Shunsaku Koga

Dynamics of microvascular oxygen pressure across the rest-exercise transition in rat skeletal muscle.

There exists substantial controversy as to whether muscle oxygen (O2) delivery (QO2) or muscle mitochondrial O2 demand determines the profile of pulmonary VO2 kinetics in the rest-exercise transition. To address this issue, we adapted intravascular phosphorescence quenching techniques for measurement of rat spinotrapezius microvascular O2 pressure (PO2m). The spinotrapezius muscle intravital microscopy preparation is used extensively for investigation of muscle microcirculatory control. The phosphor palladium-meso-tetra(4-carboxyphenyl)porphyrin dendrimer (R2) at 15 mg/kg was bound to albumin within the blood of female Sprague-Dawley rats ( approximately 250 g). Spinotrapezius blood flow (radioactive microspheres) and PO2m profiles were determined in situ across the transition from rest to 1 Hz twitch contractions. Stimulation increased muscle blood flow by 240% from 16.6 +/- 3.0 to 56.2 +/- 8.3 (SE) ml/min per 100 g (P < 0.05). Muscle contractions reduced PO2m from a baseline of 31.4 +/- 1.6 to a steady-state value of 21.0 +/- 1.7 mmHg (n = 24, P < 0.01). The response profile of PO2m was well fit by a time delay of 19.2+/-2.8 sec (P < 0.05) followed by a monoexponential decline (time constant, 21.7 +/- 2.1 sec) to its steady state level. The absence of either an immediate and precipitous fall in microvascular PO2 at exercise onset or any PO2m undershoot prior to achievement of steady-state values, provides compelling evidence that O(2) delivery is not limiting under these conditions.

Dynamic heterogeneity of exercising muscle blood flow and O2 utilization.

Resolving the bases for different physiological functioning or exercise performance within a population is dependent on our understanding of control mechanisms. For example, when most young healthy individuals run or cycle at moderate intensities, oxygen uptake (VO2) kinetics are rapid and the amplitude of the VO2 response is not constrained by O2 delivery. For this to occur, muscle O2 delivery (i.e., blood flow × arterial O2 concentration) must be coordinated superbly with muscle O2 requirements (VO2), the efficacy of which may differ among muscles and distinct fiber types. When the O2 transport system succumbs to the predations of aging or disease (emphysema, heart failure, and type 2 diabetes), muscle O2 delivery and O2 delivery-VO2 matching and, therefore, muscle contractile function become impaired. This forces greater influence of the upstream O2 transport pathway on muscle aerobic energy production, and the O2 delivery-VO2 relationship(s) assumes increased importance. This review is the first of its kind to bring a broad range of available techniques, mostly state of the art, including computer modeling, radiolabeled microspheres, positron emission tomography, magnetic resonance imaging, near-infrared spectroscopy, and phosphorescence quenching to resolve the O2 delivery-VO2 relationships and inherent heterogeneities at the whole body, interorgan, muscular, intramuscular, and microvascular/myocyte levels. Emphasis is placed on the following: 1) intact humans and animals as these provide the platform essential for framing and interpreting subsequent investigations, 2) contemporary findings using novel technological approaches to elucidate O2 delivery-VO2 heterogeneities in humans, and 3) future directions for investigating how normal physiological responses can be explained by O2 delivery-VO2 heterogeneities and the impact of aging/disease on these processes.

Modulation of the thermoregulatory sweating response to mild hyperthermia during activation of the muscle metaboreflex in humans.

1 To investigate the effect of the muscle metaboreflex on the thermoregulatory sweating response in humans, eight healthy male subjects performed sustained isometric handgrip exercise in an environmental chamber (35 °C and 50% relative humidity) at 30 or 45% maximal voluntary contraction (MVC), at the end of which the blood circulation to the forearm was occluded for 120 s. The environmental conditions were such as to produce sweating by increase in skin temperature without a marked change in oesophageal temperature. 2 During circulatory occlusion after handgrip exercise at 30% MVC for 120 s or at 45% MVC for 60 s, the sweating rate (SR) on the chest and forearm (hairy regions), and the mean arterial blood pressure were significantly above baseline values (P < 0.05). There were no changes from baseline values in the oesophageal temperature, mean skin temperature, or SR on the palm (hairless regions). 3 During the occlusion after handgrip exercise at 30% MVC for 60 s and during the occlusion alone, none of the measured parameters differed from baseline values. 4 It is concluded that, under mildly hyperthermic conditions, the thermoregulatory sweating response on the hairy regions is modulated by afferent signals from muscle metaboreceptors.

