cardiopulmonary coupling during exercise

5/24/2018 Cardiopulmonary Coupling During Exercise

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J. exp.Biol. (198a), 100, 175-193With 4 figures

stinted inGreat Britain

CARDIOPULMONARY COUPLING DURING EXERCISE BRIAN J. WHIPP

Division ofRespiratory Physiology and Medicine, Harbor-UCLA Schoolof Med icine,Harbor-UCLA MedicalCenter, Torrance, California 90509ANDSUSAN A. WARD

DepartmentofAnesthesiology, UCLA Schoolof Medicine,UCLA, Los Angeles, California 90024

SUMMARYMuscular exercise imposes the most potent sustained stress to cellularenergetics. At work rates below the anaerobic threshold (i.e. no sustainedlactic acidosis), the ventilatory and cardiovascular responses regulatearterial PQQ [H+] and Po% at or close to their resting levels in th e steadystate. However, dynamic forcing and systems-analytic techniques revealtwo phases of the non-steady-state response dynamics. In the first phase,increased gasflowo the lungs results solely from increased pulmonary bloodflow ()),with alveolar gas tensions be ing maintained at their res ting levels bya coupled increase in ventilation(J^):evidence for cardiopulmonary couplingbeing provided by experimentally-altered Qin man and dog. Arterial chemo-reception does not impose humoral feedback control in this phase. Rather,rapid feedforward mechanisms operate, with both intrathoracic (largelycardiac) and exercising-limb mechanoreception proposed as afferent sources.In the second phase, cardiogenic gas flow to the lungs is augmented byaltered mixed venous blood gas contents; ventilation responding exponenti-ally with a time constant (T) which is an inverse function of carotid bodygain. Th e close dynamic coupling of VEwith COa output (T^ 5 TFQO) mthis phase results in arterial PC O i and [H+] being maintained close to theirresting levels. However, the kinetic dissociation between VEand O2uptake,with Ty > TpQ , leads to an appreciable transient fall of arterial POi. Therespiratory compensation for the sustained lactic acidosis at higher workrates is predominantly mediated by the carotid bodies in man: the aorticbodies subserving no discernible role. Control of the respiratory andcirculatory responses to exercise is therefore mediated by both neural andhumoral mechanisms: and an important control link appears to couple theresponses, via feedforward ventilatory control of cardiac origin.

I N T R OD U C T I ONMuscular exercise is a process which depends upon the transformation of the bio-chemical energy of ingested food into the mechanical energy of muscle contraction andwork. Th e substrate free energy, however, is not used directly to fuel these reactions;rather, adenosine triphosphate, with its high free energy of hydrolysis, is the obli-


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176 B. J. W H IP P AND SUSAN A. WA RDgatory intermediary. T o m aintain the fluid milieu of the contracting muscle in a sta tecompatible with sustained exercise performance, an effective interaction of numerousphysiological systems is required.However, during normal volitional daily activity, steady states of cardiopulmonaryfunction are rare. And yet, our current concepts of ventilatory control and arterialblood gas homeostasis are based predominantly upon ensured steady-state conditions.As large and rapid changes in metabolic rate are common, the ventilatory system mustrespond both promptly and precisely to obviate significant variations of arterial bloodgas and acid-base status.We believe that it is not useful to consider ' exercise' as a single specific state withrespect to ventilatory and cardiovascular control. The determinants of the responsesare likely to change both w ith time and intensity. W e prefer to consider three temporaland three intensity domains of the work.Temporal domains

Phase 1 (0i) lasts from the onset of the work to when the gas tensions in mixedvenous blood entering the pulmonary capillaries start to change. Increased rates ofpulmonary gas exchange in 0 i therefore reflect alterations of pulm onary blood flowand its distribution, without altered mixed venous composition (Fig. 1). This cantherefore be considered the ' cardiodynam ic' phase.Phase2 (02) is the dynamic phase following 0 i , in which the new steady state isapproached, associated with changing mixed venous blood composition. The durationof 02 can therefore vary for different functions such as cardiac output ()), mixedvenous O 2 and CO2 concentrations (C5 o>, CFOo,) ventilation (J^,), CO2 output(Jfco,) and O2uptake (%,).Phase3 (03) is the steady state of the response.Intensitydomains

Moderate incorporates the range of VQt in which there is no sustained elevation ofarterial blood lactate concentration, and thus lies below the anaerobic threshold,#an (Wasserman et al. 1973). We shall regard the responses to moderate dynamicexercise to be the 'basic' responses with additional perturbations being imposed bythe higher work intensities.Heavy refers to the range in which there is a sustained elevation of arterial bloodlactate, namely between6 nand the maximumX/Ot(jiPOt)>but with the lactate concen-tration not continuing to increase systematically with time. In this intensity domain,02 is prolonged considerably resulting in the delayed, though eventual, acquisitionof a steady state.Severeis restricted to work rates greater than those requiringjiVQ, at which arterialblood lactate continues to increase throughout the work period.We shall firstly consider the temporal patterns of ventilatory response within thesedomains.


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Cardiopulmonarycoupling duringexercise 177

Pco,(torr)

/to,(torr)

Fig. 1. VentiJatory and pulmonary gas exchange responses to 125 watts cycle ergometerexercise beginning either from rest panel A) or from a baseline of unloaded cycling panel B).Arrow indicates end of phase 1. Poo , and Po , are CO , and O , partial pressures in respired air;VE, KXV ^>I m


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178 B. J. WHIPP AND SUSAN A. WARDend-tidalPOt (PE T , O I ) an anc* a decreased arterial pH (pHo) (Casa-buriet al. 1977; Whipp, 1981). Clearly, although VBand VQQ% were highly correlateddynamically during the exercise, the coupling was not sufficiently tight to obviatesmall fluctuations in arterial PCO t and [H+]o. Our findings raise the interestingpossibility that the increase in P^co, a nd [H + ] a in 02 may provide a source ofhumorally mediated control information. Or, alternatively, one must considerwhether it is just a consequence of the time constant disparities, and only modulatesa more basic control mechanism. Square-wave and incremental work-rate forcings,however, suggest an even tighter coupling between VEand l,Oi(Fig. 2).Several lines of evidence demonstrate the importance of the carotid bodies incontrolling 02Vgin m an: (i) the onset of 02 is delayed by Oa-inhalation (Cunningham,1974); (ii) the kinetics of 02 are slowed by Oa-inhalation (Casaburi et al. 1978);(iii) the kinetics of 02 are appreciably slower than normal in a group of subjects whohad previously undergone bilateral carotid body resection (Wassermanet al. 19756);and (iv) increasing the gain of the carotid chemoreflex by hypoxia (Griffiths et al.1980) or chronic metabolic acidosis (O ren, W hipp & W asserman, 1980) results infaster 02 kinetics.It is not currently known whether, or to what extent, neural mechanisms control02 VE kinetics. Eldridge, however, has suggested a central neural component of 02kinetics, with the 'respiratory centre1 neural dynamics (Eldridge, 1977) or a hypo-thalamic mechanism (Eldridgeet al. 1981) determining ventilatory dynamics, rather


