AJP - Regu Ad Instruments
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Regul Integr Comp Physiol 295: R624-R632, 2008. First published May 21, 2008; doi:10.1152/ajpregu.00797.2007
0363-6119/08 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
295/2/R624    most recent
00797.2007v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lador, F.
Right arrow Articles by Ferretti, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lador, F.
Right arrow Articles by Ferretti, G.

EXERCISE AND RESPIRATORY PHYSIOLOGY

Phase I dynamics of cardiac output, systemic O2 delivery, and lung O2 uptake at exercise onset in men in acute normobaric hypoxia

Frédéric Lador,1 Enrico Tam,1,2 Marcel Azabji Kenfack,1 Michela Cautero,3 Christian Moia,1 Denis R. Morel,4 Carlo Capelli,3 and Guido Ferretti1,5

1Département des Neurosciences Fondamentales, Centre Médical Universitaire, Genève, Switzerland; 2Dipartimento di Fisiologia Umana e Generale, Università di Bologna, Bologna; 3Dipartimento di Scienze Neurologiche e della Visione, Facoltà di Scienze Motorie, Università di Verona, Verona, Italy; 4Département d'Anesthésiologie, Pharmacologie et Soins Intensifs, Hôpital Cantonal Universitaire, Genève, Switzerland; and 5Sezione di Fisiologia Umana, Dipartimento di Scienze Biomediche e Biotecnologie, Università di Brescia, Brescia, Italy

Submitted 1 November 2007 ; accepted in final form 19 May 2008


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
We tested the hypothesis that vagal withdrawal plays a role in the rapid (phase I) cardiopulmonary response to exercise. To this aim, in five men (24.6 ± 3.4 yr, 82.1 ± 13.7 kg, maximal aerobic power 330 ± 67 W), we determined beat-by-beat cardiac output (Q), oxygen delivery (QaO2), and breath-by-breath lung oxygen uptake (VO2) at light exercise (50 and 100 W) in normoxia and acute hypoxia (fraction of inspired O2 = 0.11), because the latter reduces resting vagal activity. We computed Q from stroke volume (Qst, by model flow) and heart rate (fH, electrocardiography), and QaO2 from Q and arterial O2 concentration. Double exponentials were fitted to the data. In hypoxia compared with normoxia, steady-state fH and Q were higher, and Qst and VO2 were unchanged. QaO2 was unchanged at rest and lower at exercise. During transients, amplitude of phase I (A1) for VO2 was unchanged. For fH, Q and QaO2, A1 was lower. Phase I time constant ({tau}1) for QaO2 and VO2 was unchanged. The same was the case for Q at 100 W and for fH at 50 W. Qst kinetics were unaffected. In conclusion, the results do not fully support the hypothesis that vagal withdrawal determines phase I, because it was not completely suppressed. Although we can attribute the decrease in A1 of fH to a diminished degree of vagal withdrawal in hypoxia, this is not so for Qst. Thus the dual origin of the phase I of Q and QaO2, neural (vagal) and mechanical (venous return increase by muscle pump action), would rather be confirmed.

cardiovascular response

ALTHOUGH OUR KNOWLEDGE of the central (neural) control of the cardiovascular system at the exercise steady state is quite well established (19, 42, 57), how the circulatory readjustments upon exercise onset occur and match the increase in pulmonary oxygen uptake (VO2) is less understood, as are the mechanisms underlying this matching. The kinetics of VO2 at exercise onset were seen for a long time as reflecting essentially the metabolic adaptations in the working muscles (15, 31, 33). Some authors, however, soon identified two components of the VO2 kinetics: 1) a rapid, almost immediate phase (phase I) (5, 54, 55), which they attributed to an immediate increase in cardiac output (Q) at exercise start; and 2) a subsequent slower phase (phase II), to which they restricted the influence of muscle metabolic adjustments. The strongest support to this view came from the demonstration that the kinetics of Q (12, 13, 16, 60) and arterial O2 flow (QaO2) (27) are very rapid.

The concept of a close correspondence between VO2 and muscle O2 consumption was further undermined by the recent demonstration that, upon the onset of light exercise, the VO2 kinetics are faster than the kinetics of muscle O2 consumption estimated from the monoexponential decrease in phosphocreatine concentration (7, 14, 43). This would imply dissociation of the kinetics of VO2 and muscle O2 consumption, which should respond to different control mechanisms.

Our postulate is that the VO2 kinetics are dictated by the regulation of the systemic cardiovascular response to exercise, whereas the metabolic regulatory processes dictate only the kinetics of muscle O2 consumption. In this context, Fagraeus and Linnarsson (18) proposed that the rapid heart rate (fH) changes in exercise transients "are mediated through a withdrawal of vagal tone" (termed "vagal withdrawal" from this point), which can be defined as a quasi-immediate inhibition of vagal action on the sinus node at exercise start. In fact, they showed that the rapid phase of the fH kinetics was cancelled out under vagal blockade, whereas β-adrenergic blockade with propranolol did not affect it. In this study, we tested the hypothesis that vagal withdrawal also plays a major role in determining phase I kinetics of Q, QaO2, and VO2. If this is so, then in acute normobaric hypoxia, wherein reduced vagal activity (8, 26) and increased sympathetic activity at rest have been postulated (21, 26, 58, 59), phase I would be either absent or at least less intense compared with normoxia.

With this hypothesis in mind, the aim of this study was to perform simultaneous determinations of the phase I kinetics of fH, Q, QaO2, and VO2 upon exercise onset in normoxia and acute normobaric hypoxia. Such an experiment was never carried out in the past, to the best of our knowledge.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Subjects. Five healthy, nonsmoking young male subjects took part in the experiments. They were 24.6 ± 3.4 yr old, 1.79 ± 0.09 m tall, and weighed 82.1 ± 13.7 kg. Their maximal O2 consumption and maximal aerobic mechanical power in normoxia were 4.42 ± 0.62 l/min and 330 ± 67 W, respectively. The corresponding values in hypoxia were 3.41 ± 0.83 l/min and 255 ± 78 W, respectively. All subjects were preliminarily informed of all procedures and risks associated with the experimental testing. Informed consent was obtained from each volunteer, who was aware of his right to withdraw from the study at any time without jeopardy. The study was conducted in accordance with the Declaration of Helsinki. The protocol was approved by the Comités d'Ethique des Hôpitaux Universitaires Genevois (Switzerland). The experiments were carried out at Geneva, Switzerland.

