Evidence that a central governor regulates exercise performance during acute hypoxia and hyperoxia
1 Research Unit for Exercise Science and Sports Medicine, Department of Human Biology, University of Cape Town, Sports Science Institute of South Africa, PO Box 115, Newlands 7725, South Africa,
2 Unit for Sports and Exercise Medicine, Institute of Clinical Medicine, University of Helsinki, FIN-00250 Helsinki, Finland and
3 KIHU-Research Institute of Olympic Sports, FIN-40760 Jyväskylä, Finland
*Author for correspondence (e-mail: tdnoakes{at}sports.uct.ac.za)
Accepted July 10, 2001
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Summary |
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Key words: central governor, altitude, cardiac output, hypoxia, hyperoxia, maximal rate of oxygen uptake, muscle recruitment.
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Introduction |
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An alternative theory postulates that a central governor, which regulates the mass of skeletal muscle that is recruited during exercise, acts to protect the heart from developing myocardial ischaemia during maximal exercise (Noakes, 1997; Noakes, 1998; Noakes, 2000; Noakes, 2001). Thus, a logical starting point in the search for a central governor are those studies of cardiorespiratory function during acute hypoxia, since the possibility that myocardial ischaemia will develop is increased during maximal exercise in hypoxia. Studies of cardiorespiratory function during chronic hypoxia are potentially complicated by additional adaptations or maladaptations that might occur in response to sustained hypoxic stress.
Numerous studies have shown that O2max can be modified acutely by altering one or more of the variables considered to limit this measurement. These acute changes occur before structural adaptations, normally requiring several weeks to develop, can occur. Examples of acute modifications in
O2max are its increase in response to acute increases in the partial pressure of inspired oxygen (PIO2) and, conversely, its impairment with decreasing PIO2. Altering arterial oxygen content (CaO2), either by ascending to altitude or by descending in a deep mine to below sea level, or modifying PIO2, either in a hypobaric chamber or by breathing gas mixtures with varying oxygen fractions (FIO2), have all been reported to affect
O2max in a predictable and reproducible manner (Fagraeus et al., 1973; Welch et al., 1974; Wyndham et al., 1970). Also,
O2max increases with acute red blood cell transfusion (Gledhill, 1982; Gledhill, 1985; Spriet et al., 1986; Gledhill et al., 1999) and decreases with sympathetic blockade (Hughson and MacFarlane, 1981; Tesch, 1985; Hughson and Kowalchuk, 1991). Over a longer (chronic) period,
O2max increases with endurance training but decreases with detraining (Saltin et al., 1968a) or with prolonged exposure to high altitude (Cymerman et al., 1989; di Prampero and Ferretti, 1990; Ferretti et al., 1990; Green et al., 2000). Structural as well as functional changes in cardiorespiratory and neuromuscular function are more likely to explain these chronic changes.
The purpose of the present review is to present the evidence for the possible existence of a central governor and to discuss the possible mechanisms by which this governor might limit O2max and, hence, maximal exercise performance, certainly during hypoxia and also, perhaps, during maximal exercise at sea level.
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Origin of the central governor hypothesis |
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Studies of exercise under conditions of modified oxygen partial pressure (PIO2) |
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There is a lesser consensus of the responses of O2 to acute hyperoxia. Some studies indicate a significant increase in
O2max during hyperoxia compared with normoxia (Welch et al., 1974; Ekblom et al., 1975; Welch, 1982; Peltonen et al., 2001), whereas others failed to measure any such increase (Hughes et al., 1968; Adams and Welch, 1980). Similarly, some studies reported a similar submaximal
O2 during hyperoxia and during normoxia (Asmussen and Nielsen, 1955; Hughes et al., 1968), whereas others (Welch et al., 1974; Ekblom et al., 1975; Peltonen et al., 2001) found that the submaximal
O2 was significantly higher during hyperoxia than during normoxia.
Compared with normoxia, is either the same (Asmussen and Nielsen, 1955; Davies and Sargeant, 1974; Peltonen et al., 2001) or reduced (Nakazono and Miyamoto, 1987) during submaximal exercise in hyperoxia. Skeletal muscle blood flow is reduced during submaximal (Welch et al., 1977) but unaltered during maximal (Knight et al., 1993) exercise in hyperoxia.