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Cardioptdmonarycoupling duringexercise 179than the peripheral sensing of a stimulus which operates through the respiratoryCentre without significant temporal modulation. Tibes (1977) has also suggested thatneural mechanisms, expressly from the exercising limbs, might account for the slowventilatory response in (j>2, noting the high correlation between J^ and [K+] in thevenous effluent from the exercising muscles (K+ is predominantly a stimulant ofnon-myelinated muscle afferents, as demonstrated by Hnik et al. 1969). While thisproposal would be consistent with observations from the early cross-circulationexperiments performed by Kao (1963) in dogs, more recent results from our labora-tory (Weissmanet al. 1979) and from Breweret al. (1980) reveal that interruption ofsomatic afferent traffic from exercising hindlimbs by thoracic or upper lumbar spinalcord section has no discernible effect on 2 VE kinetics, especially when related tothe gas exchange responses. It appears, therefore, that somatic neural afferents do notsubserve an obligate role for 'normal' 02 VBkinetics, and maynot be involved.Phase3. The arterial isocapnia of the exercise hyperpnea is usually taken to reflectcrucial humoral control in ^3. In addition, besides the various neural mechanismsdescribed earlier, it has been suggested that pulmonary blood flow itself may mediatean element of the control (Brown, W asserman & W hipp , 1976; Stremelet al.1979).The proportional contribution of the carotid bodies to J^. appears to be somewhatgreater than at rest: some 15% in moderate exercise, 10% at rest. Subjects who hadpreviously undergone bilateral carotid body resection, however, had a steady-stateresponse to moderate exercise which was not different from normal with respect toblood gases or ventilation (Lugliani et al. 1971; Wasserman et al. 1975A). Oneexplanation for this is that other (presumably central) mechanisms 'take over' thenormal carotid body component. This clearly needs resolution as it is crucially relatedto the understanding of the integrative function of the respiratory center.Presently, central chemoreceptor mechanisms are believed not to be involved,based upon the failure to discern a recognizable stimulus in the cerebrospinal fluidin the steady state of moderate exercise (Leusen, 1965; Bisgardetal.1978). However,there is a preliminary rep ort (Spode & Schlaefke, 1975) that blocking Region ' S ' onthe ventral surface of the medulla actually abolished the exercise hyperpnea inperipherally-deafferented cats. Th is suggests either that central chemoreceptorafferents (thought to course through Region ' S ' : Schlaefke & Loeschcke, 1967) doplay a significant role in the exercise hyperpnoea or that some other afferent excitatoryinfluence can be inhibited by this regional block. Further consideration must,however, await detailed report of these experiments.Heavy and severe exercise

There is quite convincing evidence that the compensatory hyperventilation whichattends exercise in these intensity domains results from carotid body stimulation inman (Wasserman et al. 19756; W hipp & Wasserman, 1980). T hu s, in response towork-rate increm ents of 4 min duration or more, PO ic o begins to decrease at theanaerobic threshold, daD (Wasserman & Whipp, 1975). For shorter duration (1 minor less) increments, however, P CO i does not decrease at 6&n(Wasserman & Whipp ,1975). There exists, rather, a domain of work rates within which VKchanges fasterthanVQ but in precise proportion to the additional C O 8evolved from the bicarbonate-


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i 8 o B. J. WHIPP AND SUSAN A . WARD

(1/min)

c o ,25

co.

Fig.a. Schematic representation{panel A ) of the responses of ventilation Vt)and the venti-latory equivalent for CO, (J-i/Poo^) to the increased CO, output (I^o,) during the course of about of moderate constant-load exercise, and the actual responses{panel E)of these functionsduring the transition from unloaded cycling to 250 watts in a itsubject(i.e.below the anaerobicthreshold). Points (i), (ii) and (iii) on the Vr-^xttrelationship in panel A represent predictedVi,VQO responses at three arbitrary times during the course of the work; and the slopes of thedashed lines joining these points to the origin define the corresponding Vg/V^ responses(c.f. lower panel). Note that the actual Pi/Ifo, response fits well the predicted hyperbolicdecrease through the transition. See text for further details.

buffering of the lactic acid. This domain has been termed 'isocapnic buffering'(Wassermanet al.1977). It is puzzling that the carotid bodies appear not to respondto the decrease of pH awithin the duration of these short work-rate increments, eventhough they respond to exogenous H+ with a time constant or less than a second(Ponte & Purves, 1974).

Inter-relationships between ventilation and CorrelatedvariablesAs the exercise hyperpnea appears to be so crucially related to some controlfunction which is proportional to CO 2 output (J0 |), both in the steady- and non-steady state phases of moderate exercise (Fig 2), it is important to recognize certaininhe rent relationships between ' CO 2 ' and VE.For example, as alveolar ventilation (VA) is related to J^^ and

' a , C O ,(where 863 is the constant which ensures that all the quantities are referred to anormal body temperature and pressure, i.e.

7 + 37273 760-47 x [barometric pressure - 47]),


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Cardiopulmonary coupling during exercise 181ihenVA will change as a linear function ofVCOf at any constant level of PaiCo,- Theibsolute value of this increase in VA is dictated by the regulated level of Pa ,Co , : elower the jPa>C0|, the greater is the ventilatory requirement for a given change ofPCo,- However, the neural output of the brainstem respiratory centre effects changesin total ventilation {VE). Consequently, the physiological dead space (VD)confers anadditional degree of freedom on the I ^ - ^ o relationship. Thu s

^ = 863.VCOi^ o . C O , ( l -

whereVD/VT represents the ratio of the physiologic dead space to the tidal volume.However, the form of equation (2) does not appear, at first sight, to cohere with thewidely described observation that VE changes as a linear function ofVCOi (Fig. 2A):

V = tn V +c (1)wheretnis the slope of theVE- Ol relationship (dVE/dPCO t) and cis the VEintercept.Rearranging equation (3) in terms of the ventilatory equivalent for CO 2 {YB/'COând substituting for myields:

r? = 17? ^~7? (4)Note that the ventilatory equivalent exceeds theslope (by the variable factor O ibut approaches it asymptotically at high levels of X/COt (Fig. 2). It is important,therefore, that if values of the ventilatory equivalent for C0 2 are to be used forcharacterizing a subject's ventilatory response to exercise they should be reportedtogether w ith the values ofVCOtat which they were obtained. O r, better still, both theslope and intercept parameters of the Ê~^COX relationship should be defined.Equation (2) is, in fact, the equation of a straight line for moderate exercise whenP^CQ is regulated at its resting value (e.g. 40 mm Hg). Two pa tterns of VD/VTbehaviour during moderate exercise would be compatible with a linear VE-X rCOtrelationship and regulation of PaiCo3- Were VD/VT to be constant, independent ofwork rate, VE would be constrained to increase as a linear function of PQQ . Alter-natively, wereVD/VT to decline hyperbolically with respect to IÔi, i.e.

863-v o L . l (5*)L co,J

then, again, the relationship between VEand 1 ^ , would be linear.This second VD/VT pattern of response actually occurs. Thus, VD/VT has beenrepeatedly demonstrated to fall in response to increases of work rate, the largestchanges being evident at low work rates as equation (5) predicts (Jones, McHardy &Naimark, 1966; W hipp & Wasserman, 1969). Indeed, if VD/VT were not to declinein this hyperbolic fashion with respect to J ^ , then nonlinearities would obtain in the^ / o , relationship or Pa>COiwould not be regulated, orboth.

