A Mathematical Model of CO2 Effect On Cardiovascular Regulation

Am J Physiol Heart Circ Physiol 281: H2036H2052, 2001.
A mathematical model of CO2 effect on cardiovascular regulation

ELISA MAGOSSO AND MAURO URSINO Department of Electronics, Computer Science and Systems, University of Bologna, I40136 Bologna, Italy
Received 8 January 2001; accepted in nal form 5 July 2001
Magosso, Elisa, and Mauro Ursino. A mathematical model of CO2 effect on cardiovascular regulation. Am J Physiol Heart Circ Physiol 281: H2036H2052, 2001. The effect of changes in arterial CO2 tension on the cardiovascular system is analyzed by means of a mathematical model. The model is an extension of a previous one that already incorporated the main reex and local mechanisms triggered by O2 changes. The new aspects covered by the model are the O2-CO2 interaction at the peripheral chemoreceptors, the effect of local CO2 changes on peripheral resistances, the direct central neural system (CNS) response to CO2, and the control of central chemoreceptors on ventilation and tidal volume. A statistical comparison between model simulation results and various experimental data has been performed. This comparison suggests that the model is able to simulate the acute cardiovascular response to changes in blood gas content in a variety of conditions (normoxic hypercapnia, hypercapnia during articial ventilation, hypocapnic hypoxia, and hypercapnic hypoxia). The model ascribes the observed responses to the complex superimposition of many mechanisms simultaneously working (baroreex, peripheral chemoreex, CNS response, lung-stretch receptors, local gas tension effect), which may be differently activated depending on the specic stimulus under study. However, although some experiments can be reproduced using a single basal set of parameters, reproduction of other experiments requires a different combination of the mechanism strengths (particularly, a different strength of the local CO2 mechanism on peripheral resistances and of the CNS response to CO2). Starting from these results, some assumptions to explain the striking differences reported in the literature are presented. The model may represent a valid support for the interpretation of physiological data on acute cardiovascular regulation and may favor the synthesis of contradictory results into a single theoretical setting. hypercapnia; hypocapnic hypoxia; chemoreceptors; lungstretch receptors; central neural system response
CARBON DIOXIDE is known to have a signicant impact on the cardiovascular system. Experimental studies in animals suggest that hypocapnia causes a depression of the central vasomotor neurons (34, 35, 38) and abates the peripheral chemoreex response (4, 20, 30 32); the opposite effects occur during hypercapnia (16, 34, 35, 38). Moreover, CO2 is known to be a vasodilator
of many peripheral vascular beds (including the brain, heart, and skeletal muscle) (6, 15, 18, 28, 44, 53). Furthermore, in conditions when ventilation is free to change, hypercapnia provokes an increase in lung ination, thus stimulating slowly adapting pulmonarystretch receptors with myelinated A bers; the latter cause tachycardia and vasodilation in the vascular beds under sympathetic reex control (10, 11). Finally, changes in systemic arterial pressure (SAP), which often accompany hypercapnia or hypocapnia, modulate the action of the baroreex control system, which, in turn, exerts a powerful control on several cardiovascular parameters. Even though the main mechanisms involved in the cardiovascular response to CO2 changes have been familiar for many years, their nal effects on cardiovascular quantities are far from being completely recognized. Although several experiments indicate that hypercapnia causes an increase in total peripheral resistance (TPR), tachycardia, and an increase in mean SAP, others report a signicant decrease in total systemic resistance and a decrease in heart rate (HR) (5, 25, 48, 50, 54, 61). Moreover, changes in cardiac output (CO) exhibit an almost equal dispersion in both directions during both increasing and decreasing PCO2. These apparent contradictions of experimental data can ensue from the extreme complexity of the entire cardiovascular control system, characterized by the nonlinear superimposition among multiple mechanisms operating simultaneously. Individual variability, differences in the experimental setup (for instance free vs. articial ventilation), or a variance in hemodynamic conditions (for instance in the SAP level or in metabolism) may bring about a different balance between regulatory actions, thus resulting in opposing nal changes of the same regulated quantities. A further aspect that requires particular attention is that changes in blood PCO2 almost always occur together with O2 pressure changes (for instance during hypocapnic hypoxia or asphyxia). Because the regulatory actions triggered by changes in PO2 and PCO2 share several common afferent pathways and utilize the
Address for reprint requests and other correspondence: M. Ursino, Dipartimento di Elettronica, Informatica e Sistemistica, viale Risorgimento 2, I-40136 Bologna, Italy (E-mail: mursino@deis.unibo.it). H2036
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0363-6135/01 $5.00 Copyright 2001 the American Physiological Society
CARDIOVASCULAR RESPONSE TO CO2 CHANGES
H2037 Afferent activity from lung-stretch receptors, spikes/s Activity in the efferent sympathetic (s) bers to heart, peripheral resistances, and veins, respectively, spikes/s Parameter related with the strength of the afferent chemoreceptor response to CO2, dimensionless Gains of the central chemoreceptor sympathetic (ccs) response to CO2 acting on heart, peripheral resistances, and veins, respectively, s1 mmHg1 Gain of the local O2 response on the coronary (h), muscular (m), and cerebral (b) vascular beds, respectively, ml blood/ml O2 Gain of ventilatory response to peripheral chemoreceptors, l/mins Gain of ventilatory response to central chemoreceptors (h during hypercapnia, l during hypocapnia), l/min mmHg1 Cerebral peripheral hydraulic conductance, ml/mmHg1 s1 Basal (n) value of cerebral peripheral hydraulic conductance, ml/ mmHg1 s1 Parameter related to the central gain of the CO2 effect, coronary and muscular bed, respectively, mmHg Parameter related to the central gain of the hypoxic (ischemic) response, mmHg Parameter related to the central gain of the afferent chemoreceptor response, mmHg PCO2 basal value (n), mmHg Oxygen pressure at the central point of the afferent chemoreceptor response, mmHg Oxygen pressure at the central point of the hypoxic (ischemic) response, mmHg Coronary and skeletal muscle resistance (hydraulic), respectively, mmHg s ml1 Normal coronary and skeletal muscle resistance (hydraulic), respectively, mmHg s ml1 Respiratory rate, breaths/min Ventilation, l/min Change in ventilation induced by activation of peripheral chemoreceptors, l/min Change in ventilation induced by activation of central chemoreceptors, l/min
same effectors, the level of nonlinear superimposition becomes exceedingly complex (1). Mathematical modeling and computer simulation techniques have often been advocated as important tools to investigate the complexity of physiological control systems in rigorous quantitative terms. In recent years, we formulated a mathematical model of the short-term cardiovascular regulatory response to acute isocapnic hypoxia (59). The model includes the arterial baroreex, the peripheral chemoreex, the lungstretch receptors, the hypoxic response of the central neural system (CNS), and the local O2 effect on the vascular beds with a higher metabolic requirement. With that model, we were able to summarize several different experimental results concerning acute hypoxia into a single theoretical setting (60). The main limitation of the previous model was the absence of CO2 mechanisms, i.e., the model could be used to investigate hypoxia in isocapnic conditions only. The aim of the present subsequent study is to include the effect of blood PCO2 into the previous mathematical model in accordance with present physiological knowledge. This may be important 1) to provide a theoretical framework for the analysis of physiological experiments characterized by changes in PCO2; and 2) to provide possible explanations for the differences observed among experimental results. In particular, we aspire to analyze the putative role of each mechanism in the cardiovascular response to CO2. This paper is structured as follows. First, the mathematical model is briey described in qualitative terms, laying stress on the new aspects only. Second, physiological results concerning normoxic hypercapnia, hypocapnic hypoxia, and hypercapnic hypoxia are simulated. Finally, a sensitivity analysis on the main mechanisms is performed to gain a deeper understanding on the possible rationale for experimental differences. Glossary Cvb,O2 Cvb,O2n Oxygen gas concentration in venous (v) blood leaving brain (b), ml O2/ml blood Oxygen gas concentration in venous blood leaving brain under normal (n) conditions, ml O2/ml blood Oxygen gas concentration in venous blood leaving heart (h) and skeletal muscle (m), respectively, ml O2/ml blood Time delay of ventilatory response to peripheral chemoreceptors (p), s Time delay of ventilatory response to central chemoreceptors (c), s Baroreceptor afferent (ab) activity, spikes/s Afferent chemoreceptor (ac) activity, spikes/s
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fap fsj j h, p, v
f, KH
gccsj j h, p, v
gj,O2 j h, m, b
gVp gVc,h,gVc,l
Gbp Gbpm kj,CO2 j h, m
kisc,sj j h, p, v kac PaCO2n O2,ac P O2,sj P Rjp j h, m Rjpn j h, m RR V p V c V
Cvj,O2 j h, m
DVp DVc fab fac
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H2038 VT j h, p, v
Wc,sj
Wp,sj j h, p, v
Wb,sj j h, p, v
xb,O2 xb,CO2 xj,O2 j h, m
xj,CO2 j h, m
sj j h, p, v
sj j h, p, v ac cc isc O2 CO2 Vp Vc A, B, C, D
Tidal volume, l Synaptic weights from chemoreceptors acting on heart peripheral resistances and veins, respectively, dimensionless Synaptic weights from pulmonary (lung)-stretch receptors acting on heart, peripheral resistances, and veins, respectively, dimensionless Synaptic weights from baroreceptors acting on heart peripheral resistances and veins, respectively, dimensionless State variable representing the effect of O2 on the cerebrovascular bed, dimensionless State variable representing the effect of CO2 on cerebrovascular bed, dimensionless State variable representing the effect of O2 on coronary and muscular bed, respectively, dimensionless State variable representing the effect of CO2 on coronary and muscular bed, respectively, dimensionless Offset terms for the sympathetic response, describing the effect of gas alterations in the central neural system on efferent sympathetic activity to heart, peripheral resistances, and veins, respectively, s1 Upper saturation level of the hypoxic (ischemic) response, s1 Time constant of the afferent chemoreceptor response, s Time constant of the central chemoreceptors response, s Time constant of the hypoxic (ischemic) response, s Time constant of the peripheral O2 response, s Time constant of the peripheral CO2 responses Time constant of ventilatory response to peripheral chemoreceptors, s Time constant of ventilatory response to central chemoreceptors, s Parameters describing the cerebral blood ow response to CO2 (from Ref. 45)
MODEL DESCRIPTION
The model includes the pulsating heart, the vascular system, and various regulatory actions. Description of the regulatory mechanisms, in turn, distinguishes between the afAJP-Heart Circ Physiol VOL
ferent information from several groups of receptors (arterial baroreceptors, peripheral chemoreceptors, and lung-stretch receptors), the response of the CNS to changes in PO2 and PCO2, the activity of the efferent sympathetic bers directed to the heart and peripheral vessels, the vagus activity, the response of various effectors to the efferent activity of neural bers, the local effect of O2 and CO2 on peripheral resistances, and the ventilation response to peripheral and central chemoreceptor drive. A block diagram summarizing the main aspects of the regulatory actions is shown in Fig. 1. The description of the pulsating heart and of the entire vascular system is unchanged compared with that used in previous studies (57, 59), where all details can be found. Hence, these parts of the model are not described again for the sake of brevity. Afferent information. The arterial baroreceptors respond to changes in both the instant value of SAP and its rate of change; slowly adapting lung-stretch receptors respond to changes in VT. Both responses include a static characteristic and a rst-order dynamic. The response of both groups of receptors is the same as that used in the previous paper (59). The model of the peripheral chemoreceptors also includes a dynamic block and a static nonlinear characteristic. Description of the latter has been modied compared with that used in the previous paper (59) to account for the nonlinear peripheral interaction between O2 and CO2 pressure changes. As in the previous work, the static curve relating chemoreceptor activity to arterial PO2 (PaO2) during normocapnia exhibits an hyperbolic trend (4) with an upper saturation level. This behavior has been reproduced using a combination of exponential functions. The static relationship linking chemoreceptor activity to PCO2 during normoxia exhibits a lower threshold and a monotonic increase (20, 30 32). These data can be reproduced reasonably well through a logarithmic curve. Finally, experimental and clinical results demonstrate that hypoxia reinforces the chemoreceptor response to hypercapnia and vice versa (20, 3032); this behavior involves a multiplicative relationship between the individual O2 and CO2 static curves and a progressive shift of the lower threshold to the left during hypoxia (see Eqs. 12 in APPENDIX). Examples of the chemoreceptor response to PCO2 changes, evaluated in steady-state conditions at different arterial oxygen levels, are shown in Fig. 2 and are compared with experimental data. The parameters in these curves have been given to reproduce experimental results by Fitzgerald et al. (20) and Lahiri et al. (3032). The chemoreceptor time constant ac has been given the value of 2 s based on data by Rutherford and Vatner (51). Efferent neural pathways. The efferent pathways in the model comprise both sympathetic and parasympathetic (vagal) neural bers. The activity in these efferent bers is a nonlinear monotonic function of the weighted sum of activities from baroreceptors, chemoreceptors, and lung-stretch receptors, where the weights may be positive or negative. Moreover, afferent information is compared with an offset term; in the case of sympathetic activity, the latter is modulated by hypoxia in the CNS and by CO2 changes in the medulla (see CNS response). As justied in previous studies (57, 59), we assumed that sympathetic activity decreases with a negative monoexponential function in response to inhibitory afferent information, whereas it increases exponentially up to a saturation level in response to excitatory inputs (see APPENDIX, Eq. 3). An important modication of the present work, compared with the previous, is that we used different equations to describe