Measurements. VO2 was determined on a breath-by-breath basis. The time course of O2 and CO2 partial pressures throughout the respiratory cycles were continuously monitored with a mass spectrometer (Balzers Prisma, Balzers, Liechtenstein) calibrated against gas mixtures of known composition. The inspiratory and expiratory ventilations were measured by an ultrasonic flowmeter (Spiroson; Ecomedics, Duernten, Switzerland) calibrated with a 3-liter syringe. The alignment of traces was corrected for the time delay between the flowmeter and the mass spectrometer. Breath-by-breath VO2 and CO2 output (VCO2) were then computed off-line by means of a modified version of Grønlund's algorithm (9). Software purposely written under the Labview developing environment (Labview 5.0; National Instruments, Austin, TX) was used. The characteristics and physiological implications of Grønlund's algorithm are widely discussed elsewhere (9, 11, 27).

fH and arterial oxygen saturation (SaO2) were continuously measured using electrocardiography (Elmed ETM 2000; Heiligenhaus, Germany) and fingertip infrared oximetry (Ohmeda 2350; Finapres, Englewood, CO), respectively. In hypoxia, SaO2 data were corrected for time delay between lungs and fingertip (30). Continuous recordings of arterial pulse pressure were obtained at a fingertip of the right arm by means of a noninvasive cuff pressure recorder (Portapres; FMS, Amsterdam, The Netherlands). Beat-by-beat mean arterial pressure (P) was computed as the integral mean of each pressure profile using the Beatscope software package (FMS).

The stroke volume of the heart (Qst) was determined on a beat-by-beat basis by means of the model flow method (53), applied off-line to the pulse pressure profiles, again using the Beatscope software package. Beat-by-beat Q was computed as the product of single-beat Qst times the corresponding single-beat fH. Correction for the inaccuracy of the method was applied as previously described (2, 27, 50). To this purpose, steady-state Q values also were obtained by means of the open-circuit acetylene method (4) using a procedure that was previously described (27). Individual correction factors at rest and at each workload were calculated as previously described (27) and also applied during dynamic states with rapid changes in Q (51).

Exercise was carried out on an electrically braked cycle ergometer (Ergometrics 800-S; Ergoline, Bitz, Germany). The pedaling frequency was recorded, and its sudden increase at the exercise onset and decrease at the exercise offset were used as markers to identify precisely the start and the end of exercise. The electromechanical characteristics of the ergometer were such as to permit workload application in <50 ms. All the signals were digitalized in parallel by a 16-channel analog-to-digital converter (MP100; Biopac Systems, Goleta, CA) and stored on a computer. The acquisition rate was 100 Hz.

Blood hemoglobin concentration ([Hb]) was measured using a photometric technique (HemoCue, Ängelholm, Sweden) on 10-µl blood samples from a peripheral venous line inserted in the left forearm. Blood lactate concentration ([La]b) was measured using an electroenzymatic method (Eppendorf EBIO 6666, Erlangen, Germany) on 20-µl blood samples from the same venous line. Arterial blood gas composition was measured with microelectrodes (Instrumentation Laboratory Synthesis 10, Lexington, MA) on 300-µl blood samples taken from an arterial catheter inserted in the left radial artery.

Protocol. Experiments were first performed in normoxia and then in acute normobaric hypoxia (fraction of inspired O2, 0.11; inspired O2 partial pressure, 80 mmHg). In hypoxia, inspired gas was administered from high-pressure gas cylinders via an 80-liter Douglas bag buffer. The fraction of inspired O2 was monitored on the inspiratory line, close to the mouth. The gas flow from the cylinders was continuously adjusted to the subject's ventilation. Experiments in hypoxia were preceded by a 10-min period for gas store equilibration. The experimental protocol started with the performance of blood sampling and the measurement of acetylene Q at rest, and then 2 min of quiet resting recordings were allowed, after which the exercise at 50 W started, for a duration of 10 min. Arterial blood gas composition and [La]b were measured at minute 5 and at the end of exercise. At minute 7, the measurement of Q with the acetylene technique was initiated. The 50-W exercise was followed by a 10-min recovery, during which [La]b was measured at minutes 2, 4, and 6, and arterial blood gas composition was determined at minutes 5 and 10. The 100-W exercise was then carried out, for a 10-min duration, and with the same timing of events as at 50 W. A 10-min recovery followed, with the same characteristics as the previous one. The overall duration of this protocol was about 60 min, during which [Hb] was systematically measured at 1-min intervals.

Each subject repeated this protocol four times, in both normoxia and hypoxia. At each repetition, the performance of blood sampling for [Hb] determination was shifted by 15 s, as previously described (27), to obtain, after superposition of the four tests, an overall description of the changes in [Hb] on a 15-s time basis.

Data treatment. The superimposed time course of [Hb] was smoothed by a four-sample mobile mean, to account for interrepetition variability, and interpolated by means of a 6th degree polynomial, as previously described (27). The continuous SaO2 traces from the four repetitions were temporally aligned and superimposed by means of an ensemble average procedure. The resulting overall SaO2 trace was then interpolated by means of a 6th degree polynomial. The resulting functions, describing the time course of [Hb] and SaO2, were used to compute the time course of arterial O2 concentration (CaO2, ml/l) on an equivalent beat-by-beat time scale, established after the pulse pressure profile traces, as in a previous study (27).

The beat-by-beat fH, Qst, P, and Q values from the four repetitions of each subject were aligned temporally by setting the time of exercise start as time 0 for the analysis of on kinetics. The data were then averaged on a beat-by-beat basis to obtain a single averaged, superimposed time series for each parameter and subject. Beat-by-beat QaO2 was then calculated as

Formula 1(1)

Beat-by-beat total peripheral resistance (Rp) was calculated by dividing each Formula 1 value by the corresponding Formula 1 value, on the assumption that the pressure in the right atrium can be neglected as a determinant of peripheral resistance.