Methodological validation of the dynamic heterogeneity of muscle deoxygenation within the quadriceps during cycle exercise

The conventional continuous wave near-infrared spectroscopy (CW-NIRS) has enabled identification of regional differences in muscle deoxygenation following onset of exercise. However, assumptions of constant optical factors (e.g., path length) used to convert the relative changes in CW-NIRS signal intensity to values of relative concentration, bring the validity of such measurements into question. Furthermore, to justify comparisons among sites and subjects, it is essential to correct the amplitude of deoxygenated hemoglobin plus myoglobin [deoxy(Hb+Mb)] for the adipose tissue thickness (ATT). We used two time-resolved NIRS systems to measure the distribution of the optical factors directly, thereby enabling the determination of the absolute concentrations of deoxy(Hb+Mb) simultaneously at the distal and proximal sites within the vastus lateralis (VL) and the rectus femoris muscles. Eight subjects performed cycle exercise transitions from unloaded to heavy work rates (>gas exchange threshold). Following exercise onset, the ATT-corrected amplitudes (A(p)), time delay (TD(p)), and time constant (τ(p)) of the primary component kinetics in muscle deoxy(Hb + Mb) were spatially heterogeneous (intersite coefficient of variation range for the subjects: 10-50 for A(p), 16-58 for TD(p), 14-108% for τ(p)). The absolute and relative amplitudes of the deoxy(Hb+Mb) responses were highly dependent on ATT, both within subjects and between measurement sites. The present results suggest that regional heterogeneity in the magnitude and temporal profile of muscle deoxygenation is a consequence of differential matching of O(2) delivery and O(2) utilization, not an artifact caused by changes in optical properties of the tissue during exercise or variability in the overlying adipose tissue.

Kinetics of muscle deoxygenation and microvascular Po2 during contractions in rat: comparison of optical spectroscopy and phosphorescence-quenching techniques

The overarching presumption with near-infrared spectroscopy measurement of muscle deoxygenation is that the signal reflects predominantly the intramuscular microcirculatory compartment rather than intramyocyte myoglobin (Mb). To test this hypothesis, we compared the kinetics profile of muscle deoxygenation using visible light spectroscopy (suitable for the superficial fiber layers) with that for microvascular O(2) partial pressure (i.e., Pmv(O(2)), phosphorescence quenching) within the same muscle region (0.5∼1 mm depth) during transitions from rest to electrically stimulated contractions in the gastrocnemius of male Wistar rats (n = 14). Both responses could be modeled by a time delay (TD), followed by a close-to-exponential change to the new steady level. However, the TD for the muscle deoxygenation profile was significantly longer compared with that for the phosphorescence-quenching Pmv(O(2)) [8.6 ± 1.4 and 2.7 ± 0.6 s (means ± SE) for the deoxygenation and Pmv(O(2)), respectively; P < 0.05]. The time constants (τ) of the responses were not different (8.8 ± 4.7 and 11.2 ± 1.8 s for the deoxygenation and Pmv(O(2)), respectively). These disparate (TD) responses suggest that the deoxygenation characteristics of Mb extend the TD, thereby increasing the duration (number of contractions) before the onset of muscle deoxygenation. However, this effect was insufficient to increase the mean response time. Somewhat differently, the muscle deoxygenation response measured using near-infrared spectroscopy in the deeper regions (∼5 mm depth) (∼50% type I Mb-rich, highly oxidative fibers) was slower (τ = 42.3 ± 6.6 s; P < 0.05) than the corresponding value for superficial muscle measured using visible light spectroscopy or Pmv(O(2)) and can be explained on the basis of known fiber-type differences in Pmv(O(2)) kinetics. These data suggest that, within the superficial and also deeper muscle regions, the τ of the deoxygenation signal may represent a useful index of local O(2) extraction kinetics during exercise transients.