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Fig. 1. Block diagram describing the interactions among regulatory mechanisms according to the present model. CNS, central neural system.
the sympathetic activity to the heart ( fsh), to the peripheral resistance ( fsp), and to the veins ( fsv). In fact, experimental data on the CNS response to hypocapnia and hypercapnia can be reproduced reasonably well only assuming a dissimilar sympathetic action on arterioles and veins (see RESULTS). The weights connecting baroreceptors, peripheral chemoreceptors, and lung-stretch receptors to sympathetic neurons
have been given the same values as in the previous work (59). In contrast, the offset term depends not only on hypoxia of the CNS, but also on the CO2 level in supraspinal neural structures (especially the medulla). The vagal bers are directed to the heart only and contribute to the control of HR. Their dependence on the activity of afferent information is the same as that used previously (59).
Fig. 2. Steady-state activity in the afferent chemoreceptor bers ( fac) vs. arterial PCO2 (PaCO2), plotted at different levels of arterial PO2 (PaO2) ranging from deep hypoxia (top left) to hyperoxia (bottom right). Continuous lines are model simulation curves obtained at different levels of PaO2. Experimental data are from Fitzgerald and Parks (20) (E, , *, , ) and from Lahiri and Delaney (31) () in cats, at corresponding levels of PaO2.
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CNS response. The model assumes that changes of PO2 and PCO2 affect the sympathetic activity directly by modifying the offset term in the equation linking sympathetic response to the afferent information (Eqs. 47 in APPENDIX). Both mechanisms include a static characteristic and a rst-order, lowpass dynamic. Various experimental results suggest that the effect of CNS hypoxia on the sympathetic drive is quite negligible until PO2 is lowered below a given threshold and then it increases dramatically. This behavior has been reproduced using a sigmoidal function. According to data reported in Koehler et al. (25), this threshold is higher for the cardiac sympathetic activity (5060 mmHg) and lower for the sympathetic activity directed to peripheral vessels (3540 mmHg). All parameters describing the static and dynamic aspects of CNS hypoxia have been given to mimic data by Koehler et al. (25) and Downing et al. (16). A direct role of the CNS on the cardiovascular response to CO2 is stressed by experiments in cats and rats (34, 35, 37). These experiments show that hypocapnia can produce a decrease in arterial pressure and total systemic resistance independently of the input from arterial baroreceptors and peripheral chemoreceptors. The opposite effect is evident during hypercapnia. Moreover, superfusion of the ventral medulla with hypercapnic uid causes a sympathetically mediated increase in HR and augments sympathetic activity to the forelimb, hindlimb, and kidney (36). Results of the previous experiments can be simulated reasonably well assuming that the offset term of sympathetic activity (i.e., the quantity in Eq. 3) depends linearly on PCO2 changes. The slope of these relationships for the arterioles, venules, and the heart have been given to mimic experimental results by Lioy et al. (34) and Downing et al. (16) (see RESULTS). The time constant of the central CO2 mechanism has been taken from the arterial pressure time pattern reported in Lioy and Trzebski (37) following CO2 stimulation of central chemosensitive areas. Cardiovascular effectors for the reex control. As explained above, in the present work the sympathetic activity is subdivided into three distinct branches. The rst is directed to systemic arterioles in the splanchnic, muscular, and nonautoregulated extrasplanchnic vascular beds and modies the peripheral resistance. The second is directed to the peripheral veins and modies venous unstressed volumes in the same vascular beds. Finally, sympathetic activity to the heart affects heart period and the end-systolic elastance in the right and left ventricles. The vagal activity works on the heart only by modulating heart period. Each effector response includes a pure delay, a monotonic static function, and a rst-order, low-pass dynamic. Equations are formally identical to those used in a previous work (59) and hence are not repeated for briefness. Local effect of O2 and CO2. We assume that hypoxia in the coronary, brain, and skeletal muscle circulation causes vasodilation through a local mechanism. It is well known that the local O2 effect can be ascribed to two concurrent mechanisms, i.e., a direct effect of O2 on smooth muscle tension in the arteriolar wall and an indirect effect mediated by the release of vasodilatory metabolites (adenosine, pH, etc.) by the hypoxic tissue. Because the aim of this model is not to analyze the synergic action of these mechanisms in detail and to assess their individual role, but just to simulate the overall O2 effect on peripheral resistances, we used a single empirical equation for each compartment. In this equation, we assumed that the controlled quantity for the local O2 regulation is O2 concentration in the venous blood leaving the compartment. This choice is appropriate because venous O2
concentration is inuenced by both the arterial O2 content and local blood ow, as well as by tissue O2 consumption rate; hence, its changes reect all stimuli (direct and indirect) affecting the vascular bed. Accordingly, the peripheral hydraulic resistance in the locally regulated vascular beds is linearly related to O2 venous concentration via a rst-order dynamic, i.e., resistance decreases when O2 venous concentration falls below the basal level (Eqs. 89 and 1213 in APPENDIX). All parameters of this regulation have been given the same values as in the previous work (59). O2 venous concentration is computed from knowledge of arterial PO2 (PaO2) (which is an input for the model) by imposing a mass balance between O2 extraction rate and O2 consumption rate. To this end, the O2- and CO2-carrying capacity of blood are computed from PO2 and PCO2 by using the equations proposed by Spencer et al. (52), which account for the Bohr and Haldane effects. Throughout the present simulations the O2 consumption rate is assumed to remain constant in the brain and skeletal muscle. By contrast, consumption rate in the heart is proportional to the average power of the cardiac pump. According to several authors, CO2 has an important vasodilatory effect on the cerebral, coronary, and skeletal muscle vascular beds. This effect has been simulated, during normoxia, through a static nonlinear relationship, linking peripheral resistance to arterial PCO2 (PaCO2), and a rst-order, low-pass dynamic. The static relationships have been assigned to mimic experimental data by Reivich (45) to the cerebral vascular bed, by Case et al. (6) to the coronary circulation, and by Kontos et al. (28), Radawski et al. (44), and Stowe et al. (53) to the skeletal muscle circulation (Eqs. 1011 and 1415 in APPENDIX). The time constant of this mechanism has been given a value taken from Ursino and Lodi (58), where more details can be found. By example, Fig. 3 shows the relationship linking peripheral resistance to PaCO2 in the skeletal muscle vascular bed during normoxia in the absence of any sympathetic inuence
Fig. 3. Percent changes of peripheral muscle resistance (Rmp) in the skeletal muscle vascular bed vs. local (PCO2) measured by Refs. 28, 44, and 53 in conditions where only the local mechanism is active. Continuous line represents model results simulated by giving a value for the local vasodilatory effect of CO2 as in Table 1 (km,CO2 142.8 mmHg). The large dispersion among experimental data is remarkable. www.ajpheart.org
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(i.e., only the local CO2 effect is effective in these experiments). As clearly shown in Fig. 3, experimental data exhibit a very large dispersion. The basal parameter values for the model (continuous line in Fig. 3) have been chosen to mimic cases with a moderate peripheral reactivity to CO2. However, as shown in RESULTS, a stronger reactivity must be hypothesized to explain data by others (4850). and VT. V is regulated by both central and Control of V peripheral chemoreceptors. Because both effects are largely additive in most physiological conditions (7), we can write (Eq. 16 in APPENDIX) p V c V n V V represents ventilation and the three terms on the where V right-hand side of the previous equation denote the normal level of ventilation (i.e., ventilation during normoxia and n), and the changes in ventilation induced by normocapnia, V p) and central chemoreceptors stimulation of peripheral (V c), respectively. The effect of each group of chemorecep(V tors has been simulated using a simple rst-order linear differential equation with a pure delay (Eqs. 17 and 18 in APPENDIX) (3, 8, 9, 55). The input quantity for the peripheral mechanism is the afferent activity in the arterial chemoreceptor bers; as shown in Fig. 2, the latter implicates a nonlinear multiplicative O2-CO2 interaction. The value of the peripheral chemoreceptor gain has been assigned to reproduce the ventilatory response to a hypoxic stimulus (PaO2 40 mmHg) in isocapnic condition reported by Reynolds and Milhorn (46) (Fig. 4). The input for the central mechanism are changes in PCO2, assuming that, in physiological conditions, variations of PCO2 in blood and in the medulla surface are proportional. This is the assumption adopted in most recent mathematical models of ventilatory control tted to experimental data (3, 8, 9). The central chemoreceptor gain has been given two different values during hypercapnia and hypocapnia, reecting the existence of two regions separated by a break point in the
relationship ventilation vs. PaCO2 (7). During hypercapnia the value of the central chemoreceptor gain, together with the peripheral chemoreceptor gain assigned previously, furnishes a ventilation increase per millimeter mercury of PCO2 change (2.4 l min1 mmHg1) in the range reported in the literature (7, 19, 43). During hypocapnia, the ventilation change exhibits low CO2 sensitivity (7). The pure delay and time constant of peripheral chemoreceptors has been taken from the works of others (3, 8, 9, 55). The pure delay and the time constant of central chemoreceptor control have higher values according to the same authors. An example of the ventilation response to a hypercapnic stimulus is shown in Fig. 5, top, and compared with clinical data (47). Finally, because the input quantity for lung-stretch recep , VT, tors are changes in VT, we need a relationship linking V and respiratory rate (RR). Clinical data in humans (17, 23, 46, 47) suggest that, during moderate hypoxia or moderate can be almost completely hypercapnia, the increase in V ascribed to changes in VT. In contrast, during severe hypoxia and severe hypercapnia, changes in RR become evident, too; . The relationship as a consequence, VT increases less than V can be reproduced fairly well using an linking VT and V empirical mathematical equation (Eq. 19 in APPENDIX); the latter is shown in Fig. 6 and compared with clinical data on humans. Changes in VT during hypercapnia and hypoxia are also shown in Figs. 4 and 5 (bottom) and compared with the data by Reynolds et al. (46, 47). The set of differential equations has been numerically solved on Pentium-based personal computers by using the Runge-Kutta-Fehlberg 4/5 algorithm with adjustable step length (maximum allowed integration step 0.01 s, memorization step 0.01 s). To this end, we used the software package SIMNON (SIMNON/PCW for Microsoft Windows, version 3.0, SSPA Maritime Consulting; Go teborg, Sweden) designed for simulation of ordinary differential equations. Because all hemodynamic quantities are pulsating in nature, the mean
Fig. 4. Time pattern of minute venti , top) and tidal volume (VT, lation (V bottom) simulated with the model (left) and measured by Reynolds and Milhorn (46) (right) in response to a 10-min step isocapnic hypoxia (PaO2 40 mmHg). Clinical data are means SE for 10 subjects.
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(top) Fig. 5. Time pattern of minute V and VT (bottom) simulated with the model (left) and measured by Reynolds et al. (47) (right) in response to a 25-min step hypercapnia (PaCO2 56 mmHg). Clinical data are means SE for 14 subjects.
values during each heart period were computed from stored data using the trapezoidal integration method. All new mathematical equations are reported in APPENDIX. The parameter numerical values with references can be found in Table 1. All other parameters and equations, neces-
sary to complete the model, can be found in a previous study (59).

