Journal of Applied Physiology Fuel your research with LabChart
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

J Appl Physiol 91: 891-896, 2001;
8750-7587/01 $5.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
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 ISI 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 HighWire
Right arrow Citing Articles via ISI Web of Science (33)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kindig, C. A.
Right arrow Articles by Poole, D. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kindig, C. A.
Right arrow Articles by Poole, D. C.
Vol. 91, Issue 2, 891-896, August 2001

Effect of L-NAME on oxygen uptake kinetics during heavy-intensity exercise in the horse

Casey A. Kindig, Paul McDonough, Howard H. Erickson, and David C. Poole

Departments of Anatomy and Physiology and Kinesiology, Kansas State University, Manhattan, Kansas 66506-5602


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

There is evidence that oxidative enzyme inertia plays a major role in limiting/setting the O2 uptake (VO2) response at the transition to higher metabolic rates and also that nitric oxide (NO) competitively inhibits VO2 within the electron transport chain. To investigate whether NO is important in setting the dynamic response of VO2 at the onset of high-intensity (heavy-domain) running in horses, five geldings were run on a treadmill across speed transitions from 3 m/s to speeds corresponding to 80% of peak VO2 with and without nitro-L-arginine methyl ester (L-NAME), an NO synthase inhibitor (20 mg/kg; order randomized). L-NAME did not alter (both P > 0.05) baseline (3 m/s, 15.4 ± 0.3 and 16.2 ± 0.5 l/min for control and L-NAME, respectively) or end-exercise VO2 (56.9 ± 5.1 and 55.2 ± 5.8 l/min for control and L-NAME, respectively). However, in the L-NAME trial, the primary on-kinetic response was significantly (P < 0.05) faster (i.e., reduced time constant, 27.0 ± 2.7 and 18.7 ± 3.0 s for control and L-NAME, respectively), despite no change in the gain of VO2 (P > 0.05). The faster on-kinetic response was confirmed independent of modeling by reduced time to 50, 63, and 75% of overall VO2 response (all P < 0.05). In addition, onset of the VO2 slow component occurred earlier (124.6 ± 11.2 and 65.0 ± 6.6 s for control and L-NAME, respectively), and the magnitude of the O2 deficit was attenuated (both P < 0.05) in the L-NAME compared with the control trial. Acceleration of the VO2 kinetics by L-NAME suggests that NO inhibition of mitochondrial VO2 may contribute, in part, to the intrinsic metabolic inertia evidenced at the transition to higher metabolic rates in the horse.

nitric oxide; nitric oxide synthase inhibition; oxygen uptake slow component; oxygen deficit; nitro-L-arginine methyl ester


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

THE ABILITY OF THE EQUINE athlete to adjust rapidly to increased metabolic stress is extraordinary. Specifically, although mass-specific maximal O2 uptakes (VO2) two- to threefold greater than those found in elite human athletes are achieved, VO2 kinetics are substantially faster in horses (26) than in their human counterparts (2, 44). The capacity of the horse to generate prodigious cardiac outputs >300 l/min as well as to attain maximal levels of VO2 nearing 200 ml · kg-1 · min-1 places a heavy burden on the equine cardiovascular system to match adequately O2 delivery to metabolic demand, and thus the horse offers an exciting and relevant model in which to study the VO2 kinetic response to exercise.

Two mechanisms are thought to limit VO2 on-kinetics: 1) the rapidity with which the mitochondria adjust oxidative ATP supply to demand (oxidative enzyme inertia hypothesis) (7, 13, 14, 19, 43) or, alternatively, 2) the rate of O2 delivery to working muscle (O2 delivery hypothesis) (12, 15, 28; for review see Ref. 42). Although O2 delivery is generally not considered to be a limiting factor in response to aerobic work performed below the lactate threshold (i.e., limiting factors reside primarily within the inertia of the oxidative enzymes), there is clear evidence that perturbations expected to alter O2 delivery during the transition to heavy-domain exercise may result in similarly altered VO2 on-kinetic responses (12, 15, 28).

Nitric oxide (NO), synthesized from L-arginine and O2 in a reaction catalyzed by NO synthase (NOS), has been implicated in a myriad of biological functions (6, 10, 21, 38); however, its ability to reduce vascular smooth muscle tone has been most widely documented (for review see Ref. 21). Although not unequivocal (35, 40), NOS inhibition by L-arginine analogs has been shown to reduce skeletal muscle blood flow in response to exercise in humans (9), rats (18), and dogs (38). Thus, if nitro-L-arginine methyl ester (L-NAME) reduces O2 delivery significantly at the trot-to-gallop transition, the rapid VO2 on-kinetic profile characteristic of the horse may be slowed.