Skeletal muscle is not the only organ to which the blood flow is altered by changes in CaO2: blood flow to the heart (Hilton and Eichholtz, 1925; Baron et al., 1990; Kaijser et al., 1990; Grubbstrom et al., 1991) and brain (Jones et al., 1981) also shows considerable adaptation in response to changes in CaO2, increasing during hypoxia and falling during hyperoxia.
There is a general consensus that O2 transport to muscle is the principal determinant limiting O2max (Secher et al., 1977; di Prampero, 1985; Rowell, 1986; di Prampero and Ferretti, 1990; Rowell, 1993). Indeed, it is even more likely that O2 transport is the factor limiting the
O2max of endurance-trained athletes than of normally active or sedentary subjects (Wagner, 2000a). However, as PIO2 decreases, the role of the lungs in limiting
O2max increases, whereas the importance of the cardiovascular system diminishes (Ferretti and di Prampero, 1995).
Maximal cardiac function is reduced during chronic hypobaric hypoxia, with a reduction in both maximal heart rate (fHmax) and maximal stroke volume (VSmax) (Vogel et al., 1974; Reeves et al., 1987). The classic explanation for the reduced max during chronic hypoxia includes (i) increased blood viscosity from erythrocytosis causing an increased haematocrit; (ii) reduced cardiac filling pressures from reduced plasma volume; (iii) autonomic changes (either increased parasympathetic or reduced sympathetic activity); (iv) hypoxic myocardial dysfunction and (v) the possibility that hypoxia directly impairs skeletal muscle function, reducing exercise capacity so that
max is reduced in proportion to the reduced work output (Wagner, 2000b).
However, cardiac catheterization studies performed during Operation Everest II (Groves et al., 1987; Reeves et al., 1987) indicated that, although VSmax decreased at altitude, the decrement was proportional to the decrease in atrial filling pressure, indicating that myocardial contractility was preserved. Reeves and colleagues (Reeves et al., 1987) concluded that a reduced maximum ventricular filling resulting from tachycardia or a reduction in plasma and blood volume or both was one possible cause of the reduced VS. However, the point is that the proportional reduction in stroke volume and atrial filling pressure indicates that the heart was not ischaemic and that any increase in filling pressure should have produced an increase in the stroke volume and cardiac output.
Suarez et al. (Suarez et al., 1987) have concluded that: "Left ventricular systolic function is not a limiting factor in compromising the exercise capacity of normal humans on ascent to high altitude, even to the peak of Mount Everest". Similarly, Reeves et al. (Reeves et al., 1987) have concluded that "cardiac rate, cardiac output, and myocardial contractile function were preserved at extreme altitude... reduced heart rates and cardiac outputs at maximum effort were the result rather than the cause of the reduced maximal O2 uptake".
However, it is important to stress that any reduction in max during either acute or chronic hypoxia is paradoxical according to the classical model, which holds that the heart is simply the slave to the exercising muscles, with the unrequiting task of maximizing O2 delivery to the exercising muscle under all conditions. Hence, for the classical model to be correct, cardiac output must always be maximal at maximal exercise regardless of PIO2, FIO2 or CaO2. Hence, any intervention such as anaemia or hypoxia that reduces CaO2, thereby threatening oxygen delivery to the exercising muscles, must be countered by acute changes, the principal aim of which must be to maintain oxygen delivery to the exercising muscles. Clearly, the exact opposite holds during chronic hypobaric hypoxia. It is also of interest that the skeletal muscle blood flow is unaltered at maximal exercise during acute anaemia, even though cardiac output is submaximal (Koskolou et al., 1997).
Furthermore, the changes in left ventricular filling that are thought to cause the reduced VSmax and fHmax during chronic hypoxia cannot explain why both fHmax and max are reduced during acute hypoxia since the duration of the hypoxia is too short to alter atrial filling pressures consequent to a theoretical increase in ventilatory and urinary fluid losses.
As a result, the prevailing hypothesis is that max should be the same during acute and chronic hypoxia so that any reduction in
O2max during acute hypoxia is due to the narrowing of the arterio-venous oxygen difference [(a-v)O2] (Stenberg et al., 1966). Fig.1 explains the basis for this belief whilst introducing another interpretation that has been overlooked.