RESULTS
Fig. 6. Plot of the steady-state relationship between VT and minute according to the present model (continuous line). Clinical data are V from Dripps and Comroe (17), Hey et al. (23), and Reynolds and Milhorn (46). AJP-Heart Circ Physiol VOL
In all subsequent gures, experimental data taken from the literature are presented as means SE. Just in a few cases, SE are not presented because they could not be acquired from the original publication. Moreover, to quantitatively assess the adequacy of tting, a statistical Students t-test has been performed between the model prediction and the corresponding experimental data in all cases where the experimental SE was available. Three levels of statistical signicance are used as the following: *P 0.1, **P 0.05, and ***P 0.01. CO2 response of the CNS. A preliminary group of simulations was performed to give a numerical value to the parameters characterizing the CNS response to local CO2 changes. To this end, the action of baroreceptors, peripheral chemoreceptors, and lung-stretch receptors was excluded from the model to simulate conditions occurring in articially ventilated animals after the vagi, carotid sinus, and aortic nerves were cut (34). Exclusion of these mechanisms was achieved by articially maintaining the input quantities of these groups of receptors at their basal value throughout the simulations, i.e., these receptors work in open-loop conditions with an input quantity different from that used in the rest of the cardiovascular model. PaCO2 was then changed from 20 to 50 mmHg. The parameter affecting HR (gccsj in Eq. 6 on APPENDIX) was assigned to reproduce the HR increase measured by Downing et al. (16) in dogs (40 beats/min increase if PCO2 of the CNS superfusate is increased by 80 mmHg). The paramewww.ajpheart.org
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Table 1. Basal values of parameters and corresponding references