In contrast to the role of NO in facilitating O2 transport to skeletal muscle, recent studies have demonstrated that NO may regulate mitochondrial function through competitive inhibition of VO2 in the electron transport chain, specifically at cytochrome c oxidase (6, 37). Thus NO may serve as part of a feedback mechanism to reduce the reliance on O2 extraction to meet tissue O2 needs, and this would serve to maintain higher intramyocyte PO2 levels during exercise (38). Indeed, concomitant with a reduced cardiac output, NOS blockade resulted in an elevated fractional O2 extraction at peak exercise compared with control conditions in the horse (23). In this scenario, NOS blockade acted to reduce whole body O2 delivery while simultaneously relieving the NO inhibition of mitochondrial function. Both of these mechanisms will have contributed to the increased fractional O2 extraction observed. From the evidence presented above, it is feasible that NO inhibition of mitochondrial VO2 may contribute to an intrinsic oxidative enzyme inertia at exercise onset.

The purpose of the present investigation was to determine the VO2 kinetic profile in the horse during heavy exercise under control and NOS inhibition (by L-NAME) conditions. We hypothesized that if inhibition of mitochondrial function by NO across the on-transient plays a deterministic role in setting the VO2 on-kinetic response, alleviation of this inhibition by L-NAME will speed VO2 on-kinetics. Alternatively, L-NAME may reduce muscle blood flow to such a degree that VO2 on-kinetics are slowed because of the decreased O2 delivery. In this instance, any improvement in mitochondrial function would be masked.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Five geldings (4 Thoroughbreds and 1 quarter horse, 547 ± 21 kg, 10 ± 2 yr) acclimatized to running on a treadmill (conditioned twice weekly) were housed in a dry lot (loafing shed with paddock) and given unrestricted access to water and fed twice daily. Food was withheld >= 4 h before each experimental session. All procedures were approved by the Kansas State University Institutional Animal Care and Use Committee. Initially, peak VO2 (VO2 peak) was assessed 2 wk before this investigation [VO2 and CO2 output (VCO2), obtained by open-flow system as described below]. The protocol consisted of an 800-m trot at 3 m/s followed by a 1 m/s per 1-min interval incremental ramp (starting at 7 m/s) performed on a level equine treadmill (SATO, Uppsala, Sweden) to volitional fatigue.

Experimental Protocol

Each horse performed one control and one L-NAME exercise trial (order randomized; 2 wk between runs). Before both runs, the temperature of the equine laboratory was lowered to ~11°C (relative humidity ~55%), and two overhead fans were used to counteract the horse's inability to thermoregulate after NOS inhibition (30). After each horse was led onto the treadmill, L-NAME (20 mg/kg in 180 ml of sterile saline) or sterile saline (180 ml) was infused intravenously over a 4-min period. At 3 min after L-NAME (or saline) infusion, the exercise protocol was initiated. The protocol, which began and ended with an 800-m trot at 3 m/s, consisted of two constant-speed (i.e., increase to the required speed in <10 s) exercise bouts separated by a 4-min recovery trot at 3 m/s. These exercise bouts consisted of an initial 4-min run at 8-10 m/s (warm-up at ~50% VO2 peak) followed by a 6-min run at the speed corresponding to 80% of control VO2 peak (experimental run).

Respiratory Gas Measurement

Measurements of VO2 and VCO2 (STPD corrected) were obtained as described previously (26) using an open-flow system. Briefly, a loose-fitting mask was placed over the horse's muzzle while industrial fans drew air past the mask at a flow rate >7,500 l/min, such that no end-expired air escaped. Flow through the system was calculated by measurement of pressure differences (differential pressure transducer, model CD1-3-871, Validyne, Northridge, CA) across a flow nozzle (standard 2 in ASME). Concentrations of O2 and CO2 (mass spectrometer, model 1100, Perkin-Elmer, Pomona, CA) as well as temperature and relative humidity (model HS-ZCHDT-2R, Thunder Scientific, Albuquerque, NM) were measured distal to the flow nozzle and recorded (100-Hz sample rate) by means of a computer-based data acquisition system (DATAQ, Akron, OH).