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Rather, according to this model, the reduced PaO2 during hypoxia will reduce potential oxygen delivery to both the skeletal muscles and the heart. Furthermore, if the heart is merely the slave to the skeletal muscles, then max should be the same during maximal exercise in both hypoxia and normoxia since the hearts sole function is to maximize oxygen delivery to the hypoxic skeletal muscles. But if myocardial hypoxia must be prevented, then
max will fall in proportion to the reduction in PaO2.
A large body of evidence shows that the determinants of max (fHmax and VSmax) are both altered during maximal exercise in hypoxia. Thus, several studies found that acute hypoxia decreases fHmax in both athletic and normally active men and women (Drinkwater et al., 1979; Andersen et al., 1985; Fulco et al., 1988; Lundby et al., 2001; Lundby and Olsen, 2001; Peltonen et al., 2001). Whilst these studies might indicate that the reduced fHmax is probably associated with a reduced
max during acute hypoxia, only two studies have measured a reduced
max during acute hypoxia.
Ekblom and colleagues (Ekblom et al., 1975) reported a decreased max during carbon-monoxide-induced hypoxia (CaO2 was on average 5.1% lower than during normoxia; P<0.05). The effect was due mainly to a decreased VS. More recently, Peltonen et al. (Peltonen et al., 2001) demonstrated a reduced
max during acute hypoxia under physiological conditions (arterial desaturation caused by decreasing FIO2, not by carbon monoxide inhalation) in endurance athletes (Table1).
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Maximum heart rate is reduced, in a dose-dependant manner, in response to increasingly acute hypoxia, whereas maximal plasma norepinephrine and lactate concentrations are unchanged during acute hypoxia. Moreover, Lundby and Olsen (Lundby and Olsen, 2001) and Lundby et al. (Lundby et al., 2001) found that acutely changing the FIO2 by breathing oxygen during experimentally induced acute hypoxia increased fHmax to sea-level values. A similar result has been reported during chronic hypoxia (Kayser et al., 1994; Savard et al., 1995), in which oxygen inhalation increased peak heart rate at exhaustion, although fHmax was still lower than during normoxia. To explain their findings, Lundby and Olsen (Lundby and Olsen, 2001) and Lundby et al. (Lundby et al., 2001) reported that blockade with domperidone demonstrated that hypoxic exercise in humans activates dopamine D2-receptors, which cause a reduction in circulating levels of norepinephrine. However, this mechanism does not play a major role in the hypoxia-induced reduction of fHmax. The authors suggest that postganglionergic desensitization and not downregulation of cardiac adrenoreceptors is responsible for the early decrease in fHmax during hypoxia.
The reduction in fHmax and max during acute hypoxia favours the previous theories (Hill et al., 1924a; Hill et al., 1924b; Ferretti and di Prampero, 1995; Wagner, 2000a) that, without parallel upward adjustments in both pulmonary and muscle O2 diffusive transport conductance, a very high cardiac output would cause substantial arterial desaturation and also impair muscle O2 extraction. Although the reduced
max during acute hypoxia would be physiologically beneficial, the response remains paradoxical according to the classical model, which holds that the hearts function is to maximize oxygen delivery to muscle rather than to protect PaO2. Hence, the question that demands an answer is: What are the mechanisms that constrain the normal increases in
, VS and fH during severe exercise in acute hypoxia? As argued previously, the classical model proposed two separate mechanisms for fatigue during maximal exercise.
First was the development of myocardial hypoxia causing a progressive cardiac failure. Hence: "The enormous output of the heart of an able-bodied man, maintained for considerable periods, requires a large contemporary supply of oxygen to meet the demands for energy. When the oxygen supply becomes inadequate it is probable that the heart rapidly diminishes its output, so avoiding exhaustion" (Hill et al., 1924a)(p. 443). The function of Hills postulated governor was to reduce the work of the heart when myocardial hypoxia developed, thereby sparing the heart from damage. This concept that myocardial failure antedated the development of fatigue was included in Bainbridges textbook, edited by the North American exercise physiologists David Dill and Arlie Bock: "The blood supply to the heart, in many men, may be the weak link in the chain of circulatory adjustments during muscular exercise, and as the intensity of muscular exertion increases, a point is probably reached in most individuals at which the supply of oxygen to the heart falls short of its demands, and the continued performance of work becomes difficult or impossible" (Bainbridge, 1931)(p. 15). As a result: "The heart, as a rule, reaches the limit of its powers earlier than the skeletal muscles, and determines a mans capabilities for exertion" (Bainbridge, 1931).