fac,max 12.3 s1 (4) KH 3 (20, 31, 32) fes, 2.10 s1 (57) Wb,sp 1 (57) Wc,sp 5 (2, 1214) Wp,sp 0.34 (11) sp 6 s (25) sv 6 s1 (25) sh 53 s1 (25) gccsp 1.5 mmHg1 s1 (16, 34) PaCO2n 40 mmHg spn 13.32 s1
1
fac,min 0.835 s1 (4) f 1.4 (20, 31, 32) fes,0 16.11 s1 (57) Wb,sv 1 (57) Wc,sv 5 (2, 1214) Wp,sv 0.34 (11)
Afferent Chemoreex Pathway O2ac 45 mmHg (4) P ac 2 s (51) fes,max 60 s1 (57) Wb,sh 1 (57) Wc,sh 1 (24) Wp,sh 0 (1) kisc,sp 2 mmHg (25) kisc,sv 2 mmHg (25) kisc,sh 6 mmHg (25) gccsh 1 mmHg1 s1 (16) shn 3.6 s1 gb,O2 10 (26, 40, 41, 56) C 10570 (45) gh,O2 35 (15, 25) gm,O2 30 (26) CO2 20 s (58) PaCO2n 40 mmHg Vp 13 s (3, 8, 9) Vc 180 s (3, 8, 9)
kac 29.27 mmHg (4)
Efferent Sympathetic Pathway kes 0.0675 s (57)
CNS Response PO2sp 30 mmHg (25) O2sv 30 mmHg (25) P O2sh 45 mmHg (25) P gccsv 0 mmHg1 s1 (34) cc 20 s (16, 37) svn 13.32 s1 Cvb,O2n 0.14 (33) B 92.8 (45) Cvh,O2n 0.11 (33) Cvm,O2n 0.155 (33) O2 10 s (62) Ventilatory Response fac,n 3.6 s1 DVp 7 s (8, 9, 55) DVc 8 s (3, 8, 55)
isc 30 s (39)
Blood Flow Local Control Gbpn 0.15 ml/(mmHg s) A 20.9 (45) Rhpn 19.71 (mmHg s)/ml Rmpn 4.48 (mmHg s)/ml km,CO2 142.8 mmHg (28, 44, 53) n 7 l/min V gVp 3.6 l/min s (46) gVch 1.8l/min mmHg1 (7, 19, 43, 47) gVcl 0.12 l/min mmHg1 (7) See text denitions of all abbreviations. D 5.251 (45) kh,CO2 11.11 mmHg (6)
ters affecting peripheral resistance and CO (gccsp and gccsv) were given to reproduce the changes in the main hemodynamic quantities observed by Lioy et al. (34) in the rat. A comparison between model predictions and experimental results is shown in Fig. 7 for two different values of parameter gccsp. It is worth noting that experimental data can be reproduced reasonably well assuming that the CNS response to CO2 does not signicantly affect the venous unstressed volume. This assumption, however, will be removed when simulating other experiments (see Normoxic hypercapnia). Signicant statistical differences between simulated and real data are evident only during severe hypocapnia. Normoxic hypercapnia. Figure 8 shows the percent changes in the main hemodynamic quantities simulated with the model in response to an acute 10mmHg increase in PaCO2, performed at constant PO2 80 mmHg, i.e., the same basal value as in Ref. 25. This simulation was performed with all mechanisms working in closed-loop conditions. Results are compared with those computed from data reported in Koehler et al. (25). The agreement is satisfactory with no signicant statistical difference. However, Richardson et al. (48) observed a different pattern of hemodynamic quantities in healthy male volunteers during normoxic hypercapnia, i.e., a decrease in total systemic resistance with a notable rise in CO. As is shown in Fig. 9A, very signicant differences occur if one tries to simulate these results using the basal parameter values shown in Table 1. ConAJP-Heart Circ Physiol VOL
versely, results by Richardson et al. (48) can be reproduced quite well by the model assuming a stronger local vasodilatory effect of CO2 on the skeletal muscle vascular bed and a different strength for the CNS response to CO2 on the heart and peripheral vessels. In particular, data by Richardson et al. can be satisfactorily reproduced assuming that activation of the CNS response to hypercapnia causes vasoconstriction of peripheral veins (thus increasing mean lling pressure and venous return), whereas these receptors have a negligible role on HR and peripheral resistance (see Fig. 9 for the parameters used). The assumption of a higher local CO2 reactivity in the skeletal muscle used in the simulation of Fig. 9 can be further validated by comparing model prediction with the data reported by Richardson et al. (48) after sympathetic blockade of the forearm (Fig. 9B). In this particular simulation, we assumed that the skeletal muscle vascular bed is not under sympathetic control [i.e., muscle peripheral resistance (Rmpn) was held constant in Eq. 12 of the APPENDIX to mimic local sympathetic blockade], whereas all other parameters in the model were given the same value used in Fig. 9A. The values of skeletal muscle resistance and local blood ow measured by Richardson et al. (48) in this condition agree with those obtained by the model, conrming the existence of a high local CO2 reactivity. Hypercapnia during controlled ventilation. Several authors analyzed the effect of hypercapnia on cardiovascular variables in anesthetized animals with controlled ventilation plus hyperoxia. In these experiwww.ajpheart.org
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Fig. 7. Percent changes in mean systemic arterial pressure (SAP), skeletal muscle resistance (Rmus), total peripheral resistance (TPR), cardiac output (CO), and absolute values of heart rate (HR) vs. PaCO2, simulated with the model in steady-state conditions after elimination of all reex mechanisms (i.e., baroreex, peripheral chemoreex and lung-stretch receptor reex). In this condition, only the central neural system (CNS) response to CO2 and the local mechanisms are operative. Continuous lines have been obtained by using the parameter values for the CNS response as in Table 1 (i.e., gccsp 1.5 mmHg1 s1, gccsv 0 mmHg1 s1, gccsh 1 mmHg1 s1 , see Eq. 6 in APPENDIX). Dotted lines have been obtained using a lower value for parameter gccsp 1.0 mmHg1 s1. The latter change does not appreciably affect HR. Diamonds, mean values SE from Lioy et al. (34). * and , presence of signicant statistical differences between the model prediction and the corresponding experimental data for the two different simulations (*, gccsp 1.5 mmHg1 s1; , gccsp 1.0 mmHg1s1). HR changes (0.5 beats min1 mmHg1) agree with experimental results by Downing et al. (16).
ments, owing to articial ventilation, lung-stretch receptors have no role in the regulation, hence their input was maintained constant throughout the simulations. Two different examples are shown in Fig. 10 (50, 61) and compared with model predictions. In the experiments by Wendling et al. (61), TPR increases
Fig. 8. Steady-state percent changes in mean SAP, CO, HR, and TPR simulated with the model in response to a 10-mmHg increase in PaCO2 at constant PaO2 80 mmHg (normoxic hypercapnia). All parameters for feedback mechanisms are as in Table 1. Experimental mean values SE are from Koehler et al. (25). No signicant statistical difference is evident between model predictions and experimental data (P 0.1 for all quantities). AJP-Heart Circ Physiol VOL
during hypercapnia, whereas CO decreases. This result can be reproduced by using the basal set of parameters, but just assuming a reduction in the strength of the CNS response on HR and on TPR. The last changes may reect the use of anesthesia during the experiment. In contrast, Rothe et al. (50) observed a decrease in TPR during hypercapnia and a concomitant increase in CO. Moreover, in this experiment, mean lling pressure increased signicantly suggesting the occurrence of venoconstriction. These results, which largely differ from those by Wendling et al. (61), can be reproduced rather well at different levels of PaCO2 assuming a stronger local vasodilatory effect of CO2 on peripheral vessel and a different impact of central chemoreceptors on cardiovascular parameters (i.e., venoconstriction with almost no role on resistance and HR). These parameter changes are similar to those already used to simulate experiments by Richardson et al. (48) (see Fig. 9). Hypocapnic hypoxia. Figure 11 shows the percent changes in the main hemodynamic quantities simulated in response to an acute hypoxia, with a concomitant decrease in PCO2. Two different examples are
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Fig. 9. A: steady-state percent changes in mean SAP, CO, HR, and TPR simulated with the model in response to an acute increase in PaCO2 up to 58.5 mmHg at constant PaO2 (95 mmHg) (normoxic hypercapnia). Experimental data are mean values SE from Richardson et al. (48). SE for SAP was not available. Two examples of model simulations are shown. In the rst (basal), all parameters were given the same values as in Table 1. However, this choice leads to signicant statistical differences in the prediction of HR, CO, and TPR. To overcome these differences, we had to modify the CNS response to CO2 (gccsp 0 mmHg1 s1, gccsv 1.7 mmHg1 s1, gccsh 0 mmHg1 s1; these changes signify a greater CNS control on venous unstressed volume, with negligible CNS control on peripheral resistance and HR) and assume a greater local vasodilatory effect of CO2 on the skeletal m), muscle vascular bed (km,CO2 8.3 mmHg). B: steady-state percent changes in HR, skeletal muscle blood ow (Q and skeletal muscle peripheral resistance (Rmp), measured by Richardson et al. (48). in the forearm after local sympathetic blockade. This experiment was simulated with the model by excluding all sympathetic effects on the skeletal muscle vascular bed and using the same parameter sets as in A.
reported and compared with data obtained by Krasney and Koehler (29) in dogs and Kontos et al. (27) on human volunteers. The agreement between model simulation results and data by Krasney and Koehler (29) is satisfactory, using the basal parameter set without statistical differences. In contrast, very signicant statistical differences are evident to mean SAP and TPR if model predictions are compared with data by Kontos et al. (27). However, these differences can be overcome if
the strength of the peripheral chemoreceptor response to CO2 is just moderately increased (from KH 3 to KH 4.7, see Eq. 1 in APPENDIX). Hypercapnic hypoxia. Figure 12 shows the percent changes in the main hemodynamic quantities simulated in response to acute hypercapnia acute hypoxia. Comparison is performed with two different experimental results in dogs (25, 49). Figure 12A shows that the model is able to reproduce the experimental
Fig. 10. Percent changes in the main hemodynamic quantities measured at different levels of PaCO2 in anesthetized articially ventilated dogs. Continuous lines are model simulation results obtained using the following parameters for CO2 response: gccsp 0 mmHg1 s1, gccsv 0.4 mmHg1 s1, gccsh 0 mmHg1 s1, km,CO2 12.5 mmHg, kh,CO2 7.7 mmHg. Dashed lines have been obtained using gccsp 0.5 mmHg1 s1 and gccsh 0.2 mmHg1 s1. In all these simulations the input of lung-stretch receptors was maintained constant to mimic articial ventilation, and moderate hyperoxia was adopted (as in the original experiments). AJP-Heart Circ Physiol VOL
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Fig. 11. Steady-state percent changes in mean SAP, CO, HR, and TPR simulated with the model in response to acute hypoxia associated with hypocapnia (hypocapnic hypoxia). Final levels of hypoxia and hypocapnia used in these simulations are shown in the corresponding panels. A: mean values SE from Krasney and Koehler (29); B: mean values SE from Kontos et al. (27). In the second experiment, the starting level of PaO2 was as low as 75 mmHg. All model parameters used to simulate the rst experiment are as in Table 1. Two simulations have been performed for the second experiment. The rst simulation used the same parameter values as in Table 1. However, signicant statistical differences are evident as to SAP and TPR. These differences can be overcome using a higher strength for the peripheral chemoreceptor response to CO2 (KH 4.7 instead of KH 3.0 in Eq. 1 in APPENDIX). ***P 0.01.
results by Koehler et al. (25) fairly well using the basal set of parameters. However, we can observe that HR and so CO are overestimated. In contrast, the results by Rose et al. (49) (see Fig. 12B) exhibit a signicant decrease in TPR during hypercapnia hypoxia. The model can approximately simulate this behavior only assuming that the CNS response to CO2 has scarce effect on resistance and HR and assuming a stronger vasodilatory effect of CO2 on peripheral vascular beds. It is interesting to observe that the latter changes conform to those already hypothesized to simulate data by Richardson et al. (48) and Rothe et al. (50). Finally, it is worth noting that, in all cases, HR increases much more in the model than in the experiments, which is reected in overestimation of the CO level. This model limitation is commented in DISCUSSION. Sensitivity analysis. Because the cardiovascular responses to CO2 pressure changes reported in the literature show striking differences from one case to another (5, 25, 38, 48, 50, 54, 61), we found it useful to
perform a sensitivity analysis on the role of the individual mechanisms. To this end, Fig. 13 shows the percent changes in the main hemodynamic quantities simulated with the model in response to a PaCO2 increase from 40 to 60 mmHg during normoxia (PaO2 95 mmHg) rst when all mechanisms are intact and then after selective exclusion of a single mechanism. The individual mechanism was eliminated by opening the corresponding feedback loop and maintaining the input quantity at the basal level, thus excluding the corresponding regulatory action. However, when excluding the CNS response to CO2, we also excluded the action of central chemoreceptors on ventilation, i.e., all central inuences are simultaneously withdrawn. The results show that the baroreex plays a pivotal role in avoiding excessive derangement in the main hemodynamic quantities during hypercapnia. In the absence of this mechanism, in fact, any change in CO2 pressure would evoke very large changes in SAP and HR.
Fig. 12. A: steady-state percent changes in mean SAP, CO, HR, and TPR simulated with the model in response to an acute 10-mmHg increase in PaCO2 associated with a simultaneous reduction in PaO2 (from 80 to 40 mmHg) (hypoxic hypercapnia). All parameters for feedback mechanisms are as in Table 1. Experimental data are mean values from Koehler et al. (25). SE are not shown because they were not reported in the original paper at this level of hypoxia. B: percent changes in the same quantities measured by Rose et al. (49) (mean values SE) at a greater level of hypoxia. These changes can be roughly simulated with the model assuming a poor CNS response to CO2 (gccsp 0 mmHg1 s1, gccsv 0 mmHg1 s1, gccsh 0 mmHg1 s1) and a strong local vasodilatory effect (km,CO2 8.3 mmHg, kh,CO2 7.7 mmHg). However, it is still worth noting the existence of a great overestimation of HR by the model, which is reected in overestimation of CO and mean SAP, too.
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single mechanism may result in large differences in the pattern of hemodynamic quantities.
DISCUSSION