Kinetic Modeling/Analysis

The open-flow system utilized does not permit measurement of tidal volumes or assessment of changes in lung gas stores; however, evidence to date (17) suggests that functional residual capacity is not altered in ponies from rest to exercise. Values for VO2 were smoothed using a 4-s rolling average. Data were then analyzed by means of Kaliedagraph data analysis software (Synergy Software, Reading, PA), using a one- and two-exponential model of the following forms
<A><AC>V</AC><AC>˙</AC></A><SC>o</SC><SUB>2</SUB>(<IT>t</IT>)<IT>=</IT><A><AC>V</AC><AC>˙</AC></A><SC>o</SC><SUB>2</SUB>(b)<IT>+</IT>A<SUB>1</SUB><IT>·</IT>[1<IT>−e</IT><SUP><IT>−</IT>(<IT>t−</IT>TD<SUB>1</SUB>)<IT>/&tgr;</IT><SUB>1</SUB></SUP>]
and
<A><AC>V</AC><AC>˙</AC></A><SC>o</SC><SUB>2</SUB>(<IT>t</IT>)<IT>=</IT><A><AC>V</AC><AC>˙</AC></A><SC>o</SC><SUB>2</SUB>(b)<IT>+</IT>A<SUB>1</SUB><IT>·</IT>[1<IT>−e</IT><SUP><IT>−</IT>(<IT>t−</IT>TD<SUB>1</SUB>)<IT>/&tgr;</IT><SUB>1</SUB></SUP>]<IT>+</IT>A<SUB>2</SUB><IT>·</IT>[1<IT>−e</IT><SUP>−(<IT>t−</IT>TD<SUB>2</SUB>)<IT>/&tgr;</IT><SUB>2</SUB></SUP>]
where t is time, b is baseline (trotting at 3 m/s), A1 and A2 are the response amplitudes, TD1 and TD2 are the independent time delays, and tau 1 and tau 2 are the time constants. In all cases, a significantly improved fit to the data was found for the two-component model. In addition, time to 50, 63, 75, and 95% of the overall amplitude was determined independent of modeling procedures.

O2 deficit was calculated in two ways. First, it was calculated in the traditional manner as the area above the VO2 curve and below a horizontal line drawn from the end-exercise asymptotic value. The second method was derived from that presented by Bearden and Moffatt (5) and calculated O2 deficit in the traditional manner less the area represented by (A2 * TD2).

Statistical Analysis

Values are means ± SE. Differences between the L-NAME and control trials were tested by Student's paired t-test. Statistical significance was accepted at P<= 0.05.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

VO2 peak (initial incremental protocol) averaged 62.2 ± 5.0 l/min. The speed that corresponded to 80% VO2 peak was 11.9 ± 0.5 m/s and yielded end-exercise (control) VO2 values of 55.9 ± 5.1 l/min (89.5 ± 3.3% VO2 peak measured on the initial incremental protocol).

The VO2 on-kinetic parameters for the control and L-NAME runs are shown in Table 1 and represented graphically in Fig. 1. The mean response for all five horses (2-s average) is shown in Fig. 1, top. Figure 1, bottom, depicts a common logarithmic plot of the VO2 difference at time t (4-s average) from its asymptotic (or end-exercise) value. Although L-NAME did not affect VO2 during the warm-up at 3 m/s or at end exercise, the primary on-kinetic response was significantly faster (i.e., reduced tau 1; P < 0.05), with no change in the amplitude of the response (A1). The reduced tau 1 was confirmed, independent of time delay and monoexponential curve modeling, by a significant reduction (P < 0.05) in time to 50, 63, and 75% of the overall VO2 amplitude (however, time to 95% was not statistically different; Fig. 2). The onset of the slow component (i.e., TD2) occurred significantly sooner (P < 0.05) in the L-NAME than in the control trial. Furthermore, L-NAME significantly (P < 0.05) attenuated the magnitude of the O2 deficit irrespective of the model used (see METHODS) for its calculation (Fig. 3). In Fig. 1 (bottom) the L-NAME-induced reduction in O2 deficit is represented by the area between the control and L-NAME points [i.e., (control - L-NAME) as a function of time].

                              
View this table:
[in this window]
[in a new window]
  		Table 1.   VO2 response and related kinetic parameters



View larger version (22K):
[in this window]
[in a new window]
  		Fig. 1.   Top: mean response (2-s mean; SE bars omitted for clarity) for all 5 horses. Solid lines fit the mean primary on-kinetic parameters as presented in Table 1. Bottom: common logarithmic plot of O2 uptake (VO2) difference at time t (4-s average) from its asymptotic value (44). ss, Steady state. Solid lines are consistent with those at top and thus demonstrate the significant acceleration of the primary fast on-kinetic response in the nitro-L-arginine methyl ester (L-NAME) compared with the control trial.



View larger version (26K):
[in this window]
[in a new window]
  		Fig. 2.   Time from baseline VO2 (at 3 m/s) to 50, 63, 75, and 95% of the overall VO2 amplitude as determined independent of modeling procedures. Time to 50% (T50), 63% (T63), and 75% (T75) was significantly reduced (*P < 0.05) for L-NAME compared with control, confirming the findings of the 2-component model (i.e., reduced tau 1). There was no significant difference (NS) in time to 95% (T95).



View larger version (30K):
[in this window]
[in a new window]
  		Fig. 3.   O2 deficit was significantly less (*P < 0.05) in the L-NAME than in the control run whether calculated in the traditional manner as the area above the curve and below the end-exercise asymptotic value or by a second method (5), which calculates O2 deficit in the traditional manner less the area represented by (A2 * TD2, where A2 is slow component response amplitude and TD2 is time delay for the slow component).