Th is equation is obtained by substitution for Vt from equation (i) into equation (3).


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182 B . J . W H I P P A N D S U S A N A . W A R DExtending the range of work rates beyond the anaerobic threshold introduce^further complexity into the interpretation of the ^E~^cot relationship. This resultfrom the compensatory hyperpnoea, which serves to constrain the fall of pHa during

the metabolic (lactic) acidosis by lowering ^ , , 00 , (Whipp & Wasserman, 1969;Wassermanetal.1973; Sutton, Jones Toews, 1976). As these effects assume greaterprominence with increasing work rates above 0an> the steepening t^-J^o, relation-ship departs progressively from the linear form that it exhibited during moderateexercise.CARDIOVASCULAR RESPONSES

The increase in cardiac output (Q ) during dynamic exercise is a linear function ofthe increase in O 2uptake(POt),with rapid changes occurring at the onset of the work.In upright man, the changes are predominantly mediated by increased heart rate withstroke volume also contributing, though only over the lower third of the range ofexercise POt (Astrand & Rodahl, 1970). Cardiac output at a particular VOtdoes notchange with training but is achieved with a higher stroke volume and, consequently, alower heart rate (Astrand & Rodahl, 1970). And as maximum heart rate is not alteredby short-term training (i.e. that does not induce an effect due to simultaneous aging),then the improvement in cardiac output results from the increased stroke volume.Values for Qfor 30 1/min at maximum work are not uncomm on in trained enduranceathletes. This, coupled with an increased maximum arterio-to-venous (av) Oadifference results in the maximal J ^ (jiPOt)also being increased by training (Astrand& Rodahl, 1970).The highly linear relationship between Qand X?o^ for dynamic exercise in normaladults (exercising at sea level and in a cool environment) is well described by theequation: Q = m .Po t+c, (6)where m is the slope and cis the Q intercept, both having values of approximately5 when Q and Vo are expressed in1/min. (The values of 5 are quite representativewhen the resting values are not included in the regression.) Consequently, the(a-v) O2 difference will increase hyperbolically as XrQi increases, conforming to theapproximation equation:

fl_B)O2=2 2 S , (7)1 ~r VO twhere the (a-v) Otdifference will have the conventional units of ml/100 ml of blood.The increase of cardiac output during exercise results from increased meansystemic pressure which raises the pressure gradient for venous return, local vaso-dilatation in the contracting muscles, and autonomic effects on the heart itself (e.g.Guyton, Jones Coleman, 1973). Th e vasodilatation in the contracting m uscle, whichleads to the increase in Q being distributed preferentially to these muscles (Rowell,Blackman & Bruce, 1964; Bevegard & Shepherd, 1967), results predominantly fromthe effects of locally released metabolites on the pre-capillary resistance vessels(Folkow & Neil, 1971; Guytonet al. 1973). Little or no changes are apparent in thepost-capillary vessels (Kjellmer, 1965), although a reduction in venous compliance


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Cardiopulmonarycoupling duringexercise 183has been demonstrated (Bevegard & Shephard, 1965), which functions to reduce the m e constant for venous return . The resulting increased capillary pressure increasesthe fluid filtration force which, coupled with the increased osmotic gradient into themuscle, results in a fluid flow into the contracting fibres (Astrand & Rodahl, 1970).Th is is seen as a decreased plasma volume and increased hem atocrit during the work.

Although the precise mechanism of the exercise-induced vasodilatation remains atopic for deba te, the most prominent contenders appear to be potassium ions (Skinner& Powell, 1967), with the effect being potentiated by the decreasing local P O i, andhyperosmolality (Mellander et al. 1967). In addition, other factors such as H+(especially at high work rates), temperature and adenosine compounds resulting fromhigh-energy phosphate transfer may exert a dilator influence (Guyton et al. 1973).Neural vasodilatation in the contracting muscle mediated by local reflex effects ofnerves in the vascular wall (Honig, 1979) and also possibly from sympathetic cholin-ergic influences (U vnas, i960) especially at the onset of, or in anticipation of, the work(although the importance of this mechanism in man has not been conclusivelyestablished) may also be involved. However, such influences are thought to be lesscrucial than metabolic vasodilators in controlling the blood flow to the contractingmuscles during dynamic exercise.The diffuse adrenergic sympathetic nervous system discharge induced by exercise,which for example increases splanchnic vascular resistance and thus decreases the

splanchnic flow (Rowellet al. 1964), does not to any significant extent modulate themetabolically induced vasodilatation in the working musculature. Thus, the bloodflow to the intact and sym pathectomized limbs of a conscious, exercising dog wasvirtually identical, as was the (a-v) O2 difference (Donald, 1980). Furthermore,stimulation of the sympathetic nerves to the exercising limbs of anesthetized dogshas been shown to be relatively ineffective in inducing vasoconstriction. This lackof effect has been termed'the sympatholysis of exercise'. In conscious dogs, however,such electrical stimulation has been shown to be capable of reducing blood flow in theexercising limb, but with the proportional effect being less at higher work rates.The net effect of the vasodilatation and capillary recruitm ent in the working musclesis an increase in capillary surface area, though capillary permeability appears to beunaffected. Thus, a greater diffusive flow of O a to the working muscle fibres isensured. Whether this effect is enhanced as a result of endurance training is not clear,however. Th us , while it has been dem onstrated that the capillary - muscle fibre ratiois increased by endurance training (Saltin et al. 1977), as the fibre diameter alsotypically increases it remains to be convincingly established that an improved distancefor diffusion results.The efferent autonomic influences which enhance cardiac output during exercise

have been widely studied and reviewed (Astrand & Rodahl, 1970; Folkow & Neil,1971; Guyton et al. 1973). It is clear that the heart rate increases during exerciseresult from both reduced vagal impulses to the heart and also increased sympatheticdischarge; the latter mechanism also increasing cardiac contractility, as do circulatingcatecholamines. Total denervation of the heart results in only a modest reduction ofmaximal work rate and cardiac output ()), with little evidence of impairment at8ubmaximal work rates in the steady state. However, Qkinetics during the non-steady


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184 B. J. WHIPP AND SUSAN A . WARDstate were appreciably slowed by this procedure (Donald, 1980), as they were alsshown to be when peripheral vascular resistance was not allowed to fall (utilizingconstricting cuff on the descending aorta) during treadmill exercise in the dog(Topham & W arner, 1967). (Unfortunately, in neither of these experiments were theventilatory dynamics reported.) In contrast, following both cardiac denervation and/?-adrenergic blockade to inhibit the effects of adrenal catecholamines, work tolerancewas significantly constrained and the cardiac output increase was limited to some2-3 times the resting value (resulting from the 'Frank-Starling' effect). Beta-adrenergic blockade, alone, resulted in little impairment of maximum exercisefunction. Thus, both the sympathetic nervous system and the effects of circulatingcatecholamines are necessary to sustain cardiovascular function during high-intensityexercise.