Second, as a result, blood flow to the exercising muscles was reduced, inducing anaerobiosis with the production of lactic acid, the rising intramuscular concentrations of which ultimately caused the cessation of exercise (Hill, 1926).
Clearly, this model cannot explain the fatigue of chronic hypobaric hypoxia, including the profound muscle weakness at altitude described by Pugh (Pugh, 1958), or the inability of Peter Habeler and Reinhold Messner to walk upright to the summit of Mount Everest during their oxygen-less ascent, since (i) myocardial ischaemia does not occur during maximal exercise at extreme altitude (Reeves et al., 1987; Suarez et al., 1987) and (ii) maximum blood lactate concentrations fall in proportion to the elevation above sea level (Christensen and Forbes, 1937; West, 1986; Green et al., 1989), the so-called lactate paradox. As a result "above an altitude of 7500m, no blood lactate is predicted even for maximal exercise. If this extrapolation held good, a well-acclimatized climber who reached the summit of Mount Everest without supplementary oxygen would have no blood lactate. This is a paradox indeed, because such a climber is apparently more hypoxic during maximal exercise than in any other known situation" (West, 1986).
However the lactate paradox is only paradoxical according to the classical model, which predicts that the extreme fatigue at altitude must result from abnormally elevated blood lactate concentrations despite the very low O2 and work rates when climbing at extreme altitude.
Clearly some other mechanism(s) must be operative, at least during chronic hypoxia.
Cardiovascular limitations
Although the natural temptation, according to the classical model, is to propose that myocardial hypoxaemia explains the reduced fHmax, VSmax and max during hypoxia, the study of Blomqvist and Stenberg (Blomqvist and Stenberg, 1965) failed to reveal any electrocardiographic evidence of myocardial ischaemia during maximal exercise in acute hypoxia, as also shown during exercise in chronic hypoxia. That myocardial ischaemia does not develop even during severe exercise in either hypoxia or normoxia (Raskoff et al., 1976) is compatible with the theory of a central governor, which prevents the recruitment of so large a muscle mass that a plateau in cardiac output is reached, leading to the myocardial ischaemia predicted by the classical model (Noakes, 1998; Noakes, 2000; Noakes, 2001).
To maintain myocardial oxygen consumption during hypoxia, a more complete extraction of O2 from the coronary blood flow compensates for the reduced CaO2 compared with sea-level values. During maximal exercise, the additional compensatory mechanism of increased coronary blood flow is activated, indicating that the normal heart has a coronary flow reserve that is activated only during maximal exercise in hypoxia (Kaijser et al., 1990; Grubbstrom et al., 1991). This again supports the theory that a constrainer exists specifically to terminate the exercise before myocardial ischaemia can develop.
A possible reason why stroke volume falls during hypoxia, even when only a single leg is active (Richardson et al., 1999), could be the increase in coronary flow during hypoxia since this is accompanied by an increase in coronary arterial pressure and stiffness (Templeton et al., 1972). Any increase in left ventricular stiffness would shift the end-diastolic pressure/end-diastolic volume (PED/VED) curve to the left (Janicki et al., 1996), reducing VED at the same PED, and leading to a smaller VED with a similar PED and, thus, a smaller VS according to the FrankStarling mechanism. However, this theoretical mechanism does not occur even during chronic hypoxia since the relationship between VS and VED is the same during exercise at altitude and at sea level (Reeves et al., 1987). It is difficult to believe that this mechanism exists only during acute hypoxia.
Alternatively, ventricular interdependence could explain the reduced VS during hypoxia. Acute hypoxia raises pulmonary arterial pressure (Cudkowicz, 1970) and right ventricular pressure, causing bulging of the interventricular septum towards the left ventricular cavity (Ritter et al., 1993). This, together with a decreased pulmonary capillary wedge pressure, indicating a lowered left atrial pressure and, hence, a reduced preload, lowers the driving pressure across the mitral valve and, consequently, reduces diastolic filling during the rapid phase in early diastole (Ritter et al., 1993). However, as already argued, the unaltered relationship between VS and VED during exercise in chronic hypoxia indicates that this mechanism is not the principal factor explaining the reduced maximum cardiovascular function during chronic hypoxia.