Fig. 13. Sensitivity analysis on the role of the individual reex mechanisms to the response to an acute 20-mmHg increase in PaCO2, performed at constant PaO2 (95 mmHg). Solid bars, steady-state percent changes in mean SAP, CO, HR, and TPR simulated with the model in basal conditions (i.e., with all parameters as in Table 1). Other bars represent simulation results after selective elimination of a feedback mechanism. It is remarkable that the CNS response and the central chemoreceptor response to ventilation have been excluded together to mimic the absence of all central receptors.
The lung-stretch receptors contribute strongly to the increase in HR during hypercapnia and attenuate the peripheral resistance increase caused by peripheral and central chemoreceptor activation. In particular, in the absence of this mechanism the tachycardia normally occurring during CO2 rise is converted to moderate bradycardia, as observed in experiments performed with articial mechanical ventilation (54) (see Fig. 10). The CNS response and peripheral chemoreceptors have a similar effect on SAP in that their elimination reduces the arterial pressure increase by 50%, mainly through a reduction in TPR, whereas CO is almost unaffected. However, the mechanism of action is different in the two cases. The absence of peripheral chemoreceptors provokes a greater tachycardia in accordance with the idea that activation of this group of receptors reduces HR primarily through an increase in vagal tone. However, CO remains almost unchanged due to a decrease in sympathetic venous tone. In contrast, suppression of CNS response plus central chemoreceptors causes a fall in HR, both via a direct action on the cardiac sympathetic tone and via the reduction in the ventilatory response (which, in turn, stimulate lung-stretch receptors). Nevertheless, CO remains rather constant because the reduction of ventilation results in an increase of sympathetic tone to the veins (via the withdrawal of lung-stretch receptors activity). As it is clear from the previous analysis, the synergical-antagonistic interactions among the various regulatory actions involved in the CO2 response are quite complex, whereas weakening or reinforcement of a
The major aim of the present work was to extend a previous model of short-term cardiovascular regulation to account for the effect of PCO2 changes on cardiovascular parameters. The new aspects incorporated include the nonlinear O2-CO2 interaction at the peripheral chemoreceptors, the direct CNS response to CO2 changes, the role of central chemoreceptors on ventilation, and the local CO2 effect on peripheral resistances. The parameter values characterizing these individual mechanisms have been given on the basis of specic physiological experiments in which the contribution of each mechanism could be adequately assessed independently of the others. Subsequently, we veried that the integrated action of all these mechanisms joined with the regulatory actions described in the previous work (i.e., the baroreex response, the hypoxic CNS response, the action of lung-stretch receptors, and the local oxygen effect) is able to reproduce experimental results reasonably well in a variety of experimental conditions (normoxic hypercapnia, hypercapnia with articial ventilation, hypoxic hypercapnia, and hypocapnic hypoxia). At present, we are not aware of other models able to summarize all these regulatory actions into a single theoretical structure. In fact, although various models of the baroreex control have been presented in previous years (21, 22, 42), no one describes the effect of changes in gas tension on cardiovascular parameters in accurate quantitative terms. The present model may have several important implications: it may be useful to summarize present physiological knowledge, it may help the rational interpretation of physiological data, and it may constitute the core of future software packages of didactic value. In perspective, the model may also be of value in the clinical practice, especially in the analysis of physiopathological conditions characterized by acute changes in blood gas content. In addition, it might be combined with other models describing lung mechanics, gas exchange processes, pharmakinetics, and/or electrolyte disorders. These areas of explorations may permit deeper comprehension of the interaction between the cardiovascular system and other physiological systems, often studied separately. For instance, the model may be useful to study the effect of respiratory pathologies on cardiovascular quantities and/or to analyze the transport of various substances (not only O2, but also drugs or anesthetics) in different hemodynamic conditions. To this end, however, the model should be enriched with other aspects, not considered presently, such as equations for gas exchange at the alveoli, lung mechanics, pH balance, and capillary exchange. In the following, the main results obtained with the present simulations are critically discussed. Normoxic hypercapnia. When arterial O2 content is maintained at its basal level, the model furnishes a
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typical cardiovascular response to hypercapnia. This is characterized by a signicant ventilation increase (Fig. 5) and a moderate increase in mean SAP, HR, and TPR, whereas CO exhibits insubstantial changes (Fig. 8). As claried by the sensitivity analysis reported in Fig. 13, this response is the result of the complex superimposition among the various mechanisms simultaneously operative. In particular, according to Fig. 13, the model ascribes the increase in total systemic resistance to the synergistic action of the peripheral chemoreceptors and of the CNS response to CO2. Selective elimination of these mechanisms, in fact, attenuates the rise in TPR during hypercapnia. Conversely, the increase in HR results from the CNS response and the simultaneous stimulation of lungstretch receptors (secondary to the ventilation increase). Finally, it is worth noting the pivotal role played by the baroreex control in buffering excessive cardiovascular derangement. In the absence of this mechanism, in fact, even a moderate hypercapnia would result in large increases in mean SAP and HR. Although the results in Fig. 8 coincide with experimental data in awake dogs by Koehler et al. (25), signicant discrepancies can be observed when comparing these results with those of others. An example of such striking differences is provided by the classic experiment in human volunteers by Richardson et al. (48). In these trials (see Fig. 9), hypercapnia still induces a rise in mean SAP and HR, but these changes are now associated with a signicant decrease in TPR and a large increase in CO. Our model is still able to mimic this specic response, but using a different combination of parameters affecting peripheral resistance and venous unstressed volume. In fact, to reproduce Richardsons data with the model, we had to presuppose a stronger local vasodilatory effect of CO2 on the skeletal muscle vascular bed and an increase in the sympathetic activity to peripheral veins during hypercapnia (the latter increases mean lling pressure and CO). Conversely, the sympathetic activity to peripheral arterioles should not increase signicantly. The hypothesis of a stronger local vasodilatory effect of CO2 in Richardsons experiment is further conrmed by data measured by this author in the forearm during hypercapnia after local sympathetic blockade (Fig. 9B). Hypercapnia with articial ventilation. The signicant differences in the response to CO2 visible between Figs. 8 and 9 are not exceptional but correspond to other ndings in the physiological literature. For instance, as shown in Fig. 10, comparable differences can be also observed in experiments performed in articially ventilated dogs, i.e., without lung-stretch receptors. According to some authors, the main consequence of hypercapnia is a moderate arterial hypertension with an increase in TPR, whereas CO exhibits either inconclusive changes (54) or moderate reduction (61). The model can reproduce this scenario fairly well using the basal parameter set (but just assuming a weakening of central chemoreceptors, which can be due to anesthesia). Conversely, Rothe et al. (50) observed a progressive decrease in total resistance when increasAJP-Heart Circ Physiol VOL
ing the hypercapnic level up to 90 mmHg; moreover, these authors observed a progressive increase in central blood volume and mean lling pressure, indicating active venoconstriction through sympathetic activation. Results by Rothe et al. can be reproduced quite well assuming a strong local vasodilatory effect of CO2 on peripheral resistances and the existence of sympathetic venoconstriction from the CNS response. According to this idea, Rothe et al. suggested that about 30% of the observed increase in mean lling pressure arises from receptors in the brain. The latter scenario is similar to that hypothesized when simulating the experimental results by Richardson (48), revealing remarkable analogies between the two cases. Hypercapnic hypoxia. Similar differences in the response to CO2 can also be noticed by comparing the experimental results by Koehler et al. (25) and Rose et al. (49) during hypercapnic hypoxia in conscious dogs. According to experimental results by Koehler et al., the model suggests that moderate hypoxia (40 mmHg) with hypercapnia results in a signicant increase in SAP, CO, and HR, whereas total systemic resistance exhibits only an inconsistent change. The model explains these results ascribing the increase in HR to activation of lung-stretch receptors and to the CNS response (stimulated both by hypoxia and hypercapnia) and the increase in CO to the increase in mean lling pressure, caused by peripheral chemoreceptor activation. Meanwhile, TPR remains almost unchanged because it depends on various antagonistic actions. In fact, the CNS response and the peripheral chemoreceptor activation work to increase resistance in reexly regulated vascular beds, whereas the strong stimulation of lung-stretch receptors and the local vasodilatory effect of CO2 and O2 conspire to reduce systemic resistance in the reexly and the metabolic regulated vascular beds, respectively. If greater levels of hypoxia are simulated during hypercapnia, the model forecasts a further progressive rise in mean SAP, HR, and CO, whereas TPR remains rather constant (unpublished simulations). Conversely, contradictory scenarios are recounted in the physiological literature. Koehler et al. (25), in their fundamental work on awake dogs, also reported experimental data obtained at deeper levels of hypoxia (down to 30 mmHg). These results display that, at deeper levels of hypercapnic hypoxia, total systemic resistance and mean SAP exhibit a greater increase, whereas HR and CO settle at a saturation level, proximal to the level attained at 40 mmHg PaO2. On the contrary, Rose et al. (49) describe a completely different result on conscious dogs. In their work, systemic hemodynamic changes during combined hypercapnia and deep hypoxia (PaO2 33 mmHg) comprehend a rise in mean SAP and a notable increase in HR and CO, whereas total systemic resistance decreases signicantly. Once again, the model can account for the decrease in TPR observed by Rose et al. ascribing it to a stronger local vasodilatory effect of CO2.
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An important limit of the present model is that it predicts a very large increase in HR during severe hypoxia hypercapnia. In contrast, both data by Koehler et al. (25) and Rose et al. (49) suggest that HR cannot increase 50% of baseline in the same condition. It is probable that severe asphyxia involves some protective mechanism for the heart, limiting it from excessive cardioacceleration. Hypocapnic hypoxia. The model is able to reproduce the cardiovascular response to hypocapnic hypoxia reasonably well, both in awake dogs (29) and human volunteers (27), even though the second simulation may benet from a moderate change in the peripheral chemoreceptor sensitivity to CO2. In conclusion, the present model is able to provide a plausible theoretical summary of many different physiological data reported in the clinical literature. However, reproduction of the different results requires formulation of alternative scenarios and the use of different parameters characterizing the mechanism strengths. A rst scenario is characterized by the presence of strong vasoconstrictive mechanisms (especially caused by activation of peripheral and central chemoreceptors) during hypercapnia, which counterbalance the local vasodilatory effects. In contrast, venoconstriction is scarce. As a consequence, TPR increases or remains unchanged, whereas CO exhibit inconsistent changes (25, 61). A second scenario is characterized by the prevalence of local vasodilation and probably also by active venoconstriction from central chemoreceptors. In this scenario, TPR decreases and CO exhibits a large rise (4850). The reasons for these different scenarios may be numerous: large variabilities among individual subjects or between animal species, the alerting response in awake subjects, the effect of anesthesia in anesthetized animals, or differences in local metabolism. In general, the present study emphasizes the extreme complexity of the system regulating cardiovascular parameters following acute changes in blood gas content, and the study points out that the analysis of this system may signicantly benet from a rigorous quantitative approach based on mathematical models and computer simulation techniques. Explication of experimental results with the help of the model may provide important indications on the role of the individual mechanisms, may allow differences among contradictory ndings to be better understood, and may provide suggestions on the existence of further regulatory actions, which deserve deeper theoretical and experimental studies.
APPENDIX
Afferent Chemoreex Pathway The model of peripheral chemoreceptors includes a static function and a rst-order linear dynamic. The static characteristic has been modied compared with that used in the previous paper (59), to account for the nonlinear peripheral interaction between PO2 and PCO2 changes. As in the previous work, we assume that the chemoreceptor activity is a sigmoid function of PaO2 at constant level of PCO2. The static response to changes in PaCO2 during normoxia has been reproduced through a logarithmic curve with a lower threshold, below which the activity approaches zero. In accordance with experimental data (31), PaCO2 threshold decreases as the intensity of hypoxia increases. Finally, the overall chemoreceptor static response exhibits a multiplicative interaction between the O2 and CO2 functions. Hence, the following equations hold ac(Pa O2, Pa CO2)
fac,max fac,min exp 1 exp
O2ac PaO2 P kac
O2ac PaO2 P kac
K ln