The sensory mechanisms responsible for initiating and maintaining the neurally-mediated cardiac response to exercise remain conjectural. Possible candidates includereflexes originating in the exercising limbs activated by mechanical events or altera-tions in the local chemical environment (McCloskey & Mitchell, 1972); reflexesoriginating in the heart and adjacent vasculature activated by the increased venousreturn (Ledsome & Linden, 1964; Vatner & Pagani, 1976; Ledsome, 1977); andinfluences arising in higher centres of the brain, such as the cerebral cortex (Krogh &Lindhard , 1913) or the hypothalamus (Folkow & Neil, 1971).

CARDIOPULMONARY COUPLINGIn order that arterial blood gas and acid-base homeostasis be maintained, venti-lation is required to change as a function of both the actual blood flow through thelungs and its composition.Based largely upon the temporal response characteristics of J^., numerous investi-gators (but most conceitedly Dejours, 1964, 1967) have posited that as the initialrapid responses (Fig. 1) occurred well before any metabolite formed in the exercising

limbs could reach a known site of chemoreception (the peripheral and central chemo-receptors) the response must be neurogenic, originating in the limbs and/or thecerebral cortex. And as Kao (1963) demonstrated with complete spinal section orlateral-column section in his cross-circulation experiments in the dog; McCloskey &Mitchell (1972) with blockade of the small-diameter myelinated and non-myelinatedafferents in the dorsal roots from the exercising limbs in the cat; and Tibes (1977)with cold-block of the afferent fibres from the limbs of the dog, that the ' neurogenic'mechanism could be abolished, further credence was provided for such a mechanism.Furthermore, drugs which stimulate the muscle spindles (Gautier, Lacaisse &Dejours, 1969) could be shown to cause hyperpnoea, and drugs which suppressspindle activity (Flandrois et al. 1967) could reduce ventilation. And as the secondmono-exponential increase of VE to its steady state only began after a time commen-surate with the transit time for exercise-induced metabolites to reach the arterialchemoreceptors and that the time of onset of this second phase was lengthened whenthe arterial chemoreceptors were functionally inactivated by hyperoxia (Cunningham,1974), the mechanistic basis for the neurohumoral control theory of the exercise


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Cardiopulmonarycoupling duringexercise 185hyperpnoea appeared to be firmly established. And while, more recently, EldridgeWt al. (1981) have described a possible hypothalamic source of the transient venti-latory responses to exercise, its functional significance for the exercise hyperpnoeaappears questionable. Thus, electrical stimulation of the hypothalamic motor area inthe cat induced rapid ventilatory and gas exchange responses. These, however,appear quite unlike those of spontaneous volitional exercise, i.e. a profound and rapidhyperventilation ensued, apparently consequent to the stimulation of extrapyramidalpathways to the respiratory muscles; and hence this procedure may not be a usefulanalog of exercise.

Wasserman and his associates (Wasserman et al. 1977; Whipp, 1981), however,noted significant inconsistencies with the traditional neurohumoral theory of theexercise hyperpnoea. These included: (i) that throughout the early phase (which theytermed 'phase 1' as a temporary expedient to minimize any implied control mechan-ism) end-tidalPo andPC O land also the gas exchange ratio Rdid not typically change(F ig . i ) -were VE to change by an obligatory neurogenic mechanism, then hyper-ventilation would be expected withR and / E T , O , increasing and ^ET.CO, decreasing;(ii) that stimulation of the muscle spindle afferents by high-frequency, low-am plitudevibration (a potent spindle stimulus) failed to induce significant hyperpnoea in the cat,in the experiments of Matthews (1972); and that H ornbein, Sorensen Parkes (1969)could detect no change in the dynamic ventilatory response to exercise when the y-efferent system to the legs was blocked in man by infiltration of the lower lumbarperidural space with lidocaine; (iii) when complete spinal section at Li was performedin the dog, no appreciable change in the dynamics of the exercise hyperpnoea could beseen, or at least none out of proportion to any altered metabolic dynamics (Weissmanet al. 1979; Brewer et al. 1980); (iv) that the rapid phase 1 response in X?E was onlydiscernible if the work were instituted from rest (Broman & Wigertz, 1971; Casaburietal.1978; and Fig. 1) - when performed against a background of mild exercise, \VEwas considerably slower and virtually merged into the phase 2 response, although stilldiscernible in certain studies (Swanson, 1978; Whipp et al. 1980; Bennett et al.1981); (v) the i hyperpnoea was markedly attenuated by prior moderate hyper-ventilation (Ward et al.1981); (vi) and that there appears to be little or no differencein the response characteristics between


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186 B. J . W H I P P AND SUSAN A. WAR Dbefore),VE increased consequently, with little or no change inP a i C 0 orP E T i C O Theatherefore termed this response a 'Cardiodynamic Hyperpnoea'. And, as previous^cited (Whipp, 1981), the poet George Meredith proved to be remarkably prescientwhen, in his poem 'Hymn to Colour', he questioned 'shall man into the mystery ofbreath, from his quick-beating pulse a pathway spy?'.Subsequently, W inn, Hildebrant & Hildebrant (1979) and Eldridge & Gill-Kum ar(1980) concluded that a 'cardiodynamic' mechanism for the isoproterenol-inducedhyperpnoea was unlikely from their experiments on cat and rabbit, and asserted thatthe ventilatory response was simply a result of direct stimulation of the peripheralchemoreceptors by the drug. This contention, however, conflicted with the furtherexperiments of Wassermanet al.(1979) in the cat which reaffirmed cardiodynam ism.

The conflict may be resolved, in large part, by the studies of Juratsch et al.(1981)who demonstrated that when the carotid and central chemoreceptors were temporallydissociated from the thorax by interposing long delay loops to both carotid andvertebral arteries (with vessel flows being precisely maintained at control levels bymeans of pum ps), thereby resulting in trans it delays of some 2-4 min, an early'cardiodynamic' response to intravenous isoproterenol clearly preceded the sub-sequent direct effect upon the chem oreceptors; the separate responses being normallydifficult to distinguish owing to the temporal proximity of the heart and the arterialchemoreceptors. Furtherm ore, Joneset al. (1981) induced increased Qby raising thepaced heart rate in patients with permanent cardiac pacemakers for the managementof atrioventricular block. Their results demonstrate that' exclusive' primary changesinQcan result in a consequent hyperpnoea. These investigators judiciously point out,however, that cardiopulmonary coupling during exercise is likely to be much morecomplex.