The effect of L-NAME on the VCO2 on-kinetic response was qualitatively similar to the effect of L-NAME on the VO2 response (Table 2). Specifically, there were no differences in baseline or end-exercise VCO2 or the primary (i.e., A1) and slow component (i.e., A2) amplitudes in response to L-NAME.

                              
View this table:
[in this window]
[in a new window]
  		Table 2.   VCO2 response and related kinetic parameters

Although the onset of the VCO2 slow component occurred sooner (P < 0.05) with L-NAME in three horses, two of the five horses treated with L-NAME did not exhibit a VCO2 slow component response (Table 2). In addition, although VCO2 on-kinetics tended to be faster in the L-NAME than in the control trial (tau 1 = 35.3 ± 8.8 and 24.6 ± 5.3 s for control and L-NAME, respectively), the response was not significantly different.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

This investigation is the first to quantify VO2 on-kinetics during L-NAME-induced NOS inhibition in the exercising horse. The data suggest an important role for NO in the regulation of the equine VO2 on-kinetic response during exercise in the heavy domain. Specifically, as a result of L-NAME treatment, VO2 on-kinetics were significantly faster (i.e., reduced tau 1) and the onset of the slow component occurred significantly earlier (i.e., shorter TD2). These data suggest that NO inhibition of VO2 may be a deterministic factor contributing to the intrinsic metabolic inertia evidenced at the dynamic transition to higher metabolic rates in the horse.

Mechanism for Altered VO2 Kinetic Profile

O2 delivery. It is generally accepted (although not unequivocally so) that NO plays a modest role in skeletal muscle exercise hyperemia (21). Thus, although some investigators have reported that NOS inhibition does not reduce blood flow in exercising human muscle (35, 40), other studies in humans (9) and also in rats (18) and dogs (38) demonstrated significant reductions in the exercise hyperemic response when subjects/ animals were challenged with NOS inhibition. In the present investigation, skeletal muscle blood flow was not measured. However, L-NAME does significantly reduce cardiac output (274 ± 23 and 242 ± 20 l/min for control and L-NAME, respectively, P < 0.05) (23) and concomitantly increases fractional O2 extraction during heavy-domain exercise in the horse, suggesting that skeletal muscle blood flow may be reduced by L-NAME.

At the onset of exercise or increased work rates in humans, there is strong evidence that increases in muscle blood flow precede increases in VO2 (45) and that muscle O2 fractional extraction falls, such that venous effluent O2 content rises [albeit transiently (10-15 s)] (16). During work consistent with moderate-intensity exercise in the dog gastrocnemius muscle, neither elevated O2 delivery (13) nor a rightward-shifted O2 dissociation curve (designed to enhance hemoglobin O2 off-loading) (14) speeds VO2 kinetics. However, in a recent investigation, Grassi and colleagues (15) determined that increasing blood flow to the isolated canine gastrocnemius muscle before electrically stimulated contractions at near-maximal values resulted in faster muscle VO2 on-kinetics. This study, in combination with the work of others (12, 25), suggests that if O2 delivery was reduced by L-NAME, then a resultant slowing of VO2 dynamics may occur during heavy-domain exercise. However, if this effect was present, it must have been overcome by the inhibition of oxidative enzyme function (inertia), and the result was a net acceleration of the VO2 on-kinetic response (see below).

Oxidative enzyme inertia. Many experiments have supported the notion that the site of control of VO2 kinetics is located within the muscle (7, 13, 14, 19, 43), and this has been corroborated recently using a frog myocyte preparation (19). Specifically, Hogan (19) demonstrated that intramyocyte PO2 did not fall immediately at the onset of contractions. Rather, there was a delay of ~13 s followed by a monoexponential decline to the steady state, suggesting that a delay in VO2 at the mitochondrial level is responsible, in part, for the delayed VO2 kinetics. Given that there is strong evidence implicating intramuscular factors in the control (or limitation) of VO2 kinetics, numerous mechanisms could achieve this control. Potential mechanisms include phosphorylation state, redox potential, pyruvate dehydrogenase (PDH) activation, mitochondrial Ca2+ transients, and mitochondrial PO2. Although there is some suggestive evidence that dichloroacetate activation of PDH may speed VO2 kinetics at exercise onset in humans (20, 41), rigorous dissection of the relative importance of each of the potential controllers listed previously must await future investigation.

Notwithstanding the factors described above, the L-NAME condition did elevate core blood temperature ~0.6 ± 0.1°C above that found in the control condition (23). Elevated temperature can speed the rate of chemical reactions. However, there is solid evidence that hyperthermia does not increase the speed of VO2 kinetics in humans performing exercise that is moderate (25) or severe (32) in intensity.