Based on the conclusions arrived at in a previous study (27), the kinetics of Formula 1O2, Formula 1, and Formula 1aO2 were described by means of a two-phase model, whereby an exponential increase in flow (phase II) is preceded by a faster flow increase in the first seconds of exercise (phase I), which Barstow and Molé (5) also treated as an exponential. To compute the characteristic parameters of the exponential equations describing phase I, the four repetitions were interpolated to 1-s intervals (28) and then aligned temporally, as described above, and averaged to obtain a single superimposed time series (27). Since the tested hypothesis concerns specifically a phenomenon that takes place during phase I, in the results we report only the phase I parameters, neglecting the phase II parameters, to which the tested hypothesis does not pertain.

Statistics. Data are means and standard deviations of the values obtained for each parameter from the average superimposed files of each subject, to account for interindividual variability. The effects of exercise intensity and hypoxia on the investigated parameters were analyzed separately using a one-tailed t-test for paired observations. Bonferroni correction was then applied. The parameters of the models were estimated by utilizing a weighted nonlinear least squares procedure (10), implemented under Labview (version 5.0; National Instruments, Austin TX). Initial guesses of the parameters of the model were entered after visual inspection of the data. The effects of exercise intensity and hypoxia on these values were investigated using a one-tailed t-test for paired observations. The results were considered significant if P < 0.025.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
The [Hb], SaO2, and CaO2 values at rest and at the exercise steady state are reported in Table 1, together with arterial blood pH, PO2, and PCO2. The SaO2 and CaO2 values in hypoxia were lower than the corresponding values in normoxia. Arterial blood pH was higher in hypoxia than in normoxia and was unaffected by the exercise intensity in both conditions. PO2 and PCO2 were both lower in hypoxia than in normoxia. In the latter, they did not vary at exercise. In hypoxia, PO2 decreased during exercise (P < 0.025) and PCO2 tended to decrease (not significant, NS). In normoxia, [La]b was 1.3 ± 0.3 mM at rest and did not change at exercise. In hypoxia, [La]b was 2.0 ± 0.5 mM at rest and 2.3 ± 0.5 mM at 50 W (NS). At 100 W, [La]b increased to 3.7 ± 1.3 mM at minute 5 and 4.5 ± 1.7 mM at minute 10.


View this table:
[in this window]
[in a new window]

  		Table 1. Oxygen, hemoglobin, and pH in arterial blood

 
The mean values for Formula 1, fH, Qst, Formula 1, Rp, Formula 1aO2, and Formula 1O2, obtained at rest and at the exercise steady state at both powers, are reported in Table 2. At all metabolic powers, fH was higher in hypoxia than in normoxia. Qst was the same in hypoxia as in normoxia so that Formula 1 resulted systematically higher in hypoxia than in normoxia. At rest, Formula 1 was lower in hypoxia than in normoxia, but this difference disappeared at exercise. As a consequence, systematically lower Rp values were found in hypoxia than in normoxia (NS at rest, P < 0.025 at 50 and 100 W). Formula 1aO2 was not significantly different from normoxia at rest. At 50 and 100 W, however, Formula 1aO2 turned out lower in hypoxia than in normoxia. Formula 1O2 was the same in hypoxia as in normoxia.


View this table:
[in this window]
[in a new window]

  		Table 2. Steady-state values of cardiopulmonary parameters at rest and at exercise at 50 and 100 W

 
The time courses of fH, Qst, Formula 1, Formula 1, and Rp upon the onset of 50- and 100-W exercise are shown in Fig. 1. Beat-by-beat data collected in the 15 s that preceded and in the 45 s that followed the start of exercise are shown in Fig. 1, to draw attention to phase I events. In normoxia, a steady state for fH appeared as soon as phase I was completed at 50 W, whereas a clear slower phase II increase was evident at 100 W. In hypoxia, the relative contribution of phase I to the fH response was less than in normoxia. The time course of Qst was the same in hypoxia as in normoxia. Thus the initial change of Formula 1 in hypoxia, compared with normoxia, followed essentially the same patterns as for fH. The increase in Formula 1 was modest and slow, in both normoxia and hypoxia. Conversely, Rp underwent a sudden dramatic decrease, the amplitude of which was smaller in hypoxia than in normoxia.


Figure 1
View larger version (19K):
[in this window]
[in a new window]

  		Fig. 1. Time course of investigated cardiovascular parameters upon the onset of exercise at 50 and 100 W in normoxia and hypoxia. Values are shown for heart rate, stroke volume, cardiac output, mean arterial pressure, and total peripheral resistance (TPR). Each value is the mean of the averaged superimposed values of all subjects. Time 0 corresponds to the start of exercise.

 
The evolution of beat-by-beat fH as a function of beat-by-beat Formula 1 is shown in Fig. 2. For both normoxia and hypoxia, the resting values are located on the lower left side of the plot, and the exercise steady-state values are located on the upper right side. However, the resting values in hypoxia were displaced upward and leftward with respect to those in normoxia, as were the exercise values. In normoxia, at both workloads, the pattern of displacement of the baroreflex operational point from rest to exercise was dictated by the rapid increase in fH, as demonstrated by the small number of points required to attain the cluster of the fH and Formula 1 values at exercise. Similar patterns were observed in hypoxia, although 1) the size of the displacement of baroreflex operational point was larger than in normoxia, and 2) the number of beats required to complete this displacement in hypoxia (within 30 and 60 beats at 50 and 100 W, respectively) was greater (slower increase) than in normoxia (within 20 and 45 beats at 50 and 100 W, respectively).


Figure 2
View larger version (20K):
[in this window]
[in a new window]

  		Fig. 2. Beat-by-beat heart rate as a function of the corresponding beat-by-beat mean arterial pressure (Pmean) upon the onset of exercise at 50 and 100 W in normoxia and hypoxia. The resting values are located on at bottom left; the exercise steady-state values are at top right. The resting values in hypoxia are displaced upward and leftward with respect to the corresponding values in normoxia. The pattern of displacement of the heart rate vs. Pmean operational range from rest to exercise is completed, at 50 W, within 20 and 30 beats, and at 100 W, within 45 and 60 beats, in normoxia and hypoxia, respectively.

 
In normoxia, since SaO2 was unchanged, the evolution of CaO2 followed the changes in [Hb]. In hypoxia, CaO2 underwent larger changes than in normoxia, which were dictated not only by the changes in [Hb] but also by the decrease in SaO2 in the exercise transient. In hypoxia, a steady CaO2 level lower than at rest was attained within 2 min.