Moreover, several groups have diverted a portion of the normal venous re turn fromthe venae cavae into the aorta, and utilized a gas exchanger to attem pt to ' arterialize'the returning blood (Galletti, 1961; Rawlingset al.1975; Stremelet al. 1979). Theseexperiments have a strikingly similar result (despite considerable differences inspecific methodology); this being that as the flow through the heart and lungs isreduced, so a hypopnoea develops, even inducing apnoea with sufficient thoracichypoperfusion. These experiments, however, were performed in the resting state inexperimental animals. And so Brown et al. (1976) attempted to determine whethersuch a cardiodynamic mechanism might be operating in the steady-state of exercisein man. When these investigators infused the /^-blocking drug propranolol in thiscondition, ventilation decreased as Q fell. Interestingly, however, this isocapnichypopnoea (i.e. the subjects did not hypoventilate) only persisted until mixed venousCO2 content rose sufficiently to return pulmonary CO2 flux back to normal (i.e.^Qcy tCfr C Oi), as evidenced by CO 2output at the lung returning again to the exerciselevel. Consequently, a cardiodynamic mechanism for a component of the exercisehyperpnoea appears likely.The mechanism responsible for mediating the cardiodynamic component of theexercise hyperpnoea, however, is not likely to involve ' dow nstream ' chemoreceptionvia the peripheral and central chemoreceptors. Whipp (1978, 1981) questioned thisconcept of the mechanism on theoretical grounds, based upon the known transit


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Cardiopulmonarycoupling duringexercise 187delays from the lungs, the likely change in the error signal and the chemoreflex gains.pUrthermore, Wasserman et al. (19756) showed that, in man, the magnitude of thephase 1 component of the exercise hyperpnoea was not systematically different insubjects who had undergone bilateral carotid body resection (but were otherwisenormal) from control subjects. And as neither hypoxia, hyperoxia nor hypercapniaappear to affect the phase 1 magnitude (Cunningham, 1974), an important role forthe known chemoreceptors downstream of the lungs appears remote. Whipp et al.(1981), however, designed an experiment expressly to discern whether the cardio-dynamic phase of the exercise hyperpnoea involved the chemoreceptors. In thetemporally-isolated chemoreceptor preparation in the dog described above (andincluding, on occasion, bilateral cervical vagotomy), these investigators inducedmuscular exercise. They could document no slowing of the phase 1 ventilatoryresponse, despite any chemical signals generated at the lungs (by transient V^/Qimbalance) being delayed to the chemoreceptors by an average of 2 min.Therefore, a fundamentally new approach may be required to understand thecoupling of ventilation to cardiovascular changes during exercise, and it seems thatthe mechanism should not be unrelated to 'CO 2 \ But, although it has been proposedthat ventilation during exercise changes as a function of the CO g flux to the lung( )xCj i C O l , or Qoo,)' * e response characteristics required to regulate arterial PC O ithroughout the non-steady-state phases of exercise (i.e. both (pi and 2) have notbeen formally presented previously. And when these relationships are analysed, thereare interesting implications for the necessary coupling of cardiovascular and venti-latory responses. For example, assuming arterialPCO t equals alveolar PCOl then:

PA_ 863 Ci>COt-C a OQJ ,QQ K^ (8)^ 8 6 3 K S J K S J (9)

And as C* a iCOl/P aCOl is a constant (a) by definition and neglecting the proportionalconstant 863 for simplicity, then (as shown in Fig.3a):tr

wherefiequals Q> C O t / P o C O l . That is, in phase 1 of exercise (in which C 5 C O i is un-altered) alveolar ventilation must change in precise proportion to the actual pulmonarybloodflow.Dividing equation (10) through by C ,co yields:a

Q x C?.co, ^o ,co, cvv.co,And, hence, in phase 2 of exercise (when CfiCO| changes), the relationshiptherefore increases hyperbolically with increasing Cj_C Oi, as shown in Fig.3b,c.This analysis suggests, therefore, that any direct cardiopulmonary coupling during


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188 B. J. WHIPP AND SUSAN A . WARDB.

a a n^ * representingthe arterial and mixed venous points, respectively. The difference between the variablef t(Cyooj/iVoo,) an^ * e constant a (Co0Oj/i>a.oo,) defines the ventilation-to-perfusion ratioVAIQ . Inpanel B, VA/Q is plotted as a function of the mixed venous CO , content (Cj.oo,)-Note that prior to C ^oo, changing (i.e. phase 1),VAl0remains constant despite bothVA andQincreasing. However, whenCj,00,increases (i.e. phase a), the ratio of alveolar ventilation to thepulmonary CO, flux (l^ /O co ^ does not remain constant but rather is required to increasehyperbolically, as shown inpanel C.See text for further details.

exercise will be manifest largely in phase 1, with an additional component operativein phase 2.As argued above, this cardiopulmonary coupling in


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Cardiopulmonarycoupling duringexercise 189

Resp.' cent re '

,=k'Heart '

Lung

C.V.'centre' Resp.'centre'

'Heart 'Pa c0=k

LungFig. 4. Simplified representation of two control sche mes (A, B) capable of m aintainingarterial P c o , and [H+]a relatively constant in response to rapid changes in cardiac output.F represents neural feedforward mechanisms to respiratory (R) and cardiovascular (C) controlcentres; C, other non-neural mechanism s inducing rapid cardiac output changes (e.g.increased venous return); and VAan d 0, alveolar ventilation and cardiac outp ut. S ee text forfurther details.

roots, both the ventilatory and the cardiovascular responses were largely abolished.Similarly, of course, any component mediated via hypothalamic or limbic neurogenesiswould be likely to incorporate parallel drives.In this light, and recognizing that the chemical-control model of the cardiodynamichyperpnoea was untenable in accounting for the dominant proportion of the phase 1component of the exercise hyperpnoea, Huszczuk, Jones & Wasserman (1981)hypothesized that there might, in fact, be a mechanical source of control information.These investigators demonstrated that changes in the right ventricular moving-average pressure (i.e. a functional analogue of right ventricular load) were highlycorrelated with both the magnitude and the temporal characteristics of the ventilatoryresponse to changes in cardiovascular dynamics. And, further, that these effects couldbe dissociated from changes in cardiac outputper se, or in pulmonary artery or left-side cardiac pressures. The afferent mechanism ofthisapparent mechanically mediatedreflex appears not to be vagal (although bilateral cervical vagotomy did seem to alter


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190 B . J. W H I P P AN D S US AN A. W A R Dthe set-point forthe m ediation). Neurophysiological evidenceforthe mediationofinformation from the heart into ventilatory responses has been obtained from experi*ments in which cardiac afferent fibres were electrically stimulated (Uchida, 1976) andalso when the right ventricle was distended (Kostrevaet al.1979), the latter presum-ably operating through stretch receptors in theventricular wall (Kostreva et al.1975 c). Other possible candidates mayinclude reflexes from pulm onary arterydistension (Ledsom e, 1977) or from a ltered regional ventilation-to-perfusion relation-ships (Bartoliet al.1974; Juratsch et al. 1982), or other less detailed mechanisms ofthoracic origin (Kostreva et al. 19756; Levine, 1978) may also be involved.

