Our concern in these studies was with the cardiovascular consequences of reflexes from fatiguing inspiratory muscles in the human. We recently demonstrated that induction of inspiratory muscle fatigue in healthy subjects by means of voluntary hyperpnoea against resistance caused a gradual increase in muscle sympathetic nerve activity (MSNA) in the resting limb (St Croix et al. 2000). This finding, taken together with the finding of increased neural activity in type IV afferents from the diaphragm during fatiguing contractions of this muscle in the anaesthetized rat (Hill, 1. We recently showed that fatigue of the inspiratory muscles via voluntary efforts caused a time-dependent increase in limb muscle sympathetic nerve activity (MSNA) (St Croix et al. 2000). We now asked whether limb muscle vasoconstriction and reduction in limb blood flow also accompany inspiratory muscle fatigue.2. In six healthy human subjects at rest, we measured leg blood flow (« Q L ) in the femoral artery with Doppler ultrasound techniques and calculated limb vascular resistance (LVR) while subjects performed two types of fatiguing inspiratory work to the point of task failure (3-10 min). Subjects inspired primarily with their diaphragm through a resistor, generating (i) 60 % maximal inspiratory mouth pressure (P M ) and a prolonged duty cycle (T I /T TOT = 0.7); and (ii) 60 % maximal P M and a T I /T TOT of 0.4. The first type of exercise caused prolonged ischaemia of the diaphragm during each inspiration. The second type fatigued the diaphragm with briefer periods of ischaemia using a shorter duty cycle and a higher frequency of contraction. End-tidal P CO 2 was maintained by increasing the inspired CO 2 fraction (F I,CO 2 ) as needed. Both trials caused a 25-40 % reduction in diaphragm force production in response to bilateral phrenic nerve stimulation.3. « Q L and LVR were unchanged during the first minute of the fatigue trials in most subjects; however, « Q L subsequently decreased (_30 %) and LVR increased (50-60 %) relative to control in a time-dependent manner. This effect was present by 2 min in all subjects. During recovery, the observed changes dissipated quickly (< 30 s). Mean arterial pressure (MAP; +4-13 mmHg) and heart rate (+16-20 beats min _1 ) increased during fatiguing diaphragm contractions.4. When central inspiratory motor output was increased for 2 min without diaphragm fatigue by increasing either inspiratory force output (95 % of maximal inspiratory pressure (MIP)) or inspiratory flow rate (5 w eupnoea), « Q L , MAP and LVR were unchanged; although continuing the high force output trials for 3 min did cause a relatively small but significant increase in LVR and a reduction in « Q L .5. When the breathing pattern of the fatiguing trials was mimicked with no added resistance, LVR was reduced and « Q L increased significantly; these changes were attributed to the negative feedback effects on MSNA from augmented tidal volume.6. Voluntary increases in inspiratory effort, in the absence of diaphragm fatigue, had no effec...

The effect of arterial O2 content (Ca(O2)) on quadriceps fatigue was assessed in healthy, trained male athletes. On separate days, eight participants completed three constant-workload trials on a bicycle ergometer at fixed workloads (314 +/- 13 W). The first trial was performed while the subjects breathed a hypoxic gas mixture [inspired O2 fraction (Fi(O2)) = 0.15, Hb saturation = 81.6%, Ca(O2) = 18.2 ml O2/dl blood; Hypo] until exhaustion (4.5 +/- 0.4 min). The remaining two trials were randomized and time matched with Hypo. The second and third trials were performed while the subjects breathed a normoxic (Fi(O2) = 0.21, Hb saturation = 95.0%, Ca(O2) = 21.3 ml O2/dl blood; Norm) and a hyperoxic (Fi(O2) = 1.0, Hb saturation = 100%, Ca(O2) = 23.8 ml O2/dl blood; Hyper) gas mixture, respectively. Quadriceps muscle fatigue was assessed via magnetic femoral nerve stimulation (1-100 Hz) before and 2.5 min after exercise. Myoelectrical activity of the vastus lateralis was obtained from surface electrodes throughout exercise. Immediately after exercise, the mean force response across 1-100 Hz decreased from preexercise values (P < 0.01) by -26 +/- 2, -17 +/- 2, and -13 +/- 2% for Hypo, Norm, and Hyper, respectively; each of the decrements differed significantly (P < 0.05). Integrated electromyogram increased significantly throughout exercise (P < 0.01) by 23 +/- 3, 10 +/- 1, and 6 +/- 1% for Hypo, Norm, and Hyper, respectively; each of the increments differed significantly (P < 0.05). Mean power frequency fell more (P < 0.05) during Hypo (-15 +/- 2%); the difference between Norm (-7 +/- 1%) and Hyper (-6 +/- 1%) was not significant (P = 0.32). We conclude that deltaCa(O2) during strenuous systemic exercise at equal workloads and durations affects the rate of locomotor muscle fatigue development.