The time courses of Formula 1aO2 and Formula 1O2 upon the onset of 50- and 100-W exercise are reported in Fig. 3. The rate of readjustment of Formula 1O2 followed the same trend in hypoxia as in normoxia. In normoxia, it was slower than that of Formula 1aO2. This difference disappeared in hypoxia, because the rate of readjustment of Formula 1aO2 was slower in hypoxia than in normoxia.


Figure 3
View larger version (20K):
[in this window]
[in a new window]

  		Fig. 3. Time course of arterial O2 flow (oxygen delivery, Formula 2aO2) and lung O2 uptake (Formula 2O2) upon the onset of exercise at 50 and 100 W in normoxia and hypoxia. Each value is the mean of the averaged superimposed values of all subjects. Time 0 corresponds to the start of exercise.

 
The characteristic parameters describing the Formula 1, Formula 1aO2, Formula 1O2, and fH kinetics during phase I are presented in Table 3. For Formula 1O2, amplitude of phase I (A1) was the same in hypoxia as in normoxia. For Formula 1 and Formula 1aO2, A1 was significantly lower in hypoxia than in normoxia. In both normoxia and hypoxia, A1 was the same at 100 W as at 50 W. For Formula 1aO2 and Formula 1O2, {tau}1 was unaffected by hypoxia. For Formula 1, {tau}1 was shorter in hypoxia than in normoxia at 50 W but not at 100 W. For fH, A1 was lower in hypoxia than in normoxia at 50 W but not at 100 W. In normoxia, A1 was the same at 50 W as at 100 W, as it was in hypoxia. {tau}1 was higher in hypoxia than in normoxia at 100 W but not at 50 W. In hypoxia, {tau}1 was significantly greater at 100 W than at 50 W.


View this table:
[in this window]
[in a new window]

  		Table 3. Kinetics of systemic O2 delivery, O2 uptake, and cardiac output within the two-phase model

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
This study was carried out to test the hypothesis that vagal withdrawal determines the phase I kinetics of Formula 1, Formula 1aO2, and Formula 1O2 at exercise onset. This hypothesis implies that phase I would be either absent or eventually less intense compared with normoxia. The main finding of this study is that the amplitude of the phase I (A1) of the kinetics of Formula 1 and Formula 1aO2 at exercise onset was smaller in acute normobaric hypoxia, wherein reduced vagal activity (8, 26) and increased sympathetic activity at rest have been postulated (21, 26, 58, 59), than in normoxia, whereas its time constant {tau}1 was unchanged. No differences appeared concerning the phase I of Formula 1O2 kinetics. In hypoxia, the reductions in A1 are coherent with the concept of a lesser effect of postulated vagal withdrawal at exercise onset.

Steady-state data. The increased sympathetic activity to the heart in acute hypoxia (21, 22, 44, 45), perhaps through peripheral chemoreceptor stimulation (22), may be sufficient to explain the higher fH in hypoxia than in normoxia, both at rest and at any given work level. Since Qst is unaffected by acute hypoxia, the increase in fH entails a corresponding increase in Formula 1, as already demonstrated in several studies (1, 23, 49). The present data (see Table 2) are in full agreement with this picture.

A larger sympathetic activity, if directed to peripheral vessels as well, might also imply peripheral vasoconstriction and, hence, a greater Rp in hypoxia than in normoxia. However, this was not so in the present study, since Rp (Table 2) was lower in hypoxia than in normoxia, whether at rest or at the two investigated workloads, because a higher Formula 1 was associated with an unchanged Formula 1. Rp was rarely looked at in hypoxia in the past, yet it was possible to compute it from some studies (1, 23, 49). The obtained data are coherent with those of the present study. Moreover, increased peripheral sympathetic activation in hypoxia, though providing a potent peripheral vasoconstriction stimulus, is not accompanied by increased leg vascular resistance at rest, which was rather found to be reduced compared with normoxia (22).

This apparent contradiction may be explained by admitting either of these three hypotheses : 1) hypoxemia reduces the sensitivity and increases the activation threshold of vascular sympathetic receptors (sympatholysis); 2) hypoxemia superimposes a vasodilating stimulus in peripheral circulation; or 3) the intensity and quality of sympathetic output may differ among various target organs in hypoxia. The first hypothesis was recently contradicted by the demonstration that the vascular response to tyramine is not reduced in hypoxia (56). The two other hypotheses were supported by the observation of β2-mediated vasodilatation in resting skeletal muscle in hypoxia due to increased adrenaline release (52). Peripheral O2 sensing mechanisms may be implied in this effect. For instance, according to Stamler et al. (48), the conformation of the reduced hemoglobin determines the rise of nitric oxide (NO) in blood with consequent vasodilatation. In contradiction to this, however, Weisbrod et al. (52) failed to show a reduction of peripheral hypoxic vasodilatation after NO synthase blockade. Other SaO2-related mechanisms were postulated, which would imply ATP-mediated vasodilatation (32). A clear picture of the events that lead to decreased Rp is still far from being established.

Phase I kinetics. The hypothesis that vagal withdrawal determines phase I relies essentially on observations made on fH upon exercise onset in normoxia, the kinetics of which were similar in this and previous studies (6, 18, 37, 46). In fact, the fast component of fH kinetics 1) was cancelled out under vagal blockade (18) and 2) was not found in heart transplant recipients, whose hearts are denervated (3, 20, 40). To extend this hypothesis to explain phase I kinetics of Formula 1, Formula 1aO2, and Formula 1O2, we should be able to demonstrate that when vagal tone is attenuated, as is the case in acute normobaric hypoxia (26), the phase I should either be reduced or disappear for all these parameters. Indeed, hypoxia reduced A1 significantly, for Formula 1 and Formula 1aO2 (Table 3) at both 50 and 100 W and for fH at 50 W, but did not extinguish it. On the other hand, hypoxia acted very little on {tau}1, whose very low values were essentially invariant; we noticed only a reduction at 50 W for Formula 1 and an increase at 100 W for fH. This would mean that 1) the {tau}1 values in hypoxia also are compatible with a very rapid neural phenomenon, vagal withdrawal, as originally proposed by Fagraeus and Linnarsson (18) for normoxia; 2) vagal withdrawal has a smaller amplitude in hypoxia than in normoxia because of lesser vagal activation in the former; and 3) the patterns in the time domain of vagal withdrawal at exercise onset are fixed and invariant.