PaCO2 PaCO2n f if PaO2 80 if 40 PaO2 80 if PaO2 40 (2) (1)
K KH 1.2 KH 1.6
KH
PaO2 80 30
d fac 1 fac ac dt ac
where fac is the frequency discharge in the chemoreceptor afferent bers, fac,max and fac,min are the upper and lower O2ac is arterial PO2 at the saturation levels of the sigmoid, P central point of the sigmoid, kac is a parameter with the dimension of pressure related to the slope of the sigmoid at the central point, PaCO2n is PaCO2 basal value (i.e., 40 mmHg), and f and KH are constant parameters tuned to reproduce the CO2 static response. Finally, ac is the time constant of the mechanism. Efferent Sympathetic Pathways The efferent sympathetic pathways in the model comprise bers to the vessels and those to the heart. Compared with the previous study, the former have been distinguished between sympathetic bers to the arteries (fsp) that modify peripheral resistances of the splanchnic, skeletal muscle, and extrasplanchnic vascular beds and sympathetic bers to the veins (fsv) that affect unstressed venous volumes of the same compartments. Cardiac sympathetic bers (fsh) work on HR and contractility. As in the previous paper (59), we assume that efferent sympathetic activities are a monoexponential function of the weighted sum of afferent information from baroreceptors, peripheral chemoreceptors, and lung-stretch receptors. Weighting factors may be positive or negative, depending on whether afferent information exerts an inhibitory or excitatory effect on sympathetic activity. Furthermore, afferent information is compared with an offset term, which is modulated by hypoxia in the CNS and by PCO2 changes in the medulla (see CNS response). Hence
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Only equations concerning the new aspects of the model are presented. They describe chemoreceptor afferent pathways, efferent sympathetic activity, CNS response, the local O2 and CO2 effects on peripheral resistances, the control of ventilation, and tidal volume. All other equations are unchanged compared with the previous study (59), where an accurate description can be found.
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fes, fes,0 fes, expkes Wb,sj fab Wc,sj fac Wp,sj fap sj f sj fes,max j h, p, v
Blood Flow Local Control if fsj fes,max ( 3 ) if fsj fes,max Hypoxia causes vasodilation in the vascular beds with higher metabolic requirements (coronary, cerebral, and skeletal muscle circulation). As in the previous work, the local effect of O2 on these vascular beds has been mimicked by assuming that hydraulic peripheral conductance (i.e., the inverse of peripheral resistance) decreases linearly with venous O2 concentration through a rst-order, low-pass dynamics. According to several authors, cerebral vessel tone is profoundly affected by alterations in PaCO2. The effect of CO2 on the cerebrovascular resistance has been described through a static relationship (taken from Ref. 45) and a rst-order, low-pass lter, which mimics the mechanism dynamic. Finally, we assume that the two local mechanisms (O2 and CO2) interact in an additive manner on cerebral hydraulic conductance Gbp 1/Rbp, where Rbp is brain peripheral hydraulic resistance (for a more detailed description of this parameter, see the hydraulic analog in Ref. 59). Hence, the local metabolic control of cerebral blood ow is governed by the following equations G bp Gbpn 1 xb,O2 xb,CO2 d xb,O2 dt 1 xb,O2 gb,O2 Cvb,O2 Cvb,O2n O2 A b(Pa CO2) B 1 C expD log PaCO2 (8) (9)
where fab, fac, and fap are afferent activities from baroreceptors, peripheral chemoreceptors, and lung-stretch receptors, respectively; Wb,sj, Wc,sj, Wp,sj (j h, p, v, where h, p, and v are used to distinguish sympathethic activity to heart, peripheral resistances, and veins, respectively) are corresponding synaptic weights, and sj (j h, p, v) are the offset terms. Finally, kes, fes,, fes,0, and fes,max are constant parameters (fes,max fes,0 fes,); fes,max is the saturation level above which the sympathetic activity cannot increase. CNS Response To reproduce the CNS response, the model assumes that the offset terms sj (j h, p, v) in Eq.3, depend on PaO2 and PaCO2; both mechanisms include a static characteristic and a rst-order, low-pass dynamic. According to experimental evidence, parameters sj (j h, p, v) depend on PaO2 through a static sigmoidal function; the latter remains near zero until PaO2 is higher than a certain threshold and then increases rapidly to a saturation. The threshold is higher for cardiac sympathetic nerves (5060 mmHg) than for peripheral sympathetic activity (3540 mmHg). We have sj(Pa O2)
1 exp d O2,sj dt
sj kisc,sj
O2,sj PaO2 P
j p, v, h
(4)
B A 1 C expD log PaCO2n 1 CO2 xb,CO2 bPaCO2
( 10 )
d xb,CO2 dt j p, v, h (5)
( 11 )
1 O2,sj sj isc
O2,sj is where sj is the saturation of the hypoxic response, P the value of PO2 at the central point of the sigmoidal function, kisc,sj is a parameter with the dimension of pressure related to the slope of the static function at the central point, and isc is the time constant of the mechanism. Finally, O2,sj represents the change in the offset term caused by the CNS hypoxia. Dependence of offset terms on PaCO2 includes a static linear function and a rst-order, low-pass lter. This allows experimental results to be reproduced quite well (16, 34, 37). Hence d CO2,sj dt 1 CO2,sj gccsj PaCO2 PaCO2n cc j p, v, h
(6)
where gccsj (j h, p, v) is the constant gain factor tuned to reproduce experimental results, PaCO2n is the basal value of PaCO2, cc is the time constant, and CO2,sj represents the change in the offset term caused by central chemoreceptor stimulation. Finally, the values of the offset terms to be used in Eq. 3 are obtained by assuming a linear interaction between O2 and CO2 responses sj sjn O2,sj CO2,sj j p, v, h (7)
where xb,O2 and xb,CO2 are state variables representing the effect of O2 and CO2 on cerebral circulation, Cvb,O2 represents O2 concentration in venous blood leaving the brain, Cvb,O2n indicates its value under normal conditions, and gb,O2 is a constant gain factor. A, B, C, and D are constant parameters taken from Reivich (45), and O2 and CO2 are the time constants of the two mechanisms. Finally, Gbpn is a constant parameter denoting the basal value of peripheral cerebrovascular conductance, which is not under reex control. Several experimental results (6, 15, 28, 44, 53) reveal that variation in arterial PCO2 can affect coronary and muscular vascular resistances, too. According to these authors, coronary and muscular vascular resistances decrease linearly with PaCO2 until a saturation level that indicates maximal resistance reduction is reached. In the model, the effect of CO2 on coronary (Rhp) and muscular peripheral resistance (Rmp) has been described through a sigmoidal static relationship with an upper and lower saturation level. The sensitivity at the central point of the sigmoid is much less for Rmp than for Rhp, which is in agreement with experimental data. The static relationship has been arranged in series with a rst-order, low-pass dynamics to reproduce the temporal pattern of the mechanism. Hence, the local control of coronary and muscular peripheral resistances is governed by the following equations R jp Rjpn d xj,O2 dt 1 xj,CO2 1 xj,O2 j h, m j h, m ( 12 ) ( 13 )
where sjn represents the offset term in basal condition, i.e., during normocapnia and normoxia.
1 xj,O2 gj,O2 Cvj,O2 Cvj,O2n O2