The vast majority of quantitative data examining the effects of breathing on venous return have been derived from anaesthetized or reduced animal preparations, making an extrapolation to an upright exercising human problematic due to the lack of a hydrostatic column and an absence of muscular contraction. Thus, this study is the first to quantitatively examine the effects of different breathing mechanics on venous return from the locomotor limbs both at rest and during calf contraction exercise in the semirecumbent human. When subjects inspired using predominantly their ribcage/accessory inspiratory muscles at rest (change in gastric pressure (∆P GA ) = <2 cmH 2 O, change in oesophageal pressure (∆P ES ) = ∼−6 cmH 2 O; inspiratory time/total breath time (T I /T TOT ) = 0.5), a slight facilitation of femoral venous return was observed during inspiration (65% of all flow occurred during inspiration), with a slight reduction in femoral venous return during the ensuing expiratory phase of the breath. However, when subjects inspired using a predominantly diaphragmatic breath at rest (∆P GA = > 5 cmH 2 O, ∆P ES = ∼−6 cmH 2 O; T I /T TOT = 0.5), femoral venous return was markedly impeded (net retrograde flow of 11%) and significantly lower than that observed during ribcage breathing conditions (P < 0.01). During the ensuing expiratory phase of a diaphragmatic breath, there was a large resurgence of femoral venous blood flow. The pattern of modulation during ribcage and diaphragmatic breathing persisted during both mild (peak calf force = 7 kg) and moderate (peak calf force = 11 kg) levels of calf contraction. Despite the significant within-breath modulation of femoral venous return by breathing, net blood flow in the steady state was not altered by the breathing pattern followed by the subjects. Though popliteal blood flow appeared to be modulated by respiration at rest, this pattern was absent during mild calf contraction where popliteal outflow was phasic with the concentric phase of calf contraction. We conclude that respiratory muscle pressure production is the predominant factor modulating venous return from the locomotor limb both at rest and during calf contraction even when the veins of the lower limb are distended due to the presence of a physiologic hydrostatic column.

Our aim was to isolate the independent effects of 1) inspiratory muscle work (Wb) and 2) arterial hypoxemia during heavy-intensity exercise in acute hypoxia on locomotor muscle fatigue. Eight cyclists exercised to exhaustion in hypoxia [inspired O2 fraction (FIO 2 ) ϭ 0.15, arterial hemoglobin saturation (SaO 2 ) ϭ 81 Ϯ 1%; 8.6 Ϯ 0.5 min, 273 Ϯ 6 W; Hypoxia-control (Ctrl)] and at the same work rate and duration in normoxia (SaO 2 ϭ 95 Ϯ 1%; Normoxia-Ctrl). These trials were repeated, but with a 35-80% reduction in Wb achieved via proportional assist ventilation (PAV). Quadriceps twitch force was assessed via magnetic femoral nerve stimulation before and 2 min after exercise. The isolated effects of Wb in hypoxia on quadriceps fatigue, independent of reductions in SaO 2 , were revealed by comparing Hypoxia-Ctrl and Hypoxia-PAV at equal levels of SaO 2 (P ϭ 0.10). Immediately after hypoxic exercise potentiated twitch force of the quadriceps (Qtw,pot) decreased by 30 Ϯ 3% below preexercise baseline, and this reduction was attenuated by about one-third after PAV exercise (21 Ϯ 4%; P ϭ 0.0007). This effect of Wb on quadriceps fatigue occurred at exercise work rates during which, in normoxia, reducing Wb had no significant effect on fatigue. The isolated effects of reduced SaO 2 on quadriceps fatigue, independent of changes in Wb, were revealed by comparing Hypoxia-PAV and Normoxia-PAV at equal levels of Wb. Qtw,pot decreased by 15 Ϯ 2% below preexercise baseline after Normoxia-PAV, and this reduction was exacerbated by about one-third after Hypoxia-PAV (Ϫ22 Ϯ 3%; P ϭ 0.034). We conclude that both arterial hypoxemia and Wb contribute significantly to the rate of development of locomotor muscle fatigue during exercise in acute hypoxia; this occurs at work rates during which, in normoxia, Wb has no effect on peripheral fatigue. work of breathing; arterial oxygen content; altitude; limb blood flow; expiratory flow limitation ON THE BASIS OF STUDIES that mimicked the work of breathing (W b ) obtained during heavy and maximum exercise (1, 2) and unloaded the W b in maximal exercise (34), it has been estimated that the oxygen cost of breathing or the cardiac output devoted to the respiratory muscles approximates 10 -16% of maximal O 2 consumption (V O 2max ) or maximal cardiac output in healthy trained and untrained subjects. More direct microsphere measurements of blood flow distribution during maximal exercise in equines also showed that ϳ15-16% of cardiac output was distributed to the inspiratory and expiratory muscles of the chest wall and abdomen (47). One mechanism protecting blood flow to the respiratory muscles in heavy exercise may be the respiratory muscle metaboreflex, which has been shown to cause sympathetically mediated vasoconstriction of the exercising limb vasculature during heavy exercise in the face of developing inspiratory or expiratory muscle fatigue (32,56,57,59).We (4 -6) and others (48, 53, 62) have shown previously that whole body exercise in acute hypoxia significantly increases the rate of develo...