However, the occurrence of phase I in hypoxia with a smaller amplitude, instead of a full suppression of it, may imply that 1) hypoxia did not fully suppress vagal activity at rest so that some degree of vagal withdrawal still took place at exercise onset, or 2) other mechanisms than vagal withdrawal participate in phase I. The former may indeed be the case for fH. The latter is suggested by the apparent lack of changes in the Qst kinetics in hypoxia with respect to normoxia (Fig. 1). In the absence of a clear predetermined model for the Qst kinetics, whereby we refrained from fitting parameters through Qst data, we evaluated the contribution of Qst to Formula 1 A1, as follows. Since Formula 1 is the product of fH times Qst, the absolute Formula 1 value at the peak of phase I is equal to

Formula 2(2)

where Formula 2, fH, and Qst are the resting values and {Delta}Formula 2, {Delta}fH, and {Delta}Qst are the corresponding increments during phase I, namely, the respective A1 values. Solution of this equation for {Delta}Qst thus provides an estimate of the Qst amplitude during phase I that is necessary to sustain the observed increase in Formula 2. At 50 W, {Delta}Qst was 23.9 ± 10.5 and 14.7 ± 7.1 ml in normoxia and hypoxia, respectively. The corresponding {Delta}Qst values at 100 W were 33.1 ± 9.3 and 24.2 ± 21.2 ml. At both powers, although affected by a large scatter, {Delta}Qst did not differ in hypoxia from normoxia (P > 0.1 in both cases), suggesting that, contrary to fH, the alleged amplitude of Qst in phase I may not vary in hypoxia with respect to normoxia. This being the case, then 1) if indeed the reduction of the A1 of fH in hypoxia is due to lesser vagal withdrawal, then the same should be the case for the reduction of the A1 of Formula 2; and 2) the Qst changes during an exercise transient are independent of mechanisms related to vagal withdrawal. Concerning the latter, in supine posture, a condition in which central blood volume is increased (24, 29, 47), phase I of Formula 2 is not evident (25, 29), although resting vagal activation is greater supine than upright (25, 38). A higher central blood volume would reduce the amount of blood suddenly displaced from the periphery to the heart by muscle pump action, and thus the size of the immediate increase in venous return, thus preventing an efficient Frank-Starling mechanism. In the present study exercise was carried out in upright posture only, so it is likely that the increase in venous return due to muscle pump action would be the same in hypoxia as in normoxia, whence equivalent Qst kinetics.

In both normoxia and hypoxia, the {tau}1 of Formula 2O2 kinetics was extremely rapid and functionally instantaneous, indicating a practically immediate upward translation of Formula 2O2 that appears since the first breath. The {tau}1 of Formula 2O2 did not differ between powers and can be considered equal to those of Formula 2 and Formula 2aO2 (Table 3), given that the minimal functional time window in which Formula 2O2 can be determined is one breathing cycle. This suggests that the phase I changes in Formula 2O2 are imposed by the corresponding phase I changes in Formula 2. Because of a delay between muscle O2 consumption and Formula 2O2, we can assume that during the first seconds of exercise, arterial-venous O2 difference (CaO2-CvO2) remains equal to that at rest (5). On this basis, the Fick principle allows a prediction of the expected Formula 2O2 increase in phase I as a consequence of the observed Formula 2 increase. In normoxia, A1 of Formula 2 was on average 4.57 l/min (see Table 3). For an average resting CaO2-CvO2 of 79 ml/l, we would expect an immediate Formula 2O2 increase upon exercise start of 0.36 l/min, compared with a measured A1 of Formula 2O2 of 0.39 l/min (Table 3). By analogy, in hypoxia, A1 of Formula 2 was on average 2.52 l/min (Table 3), and the resting CaO2-CvO2 was 70 ml/l. Thus the expected Formula 2O2 increase would be 0.18 l/min, compared with a measured A1 of Formula 2O2 of 0.35 l/min (Table 3). Despite this sizeable discrepancy, the two values are not significantly different, probably because of the relatively large coefficient of variation of the data in hypoxia. Nevertheless, the results of this analysis suggest that A1 of Formula 2O2 may be a direct consequence of the rapid Formula 2 increase during phase I, in agreement with the so-called cardiodynamic hypothesis of lung Formula 2O2 transients (55).

Baroreflex resetting. At rest in normoxia, Formula 2 was 90 mmHg and fH was 74.5 min-1. Let us assume that these values set the operating point of the average baroreflex curve of present subjects and that the operating point of resting subjects in normoxia corresponds to the centering point of the baroreflex curve (42). Assume also that the maximal gain and the operating range of the baroreflex curve are as previously reported (36). On this basis, we can construct a resting baroreflex response curve for the present subjects, which is reported in Fig. 4. If we then add the average resting value observed in hypoxia to that curve, we can see that the subjects operated in hypoxia on the same baroreflex curve as in normoxia, with a displacement of the operating point along the curve toward the threshold. This is a result of the decrease in Formula 2 induced by peripheral vasodilation, to which the subjects responded with an increase in fH, supporting the notion that peripheral vascular changes play a significant role in the baroreflex response of resting humans (17, 35). If indeed hypoxemia induces vasodilation in peripheral circulation via β2-sympathetic stimulation, then we can propose a role for peripheral chemoreflexes in the displacement of the baroreflex operating point in hypoxia.


Figure 4
View larger version (10K):
[in this window]
[in a new window]

  		Fig. 4. Baroreflex response curve at rest and exercise steady state. Heart rate (fH) as a function of mean arterial pressure (Formula 2). Theoretical baroreflex curves are shown for rest (solid curve), exercise at 50 W (shaded curve), and exercise at 100 W (dashed curve). The curve at rest was constructed using the present mean resting values of Formula 2 to define the baroreflex operating point and assuming 1) that the operating point of resting subjects in normoxia corresponds to the center point (42) and 2) that the maximal gain and the operating range of the baroreflex curve are as previously reported (36). The two curves at exercise were built by shifting the former upward by an amount equal to the average reported in previous studies (34, 35, 39, 41), assuming that the gain and operating ranges do not change at exercise steady state. The average steady-state values observed at rest (solid circles), exercise at 50 W (shaded circles), and exercise at 100 W (open circles) in normoxia and hypoxia are also indicated. At rest, the point in hypoxia is displaced upward and leftward, on the corresponding theoretical baroreflex curve. At exercise, the points do not lie on the corresponding theoretical baroreflex curve but are further displaced upward and rightward.