There are at least three possible mechanisms by which NOS inhibition may reduce the intrinsic metabolic inertia at the on-transient to higher metabolic rates. First, it has been reported that NO inhibits creatine kinase (22). Thus the removal of this inhibition may speed phosphocreatine hydrolysis and ATP turnover and, in turn, increase VO2 more rapidly. Second, Howlett et al. (20) demonstrated an increased contribution of oxidative phosphorylation to ATP demand at exercise onset by means of PDH activation by dichloroacetate. Given that NO-mediated damage of PDH has been described in heart mitochondria during postischemia reperfusion (1), the possibility exists that NO may inhibit PDH activation at exercise onset. Finally, as described in the introduction, it is well documented that NO inhibits VO2 by competitive inhibition of cytochrome c oxidase in the electron transport chain (6, 37, 38). Removal of this inhibition may serve to accelerate mitochondrial O2 flux and thus speed the VO2 on-kinetic response.

Alleviation of NO Inhibition on Net VO2

In the present investigation, whole body O2 cost did not differ between L-NAME and control trials (Table 1, Fig. 1). This finding is in agreement with other studies in which NOS inhibition did not alter whole body VO2 in exercising horses (31) and humans (35) and dogs at rest (8). However, some investigations have reported an elevated VO2 in canine skeletal muscle at rest (24) and during exercise (38) after NOS inhibition. In the former study, whole body VO2 remained unchanged (24). If alterations in net muscle VO2 occurred in this investigation, this would have been manifested in the pulmonary VO2 values, given that, during near-maximal exercise, skeletal muscle receives the bulk of cardiac output (29). Furthermore, unless NO reduces mechanical or oxidative enzyme efficiency, increases muscle fiber recruitment, and/or decreases anaerobic contributions to aerobic steady-state exercise (which are thought to be minimal at best), no readily available explanation exists for an increased steady-state VO2 under L-NAME conditions.

Mechanisms for Early Onset of VO2 Slow Component With L-NAME

It is not known what precise mechanism(s) results in the "excess" O2 cost or VO2 slow component associated with sustained work performed above the lactate threshold, although the origin appears to be primarily within the working muscle (11, 34). In contrast to the magnitude of the slow component, relatively little attention has been afforded to the temporal displacement of the slow component (i.e., TD2) from the on-transition to higher metabolic rates (4, 27, 33).

To our knowledge, there is no evidence to suggest that the muscle mass recruited to perform a given workload is altered by NOS inhibition. Nevertheless, the likelihood does exist that a population of muscle fibers may fatigue more rapidly if their O2 delivery is reduced. Neither the primary (A1) nor the slow component (A2) VO2 amplitudes were significantly different between conditions. This suggests that L-NAME does not cause substantial changes in muscle recruitment. Moreover, if less-economical type IIb fibers were recruited earlier during the L-NAME condition, a reduction in A1 and an increase in A2 with no change in the time of onset (i.e., TD2) of the VO2 slow component might be expected (3). Furthermore, recent analysis of electromyogram frequency and integrated electromyogram in concert with VO2 determination during heavy-domain cycle ergometry demonstrated no correlation between the slow component and altered muscle recruitment patterns (36), in contrast to previous work (39).

As discussed above, evidence presented previously (9, 18, 23, 38) suggests that muscle blood flow was likely to be reduced during exercise in the L-NAME condition; however, this variable was not measured in the present investigation. Also it is not known to what degree the matching of O2 delivery to VO2 requirement may have been altered. In this regard, there was a trend toward elevated venous plasma lactate with L-NAME, but this was not statistically different between trials (11.7 ± 4.1 and 13.7 ± 3.4 mM for control and L-NAME, respectively) (23). Irrespective of the precise mechanism responsible, we believe that the present investigation is the first to demonstrate an experimental condition that results in an acceleration of the onset of the VO2 slow component and suggests that some component of NO control of mitochondrial function may be deterministic in setting the onset of the slow component.

To our knowledge, this is the first investigation to quantify the VO2 on-kinetic response in the exercising horse under control and NOS-inhibited (by L-NAME) conditions. Although L-NAME did not affect the primary component or slow component amplitude, the primary VO2 response increased at a greater rate and the VO2 slow component onset occurred earlier in horses performing exercise in the heavy domain. Regardless of the effect of L-NAME on muscle blood flow, these data suggest that NO may be responsible, in part, for the initial intrinsic metabolic inertia seen at exercise onset and that this effect may be mediated by inhibition of mitochondrial VO2.


    ACKNOWLEDGEMENTS

The authors thank Mark Brentano and Holly Brown for help with data acquisition.


    FOOTNOTES

This investigation was supported in part by grants from the American Quarter Horse Association and the Kansas Racing Commission and National Heart, Lung, and Blood Institute Grant HL-50306.

Address for reprint requests and other correspondence: D. C. Poole, Kansas State University, 1600 Denison Ave., Veterinary Medical Sciences, Rm. 228, Manhattan, KS 66506-5602 (E-mail: Poole{at}vet.ksu.edu).

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.