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1 exp j Pa CO2 1 exp d xj,CO2 dt
PaCO2 PaCO2n kj,CO2 kj,CO2
PaCO2 PaCO2n
j h, m
( 14 )
1 xj,CO2 jPaCO2 CO2
j h, m
( 15 )
Finally, DVp, DVc, Vp, and Vc are pure delay and time constants of the two mechanisms, respectively. Because lung-stretch receptors are sensitive to changes in , VT, and respiratidal volume (VT), an equation relating V tory rate (RR) is necessary. Clinical data (17, 23, 46, 47) have been reproduced by using an empirical relationship linking V to VT 10.65 VT 0.15 V ( 19 ) and VT Finally, RR can immediately be computed from V /VT RR V ( 20 )
REFERENCES 1. Abboud FM and Thames MD. Interaction of cardiovascular reexes in circulatory control. In: Handbook of Physiology. The Cardiovascular System. Peripheral Circulation and Organ Blood Flow. Bethesda, MD: Am Physiol Soc, 1983, sect. 2, vol. III, pt. 2, chapt. 19, p. 675753. 2. Angell James JE and Daly MB. Cardiovascular responses in apnoeic asphyxia: role of arterial chemoreceptors and the modication of their effects by a pulmonary vagal ination reex. J Physiol (Lond) 201: 87104, 1969. 3. Bellville JW, Whipp BJ, Kaufman RD, Swanson GD, Aqleh KA, and Wiberg DM. Central and peripheral chemoreex loop gain in normal and carotid body-resected subjects. J Appl Physiol 46: 843853, 1979. 4. Biscoe TJ, Purves MJ, and Sampson SR. The frequency of nerve impulses in single carotid body chemoreceptors afferent bres recorded in vivo with intact circulation. J Physiol (Lond) 208: 121131, 1970. 5. Bristow JD, Brown EB, Cunningham DJC, Goode RC, Howson MG, and Sleight P. The effects of hypercapnia, hypoxia and ventilation on the baroreex regulation of the pulse interval. J Physiol (Lond) 216: 281302, 1971. 6. Case RB, Felix A, Wachter M, Kyriakidis G, and Castellana F. Relative effect of CO2 on canine coronary vascular resistance. Circ Res 42: 410418, 1978. 7. Cunningham DJC, Robbins PA, and Wolff CB. Integration of respiratory responses to changes in alveolar partial pressures of CO2 and O2 and in arterial pH. In: Handbook of Physiology. Respiratory System. Control of Breathing. Bethesda, MD: Am Physiol Soc, 1986, sect. 3, vol. 2, pt. 2, chapt. 15, p. 475528. 8. Dahan A, DeGoede J, Berkenbosch A, and Olievier ICW. The inuence of oxygen on the ventilatory response to carbon dioxide in man. J Physiol (Lond) 428: 485499, 1990. 9. Dahan A, van den Elsen MJ, Berkenbosch A, DeGoede J, Olievier ICW, van Kleef JW, and Bovill JG. Effects of subanesthetic halothane on the ventilatory responses to hypercapnia and acute hypoxia in healthy volunteers. Anesthesiology 80: 727738, 1994. 10. Daly MB. Peripheral Arterial Chemoreceptors and RespiratoryCardiovascular Integration. Oxford: Oxford University Press, 1997. 11. Daly MB, Hazzledine JL, and Ungar A. The reex effect of alterations in lung volume on systemic vascular resistance in the dog. J Physiol (Lond) 188: 331351, 1967. 12. Daly MB and Scott MJ. The effects of stimulation of the carotid body chemoreceptors on heart rate in the dog. J Physiol (Lond) 144: 148166, 1958. 13. Daly MB and Scott MJ. An analysis of the primary cardiovascular reex effects of stimulation of the carotid body chemoreceptors in the dog. J Physiol (Lond) 162: 555573, 1962. 14. Daly MB and Ungar A. Comparison of the reex responses elicited by stimulation of the separatly perfused carotid and aortic body chemoreceptors in the dog. J Physiol (Lond) 182: 379403, 1966. 15. Daugherty RMJ, Scott GB, Dabney JM, and Haddy FJ. Local effects of O2 and CO2 on limb, renal, and coronary vascular resistances. Am J Physiol 213: 11021110, 1967. 16. Downing SE, Mitchell JH, and Wallace AG. Cardiovascular responses to ischemia, hypoxia, and hypercapnia of the central nervous system. Am J Physiol 204: 881887, 1963. www.ajpheart.org
where xj,O2 and xj,CO2 ( j h, m) are state variables representing the effect of O2 and CO2 on coronary and muscular circulation, respectively; Cvj,O2 ( j h, m) represents O2 concentration in venous blood leaving the heart and skeletal muscle; Cvj,O2n ( j h, m) indicates its value under normal conditions; gj,O2 ( j h, m) is a constant gain factor; kj,CO2 ( j h, m) is a parameter with the dimension of pressure related to the slope of the sigmoidal function at the central point; and O2 and CO2 are the time constants of the two mechanisms. The normal peripheral resistance (Rjpn) in Eq. 12 is a constant parameter in the coronary compartment ( j h), because this vascular bed is not under reex control; whereas it is not constant in skeletal muscle compartment ( j m), because it depends on the action of sympathetic nerves (see Ref. 59 for more details). As in the previous paper, O2 venous concentration in each compartment (i.e., Cvb,O2, Cvj,O2 with j h, m) has been computed by imposing a mass balance between O2 extraction and O2 consumption rate and using the equations proposed by Spencer et al. (52) for O2 and CO2 transport in blood. Ventilation and Tidal Volume Control ) is regulated by both peripheral and central Ventilation (V chemoreceptors. In most physiological conditions the two mechanisms interact in a linear way. Hence, the nal value is computed as follow of V p V c V n V V ( 16 )
n is a constant value that represents the basal level where V (i.e., during normocapnia and normoxia), V p and V c of V are the changes induced by stimulation of peripheral and central chemoreceptors, respectively. The contribution of each group of chemoreceptors has been provided by a rstorder linear differential equation with a pure delay. In the model, the input quantity for the peripheral feedback is the afferent activity in the arterial chemosensitive bers, whereas the central mechanism responds to variations of PCO2 in arterial blood. Hence, we have p d V 1 p gV fact DV fac,n V p p dt Vp c d V 1 c gV PaCO t DV PaCO n V c 2 c 2 dt Vc ( 17 )
( 18 )
where fac is the afferent chemoreceptor activity provided by Eq. 2, fac,n is its basal value (i.e., the value computed during normoxia and normocapnia), PaCO2,n is the normal value of PCO2 in arterial blood (i.e., 40 mmHg), gVp and gVc are gain factors (peripheral and central, respectively) tuned to reproduce ventilatory responses to arterial gas perturbations described in the clinical and physiological literature. The gVc has been given two different values during hypercapnia (gVch if PaCO2 PaCO2,n) and during hypocapnia (gVcl if PaCO2 PaCO2,n), reecting the existence of two regions separated by a break-point in the relation ventilation vs. PaCO2 (7).