This concept therefore shifted thefocus of thesiteof therapid feedforwardcomponent of the exercise hyperpnoea from a peripheral source, which islargelyindependent of respiratory gasflowo the lungs, to a central cardiac mechanism whichis (normally) obligatorily coupled to pulmonary CO aflux.However, experiments which utilize extra-corporeal gasexchangers in experi-mental animals to load or unload CO 2 into or out of the venous blood, either at restor during exercise, have resultedinhighly inconsistent findings. Thus , support hasbeen provided forthe ventilatory changes being isocapnic (Yamamoto & Edwards,i960; Wasserman etal . 1975a; Stremel etal. 1978; Phillipson, Duffin & Cooper,1981), reflecting aninfinite gain ofthe ventilatory control system with respecttoarterialPC O jand [H+]; and the ventilatory changes indicating a system gain whichishigher than (Linton, Miller & Cameron, 1976) and also similar to the gain oftheventilatory response to CO g inhalation (Lamb, 1966; Lewis, 1975; Grecoet al.1978;Shorset al. 1980).It is, at present, not possible to reconcile these disparate responsesintoaunified theory but, as feedforward cardiac control appears so importan t, onewonders whether the differences may not involve variations in the involvement of thismechanism.In conclusion, investigations into thecontrol of cardiovascular or respiratoryfunction during exercise have failed to explain adequately theindividual controlcharacteristics of the systems, especially with regard to their non-steady-statebe-haviour. However, the mechanisms which couple the responses of these systems to themetabolic requirements ofthe work have received little attention and, hence ,arelargely obscure, providinga tantalizing challenge tothose interested in the controlof cardiopulmonary function during exercise.

R E F E R E N C E SASTRAND,P.-O. &RODAHL,K . (1970). Textbook of Work Physiology. Ch. 6. New Y ork: M cGraw -Hill.BARTOLI, A., CROSS, B. A., Guz, A., JAIN, S. K., NOBLE, M. I. M. TRENCHARD, D. W. (1974). The

effect ofcarbon dioxideinthe airways and alveoli on ven tilation; a vagal reflex studied inthe dog.J. Pkytiol., Land.340, 91-109.BENNETT, F. M., REISCHL,P., GRODINS, F. S., YAMASHIRO, S. M. FORDYCE, W. E. (1981). Dynamicsof ventilatory responseto exerciseinhumans.J.appl.Pkytiol. 51, 194-203.BEVEOARD, B. S. SHEPHERD, J.T . (1965). C hanges in tone of limb veins du ring s upine exercise.J. appl.Pkytiol. 20 , 1-8.BEVEGARD, B. S. SHEPHERD, J.T . (1967). Regulation of the circulation dur ing exercise in man.Pkytiol. Rev. 47, 178-213.BISGARD, G. E., FORSTER,H. V., BYRNES,B., STANEK, K., KLEI N, J. MANOHAR, M. (1978). Cerebro-spinal fluid acid-base balance during muscular exercise.J.appl.Phytiol. 45,94-101.


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Cardiopulmonarycoupling duringexercise 191A R E WE R , A., CROSS, B. A., D A V E Y , A., Guz, A., JONES, P., K A T O N A , P., M C L E A N , M ., M U R P H Y , K.,

SKMPLE, S.J. G. , SOLOMON, M . STIDWELL, R. (1980). Effect ofelectrically induc ed e xerciseinanesthesized dog8on ventilation andarterial pH .J. Pkytiol., Lond. 298,4 9 P - 5 0 P .BROMAN, S. WIOERTZ, O. (1971). Transient dynamicsof ventilation and heart rate with step changes

in work load from different load levels. Acta phyriol. tcand. 81,5474.BROWN, H. V., WASSERMAN, K. WHIPP, B.J. (1976). Effect of beta-adren ergic blockade durin gexercise on ventilationand gasexchange.J.appl. Pkytiol. 41,8 8 6 - 8 9 2 .CASABURI, R., W H I P P , B. J.( WASSERMAN, K., BEAVER, W. L. K O Y A L , S. N. (1977). Ventilatory andgas exchange dynamics inresponsetosinusoidal work.J. appl. Pkytiol. 43 3 0 0 - 3 1 1 .CASABURI, R., W H I P P , B. J., WASSERMAN, K. STREMEL, R. W. (1978). Ventilatory control charac-teristics of the exercise hyperpnea as discerned from dynamic forcing techniques. Chat 73S,2 8 0 S - 2 8 3 S .CUNNINGHAM, D . J.C.(1974). The control system regulating breathing inman.Q.Rev. Biopkyt. 6,

433-483-DEJOURS, P.(1964). Control ofrespiration inmuscular exercise. InHandbook ofPkytiol: Respiration,vol. 1 (ed. W. O.Fenn andH.Rahn), pp.631-648 . W ashington , D .C .:Am.Physiol.Soc.DEJOURS, P.(1967). Neu rogen ic factors inthecontrol ofventilation during exercise. Circulation Ret.

20-21 (suppl. ) 1, I -146-I -153 .DONALD,D . E.(1980). Roleofautonomic nervesin the cardiovascular responsetoexercisein the dog.In Exercite Bioenergetict and Gat Exchange, (ed. P.Ceretelli, andB. J.Whipp) , pp. 2 6 7 - 2 7 4 .Amsterdam: Elsevier.ELDRIDOE, F. L. (1977). Maintenance of respiration bycentral neural feedback m echa nism s. Fedn

PTOC.36,2400-2404.ELDRIDGE, F.L. GILL-KUMAR, P. (1980). M echanisms of hyperpnea induced by isoproterenol.Retp. Pkytiol.40,349-363.ELDRIDGE, F.L., MILLHORN, D .E. WALDROP, T. G. (1981). Exercise hyperpnea and locomot ion:parallel activation from the hypothalamus. Science,N.Y. a n ,844-846 .FLANDROIS, R., LACOUR, J. R., MAROQUIN, J. I. CHARLOT, J. (1967). Limbs mechanoreceptorsinducing the reflex hyperpnea ofexercise. Retp. Pkytiol. a,335-343-FOLKOW, B. NEIL, E.(1971). Circulation, ch. 22.Lon don : Oxford U niv. Press.GALLETTI, P.M. (1961). Physiologic principles of partial extracorporeal circulation for mechanicalassistancetothe failing heart. Am.J. Cardiol. 7,227233.GAUTIER, H.,LACAISSE, A. DEJOURS, P.(196 9). Ventilatory resp onse tomu scle spindle stimulationby succinycholine inthe cat.Retp. Pkytiol. 7, 383-388 .G R E C O , E. C , Jr., FORDYCE, W. E., GONZALEX, F., Jr., REISCHL, P. G R O D I N S , F. S. (1978). Respira-tory responses tointravenous andintrapulmonary CO]inawake do g.J. appl. Pkytiol. 45 , 109-114 .G R I FFI T H S, T. L. , H E N S O N , L . C , H U N T S M A N , D . , WA SSE R MA N , K. W H I P P , B. J. (1980). T heinfluence ofinspired O partial pressure onventilatory and gasexchange kinetics d uring exercise.