Received 8 December 2000; accepted in final form 15 March 2001.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

1.   Abe, K, Hayashi N, and Terada H. Effect of endogenous nitric oxide on energy metabolism of rat heart mitochondria during ischemia and reperfusion. Free Radic Biol Med 26: 379-387, 2000.

2.   Barstow, TJ, Buchtal S, Zanconato S, and Cooper DM. Muscle energetics and pulmonary oxygen kinetics during moderate exercise. J Appl Physiol 77: 1742-1749, 1994[Abstract/Free Full Text].

3.   Barstow, TJ, Jones AM, Nguyen PH, and Casaburi R. Influence of muscle fiber type and pedal frequency on oxygen uptake kinetics of heavy exercise. J Appl Physiol 81: 1642-1650, 1996[Abstract/Free Full Text].

4.   Barstow, TJ, and Mole PA. Linear and nonlinear characteristics of oxygen uptake kinetics during heavy exercise. J Appl Physiol 71: 2099-2106, 1991[Abstract/Free Full Text].

5.   Bearden, SE, and Moffatt RJ. VO2 kinetics and O2 deficit in heavy exercise. J Appl Physiol 88: 1407-1412, 2000[Abstract/Free Full Text].

6.   Brown, GC. Nitric oxide as a competitive inhibitor of oxygen consumption in the mitochondrial respiratory chain. Acta Physiol Scand 168: 667-674, 2000[ISI][Medline].

7.   Ceretelli, P, Rennie DW, and Pendergrast DR. Kinetics of metabolic transients during exercise. In: Exercise Bioenergetics and Gas Exchange. Amsterdam: Elsevier, 1980, p. 187-209.

8.   Crystal, GJ, Zhou X, Halim AA, Alam S, El-Orbany M, and Salem MR. Nitric oxide does not modulate whole body oxygen consumption in anesthetized dogs. J Appl Physiol 86: 1944-1999, 1999[Abstract/Free Full Text].

9.   Dyke, CK, Proctor DN, Dietz NM, and Joyner MJ. Role of nitric oxide in exercise hyperaemia during prolonged rhythmic handgripping in humans. J Physiol (Lond) 488: 259-265, 1995[ISI][Medline].

10.   Furchgott, RF, and Zawadski JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288: 373-376, 1980[Medline].

11.   Gaesser, GA, and Poole DC. The slow component of oxygen uptake kinetics in humans. In: Exercise and Sport Science Reviews. Baltimore, MD: Williams & Wilkins, 1996, p. 35-70.

12.   Gerbino, A, Ward SA, and Whipp BJ. Effects of prior exercise on pulmonary gas-exchange kinetics during high-intensity exercise in humans. J Appl Physiol 80: 99-107, 1996[Abstract/Free Full Text].

13.   Grassi, B, Gladden LB, Samaja M, Stary CM, and Hogan MC. Faster adjustment of O2 delivery does not affect VO2 on-kinetics in isolated in situ canine muscle. J Appl Physiol 85: 1394-1403, 1998[Abstract/Free Full Text].

14.   Grassi, B, Gladden LB, Stary CM, Wagner PD, and Hogan MC. Peripheral O2 diffusion does not affect O2 on-kinetics in isolated in situ canine muscle. J Appl Physiol 85: 1404-1412, 1998[Abstract/Free Full Text].

15.   Grassi, B, Hogan MC, Kelley KM, Aschenbach WG, Hamann JJ, Evans RK, Patillo RE, and Gladden LB. Role of convective O2 delivery in determining VO2 on-kinetics in canine muscle contracting at peak VO2. J Appl Physiol 89: 1293-1301, 2000[Abstract/Free Full Text].

16.   Grassi, B, Poole DC, Richardson RS, Knight DR, Erickson BK, and Wagner PD. Muscle O2 uptake kinetics in humans: implications for metabolic control. J Appl Physiol 80: 988-998, 1996[Abstract/Free Full Text].

17.   Gutting, SM, Forster HV, Lowry TF, Brice AG, and Pan LG. Respiratory muscle recruitment in awake ponies during exercise and CO2 inhalation. Respir Physiol 86: 315-332, 1991[ISI][Medline].

18.   Hirai, T, Visnski MD, Kearns KJ, Zelis R, and Musch TI. Effects of NO synthase inhibition on the muscular blood flow response to treadmill exercise in rats. J Appl Physiol 77: 1288-1293, 1994[Abstract/Free Full Text].

19.   Hogan, MC. Fall in intracellular PO2 at the onset of contractions in Xenopus single skeletal muscle fibers. J Appl Physiol 90: 1871-1876, 2001[Abstract/Free Full Text].

20.   Howlett, RA, Heigenhauser GJF, Hultman E, Hollidge-Horvat MG, and Spriet LL. Effects of dichloroacetate infusion on human skeletal muscle metabolism at the onset of exercise. Am J Physiol Endocrinol Metab 277: E18-E25, 1999[Abstract/Free Full Text].