 
Exercise displaces the baroreflex curve upward and rightward, without changes in gain [baroreflex resetting (42)]. This phenomenon is part of the rapid cardiovascular response upon exercise start. Baroreflex resetting includes a fast phase (Fig. 2), completed within a few heartbeats, within the duration of phase I, which goes on in parallel with the rapid changes in Rp that take place at exercise start. However, the dynamics of baroreflex resetting implied a larger number of heartbeats in hypoxia than in normoxia. If vagal withdrawal sets phase I of fH, then it will also contribute to the rapid upward shift of the baroreflex curve, but its role in baroreflex resetting will be less important in hypoxia than in normoxia.

Figure 4 also reports baroreflex curves for 50- and 100-W exercises, which are shifted upward as much as described in previous studies (34, 35, 39, 41). When the 50- and 100-W steady-state Formula 2 and fH values were added to Fig. 4, they were further displaced upward and rightward with respect to the predicted exercise baroreflex curve, suggesting that in the present study, baroreflex resetting was somewhat more intense than previously reported. Moreover, at both 50 and 100 W, the segment relating the experimental point in normoxia to the experimental point in hypoxia had a greater slope than the expected baroreflex gain, suggesting that the latter experimental point may lie on a different baroreflex curve than the former in both cases. A 50-W exercise provides a higher power relative to the maximum in hypoxia than in normoxia because of the decrease in maximal O2 uptake in hypoxia, whereby implying a greater role of the chemical component of the exercise pressor reflex (42). Yet we cannot distinguish the relative roles of central command or of the exercise pressor reflex in determining baroreflex resetting from the present data (42).

Conclusions. We conclude that in hypoxia, with respect to normoxia, 1) phase I is not completely suppressed for fH, although the A1 for fH is decreased, likely because the degree of vagal withdrawal is less; 2) since phase I is partly maintained, arterial baroreflex resetting continues to be very rapid, taking place essentially within phase I; 3) {Delta}Qst is unchanged, because the increase in venous return due to muscle pump action is unchanged; 4) the coupling of a decreased A1 for fH with an unchanged {Delta}Qst would produce the observed decrease in A1 of Formula 2; and 5) the same factors that determine the phase I of Formula 2 are also responsible for the phase I of Formula 2O2. Thus the present results provide only partial support to the hypothesis that vagal withdrawal determines the phase I kinetics of cardiovascular O2 flow and lung O2 uptake, because the suppression of phase I was incomplete. Although we can attribute the decrease in A1 of fH to a diminished degree of vagal withdrawal in hypoxia, this is not so for Qst. Under these circumstances, the dual origin of the phase I of Formula 2 and Formula 2aO2, neural (vagal) and mechanical (increase in venous return by muscle pump action), would rather be confirmed.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This study was supported by Swiss National Science Foundation Grants 3200-061780 and 3200B0-114033 (to G. Ferretti) and Italian Space Agency Contract DCMC-1B133 (to C. Capelli).


   FOOTNOTES
 

Address for reprint requests and other correspondence: G. Ferretti, Département de Neurosciences Fondamentales, Centre Médical Universitaire, 1 rue Michel Servet, CH-1211 Genève 4, Switzerland (e-mail: guido.ferretti{at}medecine.unige.ch)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

