dogs, changing the frequency of pulsation with an amplitude fixed at 50 mm Hg did not affect any of the measured variables at any mean ISP, with the only exception of the lowest ISP (75 nun Hg) after vagotomy. In eontrast, changing the amplitude with the frequency fixed at 2 Hz more significantly affected the response at most mean values of ISP and very markedly in vagotomized preparations (Fig. 9). Fig. 10 is a superimposed plot of the responses of arterial pressure (a), cardiac output (b) and total peripheral resistance (c) as a function of mean ISP. Fig. 11 is a reproduction of a "speculative" figure from the paper by Angell James and DeHiirgh Daly (1970) in whieh the effect of pulsation in the sinoaortic area on ••I4tt
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Fis. 10b. Coiiil)iiu'(l eflccts of iiu'an intrasiniLS pressure and ils pulw pressure on eardiac uutput befort? (solid symbols) and after (open symboLs) vagtitoiiiy. Kor further explatiations of symbols, see the legend for FI'K. 10a.
K. SAGAWA, M. KUMADA AND A. SHOUKAS total peripheral resistance was plotted based on tlieir observations. It agrees very well with our data plotted in Fig. 10(c), but slightly differs from those eurves on mean arterial pressure {MAP)-ISP relationship plotted in Fij^. 10(a). The difference obviously derives from the eluiracteristics ot eardiac output (CO)-ISP relationship curves which shift to the left with increase in pulse pressure maintaining their slopes. In short, our findings can be snminarized by saying that increasing pulse pressure in the Ciirotid sinus considerably reduces tlie reflex control gain of total peripheral resistance but not the gain of cardiac output control as much. As a rcsnlt. the reflex control gain of arterial pressnrc is mildly influeuced by the magnitude of pulse pressure. This conclusion is shown schematically by the gain surface in a three dimensional plot in Fig. 12. Under most natnral circ-nmstances, central arterial pressnrc \'ai"i('s with elianiics in both mean and pulse pressiires. This surface is therefore u more detailed guide for predicting the change in overall reflex gain. We would also add that a statement such as "pulsatile pressure is more