.-The effect of various levels of oxygenation on quadriceps muscle fatigability during isolated muscle exercise was assessed in six male subjects. Twitch force (Qtw) was assessed using supramaximal magnetic femoral nerve stimulation. In experiment 1, maximal voluntary contraction (MVC) and Qtw of resting quadriceps muscle were measured in normoxia [inspired O2 fraction (FIO 2 ) ϭ 0.21, percent arterial O2 saturation (Sp O 2 ) ϭ 98.4%, estimated arterial O2 content (CaO 2 ) ϭ 20.8 ml/dl], acute hypoxia (FIO 2 ϭ 0.11, Sp O 2 ϭ 74.6%, CaO 2 ϭ 15.7 ml/dl), and acute hyperoxia (FIO 2 ϭ 1.0, Sp O 2 ϭ 100%, CaO 2 ϭ 22.6 ml/dl). No significant differences were found for MVC and Qtw among the three FIO 2 levels. In experiment 2, the subjects performed three sets of nine, intermittent, isometric, unilateral, submaximal quadriceps contractions (62% MVC followed by 1 MVC in each set) while breathing each FIO 2 . Qtw was assessed before and after exercise, and myoelectrical activity of the vastus lateralis was obtained during exercise. The percent reduction of twitch force (potentiated Qtw) in hypoxia (Ϫ27.0%) was significantly (P Ͻ 0.05) greater than in normoxia (Ϫ21.4%) and hyperoxia (Ϫ19.9%), as were the changes in intratwitch measures of contractile properties. The increase in integrated electromyogram over the course of the nine contractions in hypoxia (15.4%) was higher (P Ͻ 0.05) than in normoxia (7.2%) or hyperoxia (6.7%). These results demonstrate that quadriceps muscle fatigability during isolated muscle exercise is exacerbated in acute hypoxia, and these effects are independent of the relative exercise intensity. hypoxia; magnetic femoral nerve stimulation; hyperoxia ; hypoxemia; quadriceps twitch force WE AND OTHERS HAVE RECENTLY SHOWN that high-intensity whole body exercise to exhaustion caused significant peripheral limb muscle fatigue and that the level of arterial O 2 content (Ca O 2 ) via changes in inspired O 2 fraction (FI O 2 ) is a significant determinant of the rate at which peripheral muscle fatigue is developed during exercise (2,43,46). In these studies, evidence for the effects of Ca O 2 on peripheral fatigue was obtained via measures of quadriceps force output using supramaximal magnetic stimulation obtained pre-vs. postexercise and also by the rate of rise of quadriceps muscle electromyogram (EMG) during the exercise. The latter measurement presumably indicates the rate of motor unit recruitment in response to peripheral fatigue development (2, 46). Given that a changing Ca O 2 induced by breathing various FI O 2 also had significant effects on maximal peak exercise capacity during whole body exercise, the observed effect of changing Ca O 2 on peripheral limb fatigue might be attributed at least in part to changes in relative work intensity (2, 43). Different relative work intensities might be expected to influence the rate of accumulation of muscle metabolites (27) and therefore influence peripheral muscle fatigue.We tested this hypothesis by using isolated submaximal isometric contractions of th...