  1. Anchisi S, Moia C, Ferretti G. Oxygen delivery and oxygen return in humans exercising in acute normobaric hypoxia. Pflügers Arch 442: 443–450, 2001.[CrossRef][Web of Science][Medline]
  2. Azabji Kenfack M, Lador F, Licker MJ, Moia C, Tam E, Capelli C, Morel D, Ferretti G. Cardiac output by model flow method from intra-arterial and finger tip pulse pressure profiles. Clin Sci (Lond) 106: 365–369, 2004.[Medline]
  3. Banner NR, Guz A, Heaton R, Innes JA, Murphy K, Yacoub M. Ventilatory and circulatory responses at the onset of exercise in man following heart or heart-lung transplantation. J Physiol 399: 437–449, 1989.[Web of Science]
  4. Barker RC, Hopkins SR, Kellogg N, Olfert IM, Brutsaert TD, Gavin TP, Entin PL, Rice AJ, Wagner PD. Measurement of cardiac output by open-circuit acetylene technique. J Appl Physiol 87: 1506–1512, 1999.[Abstract/Free Full Text]
  5. Barstow TJ, Molé PA. Simulation of pulmonary O2 uptake during exercise transients in humans. J Appl Physiol 63: 2253–2261, 1987.[Abstract/Free Full Text]
  6. Baum K, Essfeld D, Leyk D, Stegemann J. Blood pressure and heart rate during rest-exercise and exercise-rest transitions. Eur J Appl Physiol 64: 134–138, 1992.[CrossRef][Web of Science]
  7. Binzoni T, Ferretti G, Schenker K, Cerretelli P. Phosphocreatine hydrolysis by 31P-NMR at the onset of constant-load exercise. J Appl Physiol 73: 1644–1649, 1992.[Abstract/Free Full Text]
  8. Buchheit M, Richard R, Doutreleau S, Lonsdorfer-Wolf E, Brandenberger G, Simon C. Effect of acute hypoxia on heart rate variability at rest and during exercise. Int J Sports Med 25: 264–269, 2004.[CrossRef][Web of Science][Medline]
  9. Capelli C, Cautero M, di Prampero PE. New perspectives in breath-by-breath determination of alveolar gas exchange in humans. Pflügers Arch 441: 566–577, 2001.[CrossRef][Web of Science][Medline]
  10. Carson ER, Cobelli C, Finkelstein L. The Mathematical Modelling of Metabolic and Endocrine Systems. New York: Wiley, 1983, p. 179–216.
  11. Cautero M, Beltrami AP, di Prampero PE, Capelli C. Breath-by-breath alveolar oxygen transfer at the onset of step exercise in humans. Eur J Appl Physiol 88: 203–213, 2002.[CrossRef][Web of Science][Medline]
  12. Cummin AR, Iyawe VI, Mehta N, Saunders KB. Ventilation and cardiac output during the onset of exercise, and during voluntary hyperventilation, in humans. J Physiol 370: 567–583, 1986.[Abstract/Free Full Text]
  13. De Cort SC, Innes JA, Barstow TJ, Guz A. Cardiac output, oxygen consumption and arterio-venous oxygen difference following a sudden rise in exercise level in humans. J Physiol 441: 501–512, 1991.[Abstract/Free Full Text]
  14. Di Prampero PE, Francescato MP, Cettolo V. Energetics of muscle exercise at work onset: the steady-state approach. Pflügers Arch 445: 741–746, 2003.[Web of Science][Medline]
  15. Di Prampero PE, Margaria R. Relationship between O2 consumption, high energy phosphates, and the kinetics of the O2 debt in exercise. Pflügers Arch 304: 11–19, 1968.[CrossRef][Web of Science][Medline]
  16. Eriksen M, Waaler BA, Walloe L, Wesche J. Dynamics and dimensions of cardiac output changes in humans at the onset and the end of moderate rhythmic exercise. J Physiol 426: 423–437, 1990.[Abstract/Free Full Text]
  17. Fadel PJ, Ogoh S, Watenpaugh DE, Wasmund W, Olivencia-Yurvati A, Smith ML, Raven PB. Carotid baroreflex regulation of sympathetic nerve activity during dynamic exercise in humans. Am J Physiol Heart Circ Physiol 280: H1383–H1390, 2001.[Abstract/Free Full Text]
  18. Fagraeus L, Linnarsson D. Autonomic origin of heart rate fluctuations at the onset of muscular exercise. J Appl Physiol 40: 679–682, 1976.[Abstract/Free Full Text]
  19. Gallagher KM, Fadel PJ, Smith SA, Strømstad M, Ide K, Secher NH, Raven PB. The interaction of central command and the exercise pressor reflex in mediating baroreflex resetting during exercise in men. Exp Physiol 91: 79–87, 2006.[Abstract/Free Full Text]
  20. Grassi B, Marconi C, Meyer M, Rieu M, Cerretelli P. Gas exchange and cardiovascular kinetics with different exercise protocols in heart transplant recipients. J Appl Physiol 82: 1952–1962, 1997.[Abstract/Free Full Text]
  21. Halliwill JR, Minson CT. Effect of hypoxia on arterial baroreflex control of heart rate and muscle sympathetic nerve activity in humans. J Appl Physiol 93: 857–864, 2002.[Abstract/Free Full Text]
  22. Hanada A, Sander M, Gonzalez-Alonso J. Human skeletal muscle sympathetic nerve activity, heart rate and limb haemodynamics with reduced blood oxygenation and exercise. J Physiol 551: 635–647, 2003.[Abstract/Free Full Text]
  23. Hartley LH, Vogel JA, Landowne L. Central, femoral and brachial circulation during exercise in hypoxia. J Appl Physiol 34: 87–90, 1973.[Free Full Text]
  24. Hughson RL, Cochrane JE, Butler GC. Faster O2 uptake kinetics at onset of supine exercise with than without lower body negative pressure. J Appl Physiol 75: 1962–1967, 1993.[Abstract/Free Full Text]
  25. Hughson RL, Yamamoto Y, McCullough RE, Sutton JR, Reeves TJ. Sympathetic and parasympathetic indicators of heart rate control at altitude studied by spectral analysis. J Appl Physiol 77: 2537–2542, 1994.[Abstract/Free Full Text]
  26. Koller EA, Drechsel S, Hess T, Macherel P, Boutellier U. Effects of atropine and propranolol on the respiratory, circulatory, and ECG responses to high altitude in man. Eur J Appl Physiol 57: 163–172, 1988.[CrossRef][Web of Science]
  27. Lador F, Azabji Kenfack M, Moia C, Cautero M, Morel DR, Capelli C, Ferretti G. Simultaneous determination of the kinetics of cardiac output, systemic O2 delivery and lung O2 uptake at exercise onset in men. Am J Physiol Regul Integr Comp Physiol 290: R1071–R1079, 2006.[Abstract/Free Full Text]
  28. Lamarra N, Whipp BJ, Ward SA, Wasserman K. Effect of interbreath fluctuations on characterising exercise gas exchange kinetics. J Appl Physiol 62: 2003–2012, 1987.[Abstract/Free Full Text]
  29. Leyk D, Essfeld D, Hoffmann U, Wunderlich HG, Baum K, Stegemann J. Postural effect on cardiac output, oxygen uptake and lactate during cycle exercise of varying intensity. Eur J Appl Physiol 68: 30–35, 1994.[CrossRef][Web of Science]
  30. Lindholm P, Karlsson L, Gill H, Wigertz O, Linnarsson D. Time components of circulatory transport from the lungs to a peripheral artery in humans. Eur J Appl Physiol 97: 96–102, 2006.[CrossRef][Web of Science][Medline]