J. Pkytiol, Lond. 306, 34P.GUYTON, A.C ,JONES,C. E. COLEMAN,T . G.(1973). Circulatory Phytiology: Cardiac Output and itsRegulation, ch. 25.Philadelph ia: Sau nders.H N I K , P., HUDLICKA, O., KUCERA, J. PAYNE, R. (1969). Activation of muscle afferents by non-proprioceptive stimuli. Am.J. Pkytiol. 317, 1451-1457.HONIO, C.R. (1979). Contribu tions of nerves and metabolites to exercise va sodilation: A unifyinghypothesis . Am.J. Pkytiol. 336,7 0 5 - 7 1 9 .HoRNBElN,T .F.,SORENBEN, S.C. PARKS, C.R.(1969). Roleofmuscle spindlesin lower extremitiesin breathing during bicycle exercise.J. appl. Pkytiol. Vj 4 7 6 - 4 7 9 .HUSZCZUK, A., JONES, P. W. WASSBRMAN, K.(198 1). Pressure inform ation from the right ventricleasareflex coup ler ofventilation and cardiac output. Fedn Proc. 40, 568.JENSEN, J. I.,VEJBY-CHRISTBNSEN, H. PBTERSEN, E.S. (1972). Ventilatory response to work initiatedat various times during the respiratory cycle.J.appl. Phytiol. 33,7 4 4 - 7 5 0 .JONES,N . L.,MCHARDY, C. J. R. NAIMARK, A. (1966). Physiological dead spaceandalveolar-arterialgas pressure differences during exercise. Clin. Sci. 31, 19-29 .JONES,P. W., FRENCH,W., WEISSMAN, M. L.& WASSERMAN, K.(1981). Ventilatory responses to cardiac

output changes inpatients wit h pacemakers.J. appl. Phytiol. 51,11031107.JURATSCH, C. E., HUSZCZUK, A., GIANOTTA, S. W H I P P , B. J. (1981). Evidence for a 'cardiodynamic'component oftheisoproterenol induced hyperpnea inthe dog.Fedn Proc. 40, 567.JURATSCH, C. E., W H I P P , G. J., H U N T S M A N , D. J., L A K S , M. M. WASSERMAN, K. (1982). Ventilatorycontrol during experimental maldistribution ofVA/Qinthedog.J. appl. Phytiol. 5a,2 4 5 - 2 5 3 .KAO, F. F.(1963). An experimental studyofthe pathways involved inexercise hyperpnea em ployingcross-circulation techniques. InThe Regulation ofHuman Retpiration. (ed.D . J. C.CunninghamandB. B.L loyd) , pp.461 -50 2. Oxford: Blackwell .

7-2


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192 B. J. WHIPP ANDSUSAN A.WARDKJELLMER, I.(1965). S tudiesonexercise hyperaem ia. Acta phytiol.stand.64, Suppl., 244.KOSTREVA,D. R., HOPP,F. A.,ZUPERKU,E.J. &KAMPINE,J. P.(1979).Apnea, tachycardia and hypeiltension elicitedbycardiac vagal afferents.J.appl. Pkytiol.47, 312-318.KOSTREVA, D . R., ZUPERKU, E. J., HESS, G. L., COON, R. L. KAMPINE, J. P. (19756). Pulmonaryafferent activity recorded from sympathetic nerves.J.appl.PJiysiol.39, 37-40.KOSTREVA,D. R., ZUPERKU,E. J.,PURTOCK, R. V., COON, R. L. KAMPINE, j .P. (1975a). Sympatheticafferent nerve activityofright heart origin.Am.Physiol.229, 91 1~ 9 I5 -KROGH, A. LrNDHARD,J.(1913). The regulation of respiration and circulation during theinitialstagesofmuscular work.J.Physiol.,Lond.47, 112-136.LAMB,T.W. (1966). Ventilatory responsestointravenousandinspired carbon dioxideinanesthetizedcats.Resp. Physiol.2,99-104.LEDSOME,J. R. (1977).Thereflex roleofpulmonary arterial barorecep tors.Am. Rev.resp. Dis. 115,245-250.LEDSOME,J. R.,LINDEN,R. J.&(1964). A reflex increaseinheart rate from distension of the pulm onaryvein-atrial junction s.J.Physiol.,Lond.170, 456-4 73.LEUSEN,I.(1965). Aspectsofthe acid-base balance between bloodandcerebrospinal fluid.In Cerebro-spinalFluid and theR egulationofVentilation, (ed.C.Brooks,F. F.Kao and B. B. Lloyd), pp. 55-89.Oxford: Blackwell.LEVINE, S. (1978). Ventilatory response to muscular exercise. InRegulationofVentilationand GasExchange, (ed.D. G.Daviesand C.D. Barnes),pp.31-68. New York: A cademic Press.LEWIS,S. M.(1975). Awake baboon 's ventilatory responsetovenous and inhaled CO tloading.J. appl.Physiol.39, 417-42*-LINTON, R. A. F. , MILLER, R. CAMERON, I.R. (1976). Ventilatory responsetoCO, inhalation andintravenous infusion ofhypercapnic blood.Resp. Physiol.36, 383-394.LUOLIANI, R., WHIPP , B. J., SEARD, C. WASSERMAN, K. (1971). Effects of bilateral carotid bodyresection on ventilatory controlatrest and d uring exercise in man.NewEngl.J.Med.285, 1105-1111.MATTHEWS,P.B.C.(1972).Muscle Receptors and Their Central Action,pp. 375-377. London: Arnold.MCCLOSKEY, D.I. MITCHELL, J. H. (1972). Reflex cardiovascular and respiratory responses origi-

natinginexercising m uscle.J.Physiol.,Lond.224, 173-186.MELLANDER, S., JOHANSSON, B., GRAY, S., JONSSON, O., LUNDVALL, J. LJUNG, B. (1967). The effectsof hyperosmolarity on intact and isolated vascular sm ooth m uscle. Possible role in exercise hyp eraemia.Angiologica4,310-322.OREN, A., WHIPP, G. J. WASSERMAN, K.(1980). Theeffect ofacidbase status onthekinetics ofventilation during moderate exerciseinman.Am. Rev.Respir. Dis.i a i(42), 386.PETERSEN, E. S.,WHIP P , B.J., DRYSDALE, D. B.&CUNNINGHAM, D.J.C. (1978). The relation betweenarterial blood gasoscillations inthe carotid regionand thephase ofthe respiratory cycle duringexercise inman: Testing amodel. InRegulationof Respiration During Sleep and Anesthesia (ed.R. Fitzgerald,H.Gautierand S.Lahiri),pp.335-342. NeW Y ork: Plenum Press.PHILLIPSON,E. A.,DUFFIN,J.&COOPER,J.D . (1981). Critical dependence of respiratory rhyth micity onmetabolic CO, load.J.appl. Physiol.50, 45-54 .PONTE,J.&PURVES, M.J. (1974). Frequency responseof carotid body chemoreceptors inthe cattochanges of P^oo ,, ^a.o,,andpH a .J.appl. Physiol.37, 635-647.PONTE,J.&PURVES, M.J.(1978). Carbon dioxide and venous return and their interactionaastimulitoventilationin thecat.J.Physiol.,Lond.274, 455-47 5.RAWLINGS, C. A., BISGARD, G. E., DUFKEK, J. H., Buss, D . D., W I L L , J. A., BIRNBAUM, M. L.(CHOPRA,P. S. KAHN, D. R. (1975). Prolonged perfusion witha membrane oxygenator inawakeponies..7. Thorac.C ardiovasc. Sur., 69 , 539-551.ROWELL, L.B. , BLACKMON,J. R. BRUCE, R.A. (1964). Ind ocyanine green clearanceandestimatedhepatic blood flow during mildtomaximal exerciseinupright man.J.clin. Invest. 43, 1677.SALTIN, B.,HENRIKSEN,J.,NYOAARD,E. &ANDERSON,P. (1977). Fiber types and metabolic potentialsof skeletal musclesinsedentary manandendurance run ners.Ann.N.Y.Acad.Set.301, 329.SKINNER,N. S.&POWELL,W.J.(1966). Actionofoxygen and potassiumonvascular resistanceofdog