A third explanation would be simply that the reduced peak workload during hypoxia (Peltonen et al., 2001) reduces the action of the muscle pump, thereby reducing venous return (Rowell, 1993), so that the measured cardiovascular changes are the result and not the cause of the reduced workload during hypoxia.
It has also been argued that, since pericardiectomy increases max in dogs (Stray-Gundersen et al., 1986), diastolic filling therefore limits maximal cardiac output in humans during maximal exercise in the upright position. Yet this logic does not follow since dogs exercise on all four legs, in which position most of their blood volume is at the level of the heart (Rowell, 1986; Rowell, 1993) such that diastolic filling pressures are optimized.
Hence, the model of exercise studied by Stray-Gundersen et al. (Stray-Gundersen et al., 1986) is the equivalent of humans exercising in the supine position in which position diastolic filling pressures are higher at O2max than when humans exercise in the upright position (Rowell, 1993). Thus, the conclusion must be that, during maximal exercise in the upright position in humans, the heart is not at the limit of its capacity for diastolic filling. Rather, any limitation to diastolic filling must exist before the heart, as may also occur during maximal exercise in hypoxia.
Finally, an increased afterload cannot explain the reduced VS during acute hypoxia since peripheral vascular resistance (Vogel et al., 1974) and mean arterial pressure (Wolfel et al., 1991) are unaffected during acute hypoxia (Rowell and Blackmon, 1987) and elevated only during chronic hypoxia.
Furthermore, the finding that the peak exercise heart rate is higher in silent ischaemia than in symptomatic ischaemia (Visser et al., 1990) can be interpreted as evidence that the response to the sensory signals that cause exercise to terminate with submaximal heart rates during acute hypoxia, as in ischaemia, may arise from outside the myocardium itself, possibly in the central nervous system.
In summary, direct cardiovascular factors, including myocardial dysfunction secondary to hypoxia or ischaemia, altered left ventricular diastolic function secondary to an increased coronary blood flow or an increased pulmonary arterial pressure, are unable to explain the reduced max during hypoxia. Nor is the reduction in
max during hypoxia compatible with the classical model, which holds that the heart is the slave of the exercising muscles and must therefore maintain the same
max, especially when oxygen delivery to the exercising muscles is threatened by any factor that reduces CaO2.
Central nervous system limitation
The elevated and fH during acute hypoxia at a given submaximal
O2 suggest an augmented sympathetic activity (Suarez et al., 1987) with increased circulating catecholamine concentrations (Cunningham et al., 1965; Manchanda et al., 1975; Escourrou et al., 1984). However, the close relationships between blood norepinephrine concentrations, heart rate and percentage
O2max are essentially unaffected by hypoxaemia; that is, they are all changed in the same relative proportions (Rowell, 1986). Therefore, it is interesting that
max, fHmax, VSmax and peak workrate (Pmax) are each reduced during acute hypoxia, in a situation in which maximal sympathetic activity would be expected.
One possible explanation for the reduced max and Pmax during hypoxia is that the limitation originates centrally in the brain. If the level of sympathetic activity at a given heart rate is the same under normoxic and hypoxic conditions (Rowell, 1986), then the lower fHmax values during hypoxia could indicate a lesser sympathetic stimulation.
However, the finding that plasma norepinephrine and lactate concentrations were similar to normoxic values after maximal exercise during acute hypoxia, despite a lower fHmax with increasing altitude (Lundby et al., 2001), suggests that sympathetic activity per se was not reduced but that the response of the heart to sympathetic stimulation was blunted.
These authors (Lundby et al., 2001) concluded that postganglionic desensitization and not a reduction in cardiac adrenoreceptor numbers is responsible for the early decrease in fHmax during maximal exercise in hypoxia. In accordance with this interpretation, Manchanda et al. (Manchanda et al., 1975) reported that acute hypoxia reduced the stimulatory effects of catecholamines on cardiac function even during submaximal exercise. They found that, although cardiac performance increased in proportion to the rise in plasma catecholamine concentrations during normoxia, the response was blunted during acute hypoxia even though plasma catecholamine concentrations were elevated. They postulated that the depressant effect of increased hypoxaemia and acidosis during moderately heavy exercise in acute hypoxia may override the cardiostimulatory effects of elevated circulating catecholamine concentrations.