21.   Joyner, MJ, and Dietz NM. Nitric oxide and vasodilation in human limbs. J Appl Physiol 83: 1785-1796, 1997[Abstract/Free Full Text].

22.   Kaasik, A, Minajeva A, DeSousa E, Ventura-Clapier R, and Veksler V. Nitric oxide inhibits cardiac energy production via inhibition of mitochondrial creatine kinase. FEBS Lett 444: 75-77, 1999[ISI][Medline].

23.   Kindig, CA, Gallatin LL, Erickson HH, Fedde MR, and Poole DC. Cardiorespiratory impact of the nitric oxide synthase inhibitor L-NAME in the exercising horse. Respir Physiol 120: 151-166, 2000[ISI][Medline].

24.   King, CE, Melinyshyn MJ, Mewburn JD, Curtis SE, Winn MJ, Cain SM, and Chapler CK. Canine hindlimb blood flow and O2 uptake after inhibition of EDRF/NO synthesis. J Appl Physiol 76: 1166-1171, 1994[Abstract/Free Full Text].

25.   Koga, S, Shiojiri T, Kondo N, and Barstow TJ. Effects of increased muscle temperature on oxygen uptake kinetics during exercise. J Appl Physiol 83: 1333-1338, 1997[Abstract/Free Full Text].

26.   Langsetmo, I, Weigle GE, Fedde MR, Erickson HH, Barstow TJ, and Poole DC. VO2 kinetics in the horse during moderate and heavy exercise. J Appl Physiol 83: 1235-1241, 1997[Abstract/Free Full Text].

27.   Linnarsson, D. Dynamics of pulmonary gas exchange and heart rate changes at start and end of exercise. Acta Physiol Scand Suppl 415: 1-68, 1974.

28.   MacDonald, M, Pedersen PK, and Hughson RL. Acceleration of VO2 kinetics in heavy submaximal exercise by hyperoxia and prior high-intensity exercise. J Appl Physiol 83: 1318-1325, 1997[Abstract/Free Full Text].

29.   Manohar, M. Blood flow to the respiratory and limb muscles and to abdominal organs during maximal exertion in ponies. J Physiol (Lond) 377: 25-35, 1986[Abstract/Free Full Text].

30.   Mills, PC, Marlin DJ, Scott CM, and Smith NC. Nitric oxide and thermoregulation during exercise in the horse. J Appl Physiol 82: 1035-1039, 1997[Abstract/Free Full Text].

31.   Mills, PC, Marlin DJ, Scott CM, and Smith NC. Metabolic effects of nitric oxide synthase inhibition during exercise in the horse. Res Vet Sci 66: 135-138, 1999[ISI][Medline].

32.   Nybo, L, Jensen T, Nielsen B, and Gonzalez-Alonso J. Marked hyperthermia with and without dehydration does not alter VO2 on-kinetics despite reducing maximal oxygen uptake. J Appl Physiol 90: 1057-1064, 2001[Abstract/Free Full Text].

33.   Paterson, DH, and Whipp BJ. Asymmetries of oxygen uptake transients at the on- and offset of heavy exercise in humans. J Physiol (Lond) 443: 575-583, 1991[Abstract/Free Full Text].

34.   Poole, DC, Schaffartzik W, Knight DR, Derion T, Kennedy B, Guy HJ, Prediletto R, and Wagner PD. Contribution of exercising legs to the slow component of oxygen uptake kinetics in humans. J Appl Physiol 71: 1245-1253, 1991[Abstract/Free Full Text].

35.   Radegran, G, and Saltin B. Nitric oxide in the regulation of vasomotor tone in human skeletal muscle. Am J Physiol Heart Circ Physiol 276: H1951-H1960, 1999[Abstract/Free Full Text].

36.   Scheuermann, BW, Hoelting BD, Noble ML, and Barstow TJ. The slow component of O2 uptake is not accompanied by changes in muscle EMG during repeated bouts of heavy exercise. J Physiol (Lond) 531: 245-256, 2001[Abstract/Free Full Text].

37.   Shen, W, Xu X, Ochoa M, Zhao G, Wolin MS, and Hintze TH. Role of nitric oxide in the regulation of oxygen consumption in conscious dogs. Circ Res 75: 1086-1095, 1994[Abstract/Free Full Text].

38.   Shen, W, Xu X, Ochoa M, Zhao G, Bernstein RD, Forfia P, and Hintze TH. Endogenous nitric oxide in the control of skeletal muscle oxygen extraction during exercise. Acta Physiol Scand 168: 675-686, 2000[ISI][Medline].

39.   Shinohara, M, and Moritani T. Increase in neuromuscular activity and oxygen uptake during heavy exercise. Ann Physiol Anthrop 11: 257-262, 1992[Medline].

40.   Shoemaker, JK, Halliwill JR, Hughson RL, and Joyner MJ. Contributions of acetylcholine and nitric oxide to forearm blood flow at exercise onset and recovery. Am J Physiol Heart Circ Physiol 273: H2388-H2395, 1997[Abstract/Free Full Text].