skeletal muscle.Am.J.Physiol.212, 533-540.SCHLABFKE,M. E.&LOESCHCKE,H. H. (1967). Lokalisation einesan derRegulation von A tmung undKreislauf beteiligten Gebeites ander ventralen oberglache derMedulla oblongata durch Kalts-blockade.Pflugers Archiv.297, 201-220.SHORS, E.C , HUSZCZUK, A., WASSERMAN, K.& WHIPP , B.J.(1980). Ventilatory responsestovenousCO , unloading during steady-state exercisein thedog. Fedn Proc.39 (3), 583.SPODE,R. SCHLAEFKE, M. E.(1975). Influence ofmuscular exerciseon respiration after centralandperipheral denervation. Pflugers Archiv. Suppl., 359, R49.STRBMEL, R. W., HUNTSMAN, D. J., CASABURI, R., W H I P P , B. J. WASSERMAN, K. (1978). Control ofventilation during intravenous CO, loadingin theawake dog.J.appl. Physiol.44, 311-316.


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CardiopuUmonarycoupling duringexercise 193|TREMEL, R. W., W H I P P , B. J., CASABURI,R , HUNTSMAN,D. J. WASSERMAN, K. (1979). Hypopneaconsequent todiminished blood flowinthedog.J.appl. Phytiol.46,1171-1177.SUTTON,J.R.,JONES,N. L.&TOEWS,C.J. (1976). Growth hormone secretioninacid-base alterationsat restandduring exercise. Clin.Sci. Mol. Med.50,240-247.SWANSON,G. D. (1978). Input stimulus designformodel discriminationinhuman respiratory control.InModellingof aBiological Control System: TheRegulationofBreathing, (ed.E. R.Carson,D.J. C.Cunningham, R. Herczynski, D.J.Murray-Smith and E. S.Petersen), p. 165.Oxford: Inst.Measurement andControl.TIBBS,U.(1977). Reflex inputstothe cardiovascularandrespiratory centers from dynamically workingcanine muscles. Circ. Res.4 1 ,332341.TOPHAM, W.S.&WARNER,H. R.(1967).Thecontrolof cardiac output during exercise. In PhysicalBasesof Circulatory Transport, (ed.E. B. Reeve andA. C.Guyton), pp.77-90 . Philadelphia:Saunders.UCHIDA, Y. (1976). Tachypnea after stimulation ofafferent cardiac sympa thetic nerve fibres. Am.J.

Phytiol. 330, 1003-1007.UVNAS,B. (i960). Sympathetic vasodilator systemandblood flow.Physiol. Rev. 40, suppl.4.VATNER, S. F. PAGANI, M. (1976). Cardiovascular adjustments to exercise: hemodynamicsandmechanisms. Progr.C ardiovasc. Dis., 19, 91-108.WARD, S. A., KOYAL, S., WASSERMAN, K. WHIPP, B.J. (1981). Influence of body CO,storesonventilatory dynamicsinexercise.F edn Proc.40, 567.WASSERMAN, K., MITCHELL,R. A., BERGER,A. J., CASABURI,R. DAVIS, J. A. (1979). Mechanism ofthe isoproterenol hyperpnea inthecat. Resp. Physiol.38, 359-376.WASHERMAN, K.&WHIPP, B.J. (1975). Exercise physiology inhealth anddisease.Am. Rev.Respir.Dis. 11a, 219249.WASSERMAN,K.& WHIPP, B.J.(1976).Thecarotid bodiesandrespiratory controlinman.InMorpho-logy andMechanismsofChem oreceptors, (ed. A. S.Paintal),pp.156-175. Delhi: V .P.C.I.WASSERMAN, K., W H I P P ,B. J., CASABURI,R., BEAVER,W. L. BROWN,H. V. (1977). CO, flow to thelungs andventilatory control. InMuscular Exerciseand theLung, (ed.J.A. Dempsey andC.E.Reed),pp.103-135. Madison:U.Wisconsin Press.WASSERMAN,K., W H I P P ,B. J., CASABURI,R., HUNTSMAN,D. J., CASTAGNA,J. LUGLIANI,R. (1975a).Regulationofarterial Po o, during intravenous C O , loading.J.appl. Physiol.38, 651-656.WASSERMAN,K.,WHIPP, B.J.&CASTAGNA,J.(1974). Cardiodynamic h yperpn ea: H yperpnea secondaryto cardiac output increase.J.appl. Physiol.36, 457-464.WASSERMAN, K., WHIPP, B.J., KOYAL, S. N. BEAVER, W. L. (1973). Anaerobic threshold andrespiratory gasexchange during exercise.J.appl. Physiol.35, 236-243 .WASSERMAN,K., WHIPP , B.J.,KOYAL,S. N.&CLEARY,M. G.(19756).Effect of carotid body resectionon ventilatoryandacid-base control during exercise.J. appl. Physiol.39, 354-358.WEISSMAN, M. L., WASSERMAN, K., HUNTSMAN, D. J. W H I P P , B. J. (1979). Ventilation and gasexchange during phasic hindlimb exerciseinthedog.J.appl. Physiol.46,878-884.WHIPP, B.J.(1978). Ten etsoftheexercise hyperpnea and their degreeofco rroboration. Chest, 73S,274-277-WHIPP, B.J. (1981). Thecontrol of exercise hyperpnea. In TheReg ulationofBreathing, (ed. T.Hornbein),pp.1069-1139. New York: Dekker.WHIPP, B.J., HUSZCZUK, A., GIANOTTA, S. JURATSCH, C. E.(1981). Chemoreceptor control and thecardiodynamic exercise hyperpnea indog.Fedn Proc.40, 567.WHIPP, B.J., SYLVESTER, J. T., SEARD,C.&WASSERMAN, K. (1971). Intrabreath respiratory responsesfollowing theonset of cycle ergometer exercise. InLung Functionand Work Capacity,(ed. J. D.Brooke), pp. 45-64. Salford, England:U.ofSalford.WHIPP, B.J.&WASSERMAN,K.(1969). Alveolar-arterial gas tension differences dur ing graded exercise.J. appl. Physiol.vj,361-365.WHIPP, B.J. WASSERMAN, K. (1980). Carotid bodies andventilatory control dynam ics in man.

Fedn Proc.39, 2638-2673.W H I P P , B. J., WASSERMAN,K., DAVIS, J. A., LAMARRA,N . WARD, S. A. (1980). Determinants of O ,and CO, kinetics during exerciseinman.InExercise Bioenergeticta ndGas Exchange,(ed. P. Ceretelliand B.J.Whipp),pp.175-185. Am sterdam : Elsevier.WINN, R., HILDEBRANT,J. R. HILDEBRANT, J. (1979). Cardiorespiratory responses followingiso-proterenol injection inrabbits.J. appl. Physiol.47, 352-359.YAMAMOTO,W. S.&EDWARDS, M. W.,Jr.(i960 ). H omeostasisofcarbon dioxide during intravenousinfusion ofcarbon dioxide.J. appl. Physiol.15, 807-818.

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