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CARDIOVASCULAR RESPONSE TO CO2 CHANGES 41. McPherson RW, Koehler RC, and Traystman RJ. Hypoxia, 2-adrenergic, and nitric oxide-dependent interactions on canine cerebral blood ow. Am J Physiol Heart Circ Physiol 266: H476 H482, 1994. 42. Melchior F, Srinivasan RS, Thullier PH, and Cle ` re J. Simulation of cardiovascular response to lower body negative pressure from 0 to 40 mmHg. J Appl Physiol 77: 630640, 1994. 43. Mines AH. Respiratory Physiology. New York: Raven, 1993. 44. Radawski D, Dabney JM, Daugherty RMJ Haddy FJ, and Scott JB. Local effects of CO2 on vascular resistances and weight of the dog forelimb. Am J Physiol 222: 439443, 1972. 45. Reivich M. Arterial PCO2 and cerebral hemodynamcis. Am J Physiol 206: 2535, 1964. 46. Reynolds WJ and Milhorn HTJ. Transient ventilatory response to hypoxia with and without controlled alveolar PCO2. J Appl Physiol 35: 187196, 1973. 47. Reynolds WJ, Milhorn HTJ, and Holloman GHJ. Transient ventilatory response to graded hypercapnia in man. J Appl Physiol 33: 4754, 1972. 48. Richardson DW, Wasserman AJ, and Patterson JL. General and regional circulatory responses to change in blood pH and carbon dioxide tension. J Clin Invest 40: 3143, 1961. 49. Rose Jr, CE Latham LB, Brashers VL, Rose KY, Sandridge MP, Carey RM, Althaus JS, and Miller Jr, ED. Hypoxemia and hypercapnia in conscious dogs: opioid modulation by catecholamines. Am J Physiol Heart Circ Physiol 254: H72H80, 1988. 50. Rothe CF, Maass-Moreno R, and Flanagan AD. Effects of hypercapnia and hypoxia on the cardiovascular system: vascular capacitance and aortic chemoreceptors. Am J Physiol Heart Circ Physiol 259: H932H939, 1990. 51. Rutherford JD and Vatner SF. Integrated carotid chemoreceptor and pulmonary ination reex control of peripheral vasoactivity in conscious dogs. Circ Res 43: 200208, 1978. 52. Spencer JL, Firouztale E, and Mellins RB. Computational expressions for blood oxygen an carbone dioxide concentrations. Ann Biomed Eng 7: 5966, 1979. 53. Stowe DF, Owen TL, Anderson DK, Haddy FJ, and Scott JB. Interaction of O2 and CO2 in sustained exercise hyperemia of canine skeletal muscle. Am J Physiol 229: 2833, 1975. 54. Suutarinen T. Cardiovascular response to changes in arterial carbon dioxide tension. Acta Physiol Scand 67, Suppl 266: 176, 1966. 55. Takahashi E and Doi K. Destabilization of the respiratory control by hypoxic ventilatory depressions: a model analysis. Jpn J Physiol 43: 599612, 1993. 56. Ulatowski JA, Bucci E, Razynska A, Traystman RJ, and Koehler RC. Cerebral blood ow during hypoxic hypoxia with plasma-based hemoglobin at reduced hematocrit. Am J Physiol Heart Circ Physiol 274: H1933H1942, 1998. 57. Ursino M. Interaction between carotid baroregulation and the pulsating heart: a mathematical model. Am J Physiol Heart Circ Physiol 275: H1733H1747, 1998. 58. Ursino M and Lodi CA. Interaction among autoregulation, CO2 reactivity, and intracranial pressure: a mathematical model. Am J Physiol Heart Circ Physiol 274: H1715H1728, 1998. 59. Ursino M and Magosso E. Acute cardiovascular response to isocapnic hypoxia. I. A mathematical model. Am J Physiol Heart Circ Physiol 279: H149H165, 2000. 60. Ursino M and Magosso E. Acute cardiovascular response to isocapnic hypoxia. II. Model validation. Am J Physiol Heart Circ Physiol 279: H166H175, 2000. 61. Wendling MG, Eckstein JW, and Abboud FM. Cardiovascular responses to carbon dioxide before and after -adrenergic blockade. J Appl Physiol 22: 223226, 1967. 62. Winn HR, Rubio R, and Berne RM. Brain adenosine concentration during hypoxia in rats. Am J Physiol Heart Circ Physiol 241: H235H242, 1981.
17. Dripps RD and Comroe JH. The respiratory and circulatory response of normal man to inhalation of 7.6 and 104 percent CO2 with a comparison of the maximal ventilation produced by severe muscular exercise, inhalation of CO2 and maximal voluntary hyperventilation. Am J Physiol 149: 4351, 1947. 18. Duling BR. Changes in microvascular diameter and oxygen tension induced by carbon dioxide. Circ Res 32: 370376, 1973. 19. Edelman NH, Epstein PE, Lahiri S, and Cherniack NS. Ventilatory responses to transient hypoxia and hypercapnia in man. Respir Physiol 17: 302314, 1973. 20. Fitzgerald RS and Parks DC. Effect of hypoxia on carotid chemoreceptor response to carbon dioxide in cats. Respir Physiol 12: 218229, 1971. 21. Grenway CV and Scott GD. Quantitative integration of the cardiovascular system and synthesis of drug actions: another attempt. Can J Physiol Pharmacol 68: 12991307, 1990. 22. Guyton AC, Coleman TG, and Granger HJ. Circulation: overall regulation. Annu Rev Physiol 34: 1346, 1972. 23. Hey EN, Lloyd BB, Cunningham DJC, Jukes MGM, and Bolton DPG. Effects of various respiratory stimuli on the depth and frequency of breathing. Respir Physiol 1: 193205, 1966. 24. Karim F, Hainsworth R, Sofola OA, and Wood LM. Responses of the heart to stimulation of aortic body chemoreceptors in dogs. Circ Res 46: 7783, 1980. 25. Koehler RC, McDonald BW, and Krasney JA. Inuence of CO2 on cardiovascular response to hypoxia in conscious dogs. Am J Physiol Heart Circ Physiol 239: H545H558, 1980. 26. Koehler RC, Traystman RJ, and Douglas Jones M. Inuence of reduced oxyhemoglobin afnity on cerebrovascular response to hypoxic hypoxia. Am J Physiol Heart Circ Physiol 251: H756H763, 1986. 27. Kontos HA, Levasseur JE, Richardson DW, Mauck HP, and Patterson JL. Comparative circulatory responses to systemic hypoxia in man in ananesthetized dog. J Appl Physiol 23: 381386, 1967. 28. Kontos HA, Thames MD, Lombana A, Watlington CO, and Forrest J. Vasodilatory effects of local hypercapnic acidosis in dog skeletal muscle. Am J Physiol 220: 15691572, 1971. 29. Krasney JA and Koehler RC. Inuence of arterial hypoxia on cardiac and coronary dynamics in the conscious sinoaortic-denervated dog. J Appl Physiol 43: 10121018, 1977. 30. Lahiri S and Delaney RG. Relationship between carotid chemoreceptor activity and ventilation in the cat. Respir Physiol 24: 267286, 1975. 31. Lahiri S and Delaney RG. Stimulus interaction in the responses of carotid body chemoreceptor single afferent bers. Respir Physiol 24: 249266, 1975. 32. Lahiri S, Mokashi A, Mulligan E, and Nishino T. Comparison of aortic and carotid chemoreceptor responses to hypercapnia and hypoxia. J Appl Physiol 51: 5561, 1981. 33. Levick JR. An Introduction to Cardiovascular Physiology. Oxford: Butterworth-Heinemann, 1991. 34. Lioy F, Blinkhorn MT, and Garneau C. Regional hemodynamic effects of changes in PaCO2 in the vagotomized, sinoaortic de-afferented rat. J Auton Nerv Syst 12: 301313, 1984. 35. Lioy F, Hanna BD, and Polosa C. CO2-dependent componet of the neurogenic vascular tone in the cat. Pu gers Arch 374: 187191, 1978. 36. Lioy F, Hanna BD, and Polosa C. Cardiovascular control by medulla surface chemoreceptors. J Auton Nerv Syst 3: 17, 1981. 37. Lioy F and Trzebski A. Pressure effect of CO2 in the rat: different thesholds of the central cardiovascular and respiratory responses to CO2. J Auton Nerv Syst 10: 4354, 1984. 38. Marshall JM. Peripheral chemoreceptors and cardiovascular regulation. Physiol Rev 74: 543594, 1994. 39. Matsumoto S, Mokashi A, and Lahiri S. Cervical preganglionic sympathetic nerve activity and chemoreexes in the cat. J Appl Physiol 62: 17131720, 1987. 40. McPherson RW, Eimerl D, and Traystman RJ. Interaction of hypoxia and hypercapnia on cerebral hemodynamics and brain electrical activity in dogs. Am J Physiol Heart Circ Physiol 253: H890H897, 1987.
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A mathematical model of CO2 effect on cardiovascular regulation

0363-6135/01 $5.00 Copyright 2001 the American Physiological Society

CARDIOVASCULAR RESPONSE TO CO2 CHANGES

Gbp Gbpm kj,CO2 j h, m

kisc,sj j h, p, v kac PaCO2n O2,ac P O2,sj P Rjp j h, m Rjpn j h, m RR V p V c V

DVp DVc fab fac

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xb,O2 xb,CO2 xj,O2 j h, m

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sary to complete the model, can be found in a previous study (59).

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Table 1. Basal values of parameters and corresponding references

kac 29.27 mmHg (4)

Efferent Sympathetic Pathway kes 0.0675 s (57)

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CARDIOVASCULAR RESPONSE TO CO2 CHANGES

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fac,max fac,min exp 1 exp

O2ac PaO2 P kac

O2ac PaO2 P kac

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B A 1 C expD log PaCO2n 1 CO2 xb,CO2 bPaCO2

1 xj,O2 gj,O2 Cvj,O2 Cvj,O2n O2

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1 exp j Pa CO2 1 exp d xj,CO2 dt

PaCO2 PaCO2n kj,CO2 kj,CO2

1 xj,CO2 jPaCO2 CO2

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