41.   Timmons, JA, Gustafsson T, Sundberg CJ, Jansson E, and Greenhaff PL. Muscle acetyl group availability is a major determinant of oxygen deficit in humans during submaximal exercise. Am J Physiol Endocrinol Metab 274: E377-E380, 1998[Abstract/Free Full Text].

42.   Tschakovsky, ME, and Hughson RL. Interaction of factors determining oxygen uptake at the onset of exercise. J Appl Physiol 86: 1101-1113, 1999[Abstract/Free Full Text].

43.   Whipp, BJ, and Mahler M. Dynamics of pulmonary gas exchange during exercise. In: Pulmonary Gas Exchange. New York: Academic, 1980, p. 33-96.

44.   Whipp, BJ, and Wasserman K. Oxygen uptake kinetics for various intensities of constant-load work. J Appl Physiol 33: 351-356, 1972[Free Full Text].

45.   Yoshida, T, and Whipp BJ. Dynamic asymmetries of cardiac output transients in response to muscular exercise in man. J Physiol (Lond) 480: 355-359, 1994[ISI][Medline].

J APPL PHYSIOL 91(2):891-896
8750-7587/01 $5.00 Copyright © 2001 the American Physiological Society


This article has been cited by other articles:


Home page
 J. Physiol.Home page
P. McDonough, A. M. Jones, and D. C. Poole
Nitric oxide and muscle VO2 kinetics
J. Physiol., June 1, 2006; 573(2): 565 - 566.
[Full Text] [PDF]

Home page
 J. Physiol.Home page
B. Grassi, M. C. Hogan, and L. B. Gladden
Reply from Bruno Grassi, Michael C. Hogan and L. Bruce Gladden
J. Physiol., June 1, 2006; 573(2): 567 - 568.
[Full Text] [PDF]

Home page
 J. Physiol.Home page
B. Grassi, M. C Hogan, K. M Kelley, R. A Howlett, and L. B. Gladden
Effects of nitric oxide synthase inhibition by L-NAME on oxygen uptake kinetics in isolated canine muscle in situ
J. Physiol., November 1, 2005; 568(3): 1021 - 1033.
[Abstract] [Full Text] [PDF]

Home page
 Exp PhysiolHome page
D. J Krause, J. L Hagen, C. A Kindig, and R. T Hepple
Nitric oxide synthase inhibition reduces the O2 cost of force development in rat hindlimb muscles pump perfused at matched convective O2 delivery
Exp Physiol, November 1, 2005; 90(6): 889 - 900.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
D. P Wilkerson, J. Rittweger, N. J. A Berger, P. F Naish, and A. M Jones
Influence of recombinant human erythropoietin treatment on pulmonary O2 uptake kinetics during exercise in humans
J. Physiol., October 15, 2005; 568(2): 639 - 652.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
C. A. Kindig, C. M. Stary, and M. C. Hogan
Effect of dissociating cytosolic calcium and metabolic rate on intracellular PO2 kinetics in single frog myocytes
J. Physiol., January 15, 2005; 562(2): 527 - 534.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
D. P Wilkerson, I. T Campbell, and A. M Jones
Influence of nitric oxide synthase inhibition on pulmonary O2 uptake kinetics during supra-maximal exercise in humans
J. Physiol., December 1, 2004; 561(2): 623 - 635.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
A. M Jones, D. P Wilkerson, and I. T Campbell
Nitric oxide synthase inhibition with L-NAME reduces maximal oxygen uptake but not gas exchange threshold during incremental cycle exercise in man
J. Physiol., October 1, 2004; 560(1): 329 - 338.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
L. J. Haseler, C. A. Kindig, R. S. Richardson, and M. C. Hogan
The role of oxygen in determining phosphocreatine onset kinetics in exercising humans
J. Physiol., August 1, 2004; 558(3): 985 - 992.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
A. M. Jones, D. P. Wilkerson, S. Wilmshurst, and I. T. Campbell
Influence of L-NAME on pulmonary O2 uptake kinetics during heavy-intensity cycle exercise
J Appl Physiol, March 1, 2004; 96(3): 1033 - 1038.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
B. Grassi, S. Pogliaghi, S. Rampichini, V. Quaresima, M. Ferrari, C. Marconi, and P. Cerretelli
Muscle oxygenation and pulmonary gas exchange kinetics during cycling exercise on-transitions in humans
J Appl Physiol, July 1, 2003; 95(1): 149 - 158.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
R. A. Howlett and M. C. Hogan
Dichloroacetate accelerates the fall in intracellular PO2 at onset of contractions in Xenopus single muscle fibers
Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2003; 284(2): R481 - R485.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
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 ISI 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 HighWire
Right arrow Citing Articles via ISI Web of Science (33)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kindig, C. A.
Right arrow