There are, however, studies to indicate that the central nervous system itself may act as a central governor during maximal exercise in hypoxia. First, the typical signs of peripheral neuromuscular fatigue, i.e. an increase in the integrated electromyogram signal (IEMG) are absent during chronic (Kayser et al., 1994) and acute (Peltonen et al., 1997) hypoxia. Rather, IEMG activity is reduced at peak exercise but increases with oxygen administration at altitude (Kayser et al., 1994). Hence, Kayser et al. (Kayer et al., 1994) conclude that: "during chronic hypobaric hypoxia, the central nervous system may play a primary role in limiting exhaustive exercise and maximum accumulation of lactate in blood". Second, blunting of afferent sensory signals from the working muscles does not diminish the hypoxia-induced cardiovascular adaptations to acute hypoxia, suggesting that the limitations in exercise performance are of central origin (Kjaer et al., 1999). Third, vasomotor depression on exposure to acute hypoxia is induced by central hypoxia in non-acclimatized subjects (Koller et al., 1991). Fourth, the animal experiments of Jones et al. (Jones et al., 1981) have shown that, as CaO2 falls, regardless of whether this is due to a reduction in PO2 or in haematocrit or both, there is a reciprocal increase in cerebral blood flow such that cerebral O2 delivery remains constant. This indicates that the brain has the ability to sense acute hypoxia and to increase blood flow in response. The finding that the extent of the cerebral microvasculature increases with chronic exposure to hypoxia (Harik et al., 1996) further indicates the capacity of the central nervous system to sense, and to respond to, hypoxia. Moreover, hypoxia has a tendency to increase both overall and respiratory perceptions of effort for a given absolute O2 (Shephard et al., 1992).
All these findings, but most especially those of Kayser et al. (Kayser et al., 1994), support the original central governor hypothesis of Hill and colleagues (Hill et al., 1924a; Hill et al., 1924b), as modified by Noakes (Noakes, 1998; Noakes, 2000; Noakes, 2001), that skeletal muscle recruitment during severe exercise is regulated by a central governor specifically to prevent the development of progressive arterial desaturation leading to myocardial ischaemia or cerebral hypoxia. Thus, reduced max and
O2max during acute hypoxia might be the result rather than the cause of the reduced skeletal muscle recruitment (Peltonen et al., 2001). The postulated pathways for this effect are presented in Fig.2.
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Although exercise performance and O2max do not change equally with changes in FIO2, an interesting finding is the strongly positive correlation between changes in maximal workload and
max during both hypoxia and hyperoxia (Peltonen et al., 2001), supporting the theoretical existence of a central governor linking cardiac function and exercise performance (Fig.2).
Finally, it is of interest to speculate about the site of the oxygen sensor that appears to link cardiovascular function and exercise performance during hypoxia and hyperoxia. Noakes original suggestion was that the oxygen tension in the coronary vascular bed would be the monitored variable to prevent the development of a progressive myocardial ischaemia (Noakes, 1998; Noakes, 2000; Noakes, 2001)(Fig.2).
Alternatively, other studies suggesting that a central governor limits exercise during hypoxia or at altitude (Koller et al., 1991; Kayser et al., 1994; Harik et al., 1996; Peltonen et al., 1997; Kjaer et al., 1999) can be interpreted to show that the efferent information to the central governor (Fig.2), and which terminates exercise at a lower fHmax, VSmax and max, may arise not in the coronary vessels or myocardium but possibly in the central nervous system itself.
For example, the evidence presented here can be interpreted as indicating that skeletal muscle has the potential to increase its blood flow and oxygen utilization up to the point at which a short mean capillary transit time causes a peripheral oxygen diffusion limitation to develop. However, if a similar diffusion limitation exists in the central nervous system, this would also offer a possible explanation for the observed reductions in , fH, exercise performance and electromyographic activity during acute hypoxia since all would slow the transit time in the cerebral capillaries, thereby preventing the development of cerebral hypoxia. However, the same model would also explain how the central governor would prevent the development of myocardial ischaemia.
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Concluding remarks |
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If this model is correct, it suggests that a search for the possible factors limiting maximal exercise performance should include studies of the central nervous system, since such studies might uncover the possible existence and mode of action of the proposed central governor.
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Acknowledgments |
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References |
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