  31. Mahler M. First-order kinetics of muscle oxygen consumption, and an equivalent proportionality between QO2 and phosphorylcreatine level. Implications for the control of respiration. J Gen Physiol 86: 135–165, 1985.[Abstract/Free Full Text]
  32. McCullough WT, Collins DM, Ellsworth ML. Arteriolar responses to extracellular ATP in striated muscle. Am J Physiol Heart Circ Physiol 272: H1886–H1891, 1997.[Abstract/Free Full Text]
  33. Meyer RA. A linear model of muscle respiration explains monoexponential phosphorcreatine changes. Am J Physiol Cell Physiol 254: C548–C553, 1988.[Abstract/Free Full Text]
  34. Norton KH, Boushel R, Strange S, Saltin B, Raven PB. Resetting of the carotid arterial baroreflex during dynamic exercise in humans. J Appl Physiol 87: 332–338, 1999.[Abstract/Free Full Text]
  35. Ogoh S, Fadel PJ, Nissen P, Jans O, Selmer C, Secher NH, Raven PB. Baroreflex-mediated changes in cardiac output and vascular conductance in response to alterations in carotid sinus pressure during exercise in humans. J Physiol 550: 317–324, 2003.[Abstract/Free Full Text]
  36. Ogoh S, Fisher JP, Dawson EA, White MJ, Secher NH, Raven PB. Autonomic nervous system influence on arterial baroreflex control of heart rate during exercise in humans. J Physiol 566: 599–611, 2005.[Abstract/Free Full Text]
  37. Orizio C, Perini R, Comandé A, Castellano M, Beschi M, Veicsteinas A. Plasma catecholamines and heart rate at the beginning of muscular exercise in man. Eur J Appl Physiol 57: 644–651, 1988.[CrossRef][Web of Science]
  38. Pagani M, Lombardi F, Guzzetti S, Rimoldi O, Furlan R, Pizzinelli P, Sandrone G, Malfatto G, Dell'Orto S, Piccaluga E, Turiel M, Baselli G, Cerutti S, Malliani A. Power spectral analysis of heart rate and arterial pressure variabilities as a marker of sympatho-vagal interaction in man and conscious dog. Circ Res 59: 178–193, 1986.[Abstract/Free Full Text]
  39. Papelier Y, Escourrou P, Gauthier JP, Rowell LB. Carotid baroreflex control of blood pressure and heart rate in men during dynamic exercise. J Appl Physiol 77: 502–506, 1994.[Abstract/Free Full Text]
  40. Perini R, Orizio C, Gamba A, Veicsteinas A. Kinetics of heart rate and catecholamines during exercise in humans. The effect of heart denervation. Eur J Appl Physiol 66: 500–506, 1993.[CrossRef][Web of Science]
  41. Potts JT, Shi XR, Raven PB. Carotid baroreflex responsiveness during dynamic exercise in humans. Am J Physiol Heart Circ Physiol 265: H1928–H1938, 1993.[Abstract/Free Full Text]
  42. Raven PB, Fadel PJ, Ogoh S. Arterial baroreflex resetting during exercise: a current perspective. Exp Physiol 91: 37–49, 2006.[Abstract/Free Full Text]
  43. Rossiter HB, Ward SA, Doyle VL, Howe FA, Griffiths JR, Whipp BJ. Inferences from pulmonary O2 uptake with respect to intramuscular [phosphocreatine] kinetics during moderate exercise in humans. J Physiol 518: 921–932, 1999.[Abstract/Free Full Text]
  44. Rowell LB, Johnson DG, Chase PB, Comess KA, Seals DR. Hypoxemia raises muscle sympathetic activity but not norepinephrine in resting humans. J Appl Physiol 66: 1736–1743, 1989.[Abstract/Free Full Text]
  45. Saito M, Mano S, Iwase K, Koga K, Abe H, Yamazaki Y. Responses in muscle sympathetic activity to acute hypoxia in humans. J Appl Physiol 65: 1548–1552, 1988.[Abstract/Free Full Text]
  46. Sietsema KE, Daly JA, Wasserman K. Early dynamics of O2 uptake and heart rate as affected by exercise work rate. J Appl Physiol 67: 2535–2541, 1989.[Abstract/Free Full Text]
  47. Spaak J, Montmerle S, Sundblad P, Linnarsson D. Long-term bed rest-induced reductions in stroke volume during rest and exercise: cardiac dysfunction vs. volume depletion. J Appl Physiol 98: 648–654, 2005.[Abstract/Free Full Text]
  48. Stamler JS, Jia L, Eu JP, Mcmahon TJ, Demchenko IT, Bonaventura J, Gernert K, Piantadosi CA. Blood flow regulation by S-nitrosohemoglobin in the physiological oxygen gradient. Science 276: 2034–2037, 1997.[Abstract/Free Full Text]
  49. Stenberg J, Ekblom B, Messin R. Hemodynamic response to work at simulated altitude, 4000 m. J Appl Physiol 21: 1589–1594, 1966.[Free Full Text]
  50. Tam E, Azabji Kenfack M, Cautero M, Lador F, Antonutto G, di Prampero PE, Ferretti G, Capelli C. Correction of cardiac output obtained by Modelflow from finger pulse pressure profiles with a respiratory method in humans. Clin Sci (Lond) 106: 371–376, 2004.[Medline]
  51. Van Lieshout JJ, Toska K, Van Lieshout EJ, Eriksen M, Walloe L, Wesseling KH. Beat-to-beat non-invasive stroke volume from arterial pressure and Doppler ultrasound. Eur J Appl Physiol 90: 131–137, 2003.[CrossRef][Web of Science][Medline]
  52. Weisbrod CJ, Minson CT, Joyner MJ, Halliwill JR. Effects of regional phentolamine on hypoxic vasodilatation in healthy humans. J Physiol 537: 613–621, 2001.[Abstract/Free Full Text]
  53. Wesseling KH, Jansen JR, Settels JJ, Schreuder JJ. Computation of aortic flow from pressure in humans using a nonlinear, three-element model. J Appl Physiol 74: 2566–2573, 1993.[Abstract/Free Full Text]
  54. Whipp BJ, Ward SA. Physiological determinants of pulmonary gas exchange kinetics during exercise. Med Sci Sports Exerc 22: 62–71, 1990.[Web of Science][Medline]
  55. Whipp BJ, Wasserman K. Effect of anaerobiosis on the kinetics of O2 uptake during exercise. Fed Proc 45: 2942–2947, 1986.[Web of Science][Medline]
  56. Wilkins BW, Schrage WG, Liu Z, Hancock KC, Joyner MJ. Systemic hypoxia and vasoconstrictor responsiveness in exercising human muscle. J Appl Physiol 101: 1343–1350, 2006.[Abstract/Free Full Text]
  57. Williamson JW, Fadel PJ, Mitchell JH. New insights into central cardiovascular control during exercise. Exp Physiol 91: 51–58, 2006.[Abstract/Free Full Text]
  58. Xie A, Skatrud JB, Puleo DS, Morgan BJ. Exposure to hypoxia produces long-lasting sympathetic activation in humans. J Appl Physiol 91: 1555–1562, 2001.[Abstract/Free Full Text]
  59. Yamamoto Y, Hoshikawa Y, Miyashita M. Effects of acute exposure to simulated altitude on heart rate variability during exercise. J Appl Physiol 81: 1223–1229, 1996.[Abstract/Free Full Text]
  60. Yoshida T, Whipp BJ. Dynamic asymmetries of cardiac output transients in response to muscular exercise in man. J Physiol 480: 355–359, 1994.[Abstract/Free Full Text]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
295/2/R624    most recent
00797.2007v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lador, F.
Right arrow Articles by Ferretti, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lador, F.
Right arrow Articles by Ferretti, G.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2008 by the American Physiological Society.