Dissociation between the time courses of femoral artery blood flow and pulmonary V̇O2 during repeated bouts of heavy knee extension exercise in humans

It has frequently been demonstrated that prior heavy cycling exercise facilitates pulmonary V̇O2 kinetics at the onset of subsequent heavy exercise. This might be due to improved muscle perfusion via acidosis‐induced vasodilating effects. However, it is difficult to measure the blood flow (BF) to the working muscles (via the femoral artery) during cycling exercise. We therefore selected supine knee extension (KE) exercise as an alternative, and investigated whether the faster V̇O2 kinetics in the 2nd bout was matched by proportionally faster BF kinetics to the exercising muscle. Nine healthy subjects (aged 21–44 years) volunteered to participate in this study. The protocol consisted of two consecutive 6‐min KE exercise bouts in a supine position (work rate: 70–75% of peak power) separated by a 6‐min baseline rest (EX1 to EX2). During the protocol, a pulsed Doppler ultrasound technique was utilized to continuously measure the BF in the right femoral artery. The protocol was repeated at least 6 times to characterize the precise kinetics. In agreement with previous studies using cycling exercise, the V̇O2 kinetics in the 2nd bout were facilitated compared with that in the 1st bout [mean ±s.d. of the ‘effective’ time constant (τ): EX1, 68.6 ± 15.9, versus EX2, 58.0 ± 14.4 s. Phase II‐τ: EX1, 48.7 ± 9.0, versus EX2, 41.2 ± 13.3 s. Empirical index of the slow component (ΔV̇O2(6–3)): EX1, 78 ± 44, versus EX2, 57 ± 36 ml min−1 (P < 0.05)]. However, no substantial difference was observed for the facilitation of the femoral artery BF response to the 1st and 2nd exercise bouts [i.e. the ‘effective’τ of the femoral artery BF: EX1, 40.8 ± 16.9, versus EX2, 39.0 ± 17.1 s (P > 0.05)]. It was concluded that the faster pulmonary V̇O2 kinetics during heavy KE exercise following prior heavy exercise was not associated with a similar modulation in the BF to the working muscles.

Effects of chemoreflexes on hyperthermic hyperventilation and cerebral blood velocity in resting heated humans

We tested the hypothesis that hyperthermic hyperventilation in part reflects enhanced chemoreceptor ventilatory O2 drive, and that the resultant hypocapnia attenuates ventilatory responses and/or middle cerebral artery mean blood velocity (MCAVmean) in resting humans. Eleven healthy subjects were passively heated for 50–80 min, causing oesophageal temperature (Toes) to increase by 1.6°C. During heating, minute ventilation increased (P < 0.05), while end‐tidal CO2 pressure (P  ET,CO 2 ) and MCAVmean declined. A hyperoxia test in which three breaths of hyperoxic air were inspired was performed once before heating and three times during the heating. When we observed hypocapnia (P  ET,CO 2 below 40 mmHg), P  ET,CO 2 was restored to the eucapnic level by adding 100% CO2 to the inspired air immediately before the last two tests. Minute ventilation was significantly reduced by hyperoxia, and that reduction gradually increased with increasing Toes. However, the percentage decrease in from the normoxic level was small (20–29%) and unchanged during heating. When P  ET,CO 2 was restored to eucapnic levels, was unchanged, but MCAVmean was partly restored to the level seen prior to heating (28.1% restoration at Toes 37.6°C and 38.1% restoration at Toes 38.0°C). These findings suggest that although hyperthermia increases chemoreceptor ventilatory O2 drive in resting humans, the relative contribution of the chemoreceptor ventilatory O2 drive to hyperthermic hyperventilation is small (∼20%) and unaffected by increasing core temperature. Moreover, hypocapnia induced by hyperthermic hyperventilation reduces cerebral blood flow but not ventilatory responses.

Kinetics of oxygen uptake and cardiac output at onset of arm exercise

Pulmonary oxygen uptake (V O2) kinetics at onset of exercise is reported to be slower for arm than for leg exercise. This could be attributed to reduced cardiac output (Q) or reduced arteriovenous O2 content difference or both. To test this, V O2 mean tissue oxygen consumption (V O2T) and Q kinetics in arm cranking were compared with corresponding values found in leg cycling. The increase in V O2 during phase 1 (abrupt increase after onset of exercise) was less in arm than in leg exercise, suggesting that immediate Q adjustments to arm exercise were less pronounced. Mean response times (MRT, the relative rates at which a steady state was attained) for V O2, V O2T, and Q were prolonged during arm exercise. The MRT of VO 2 in arm exercise at a given blood lactate increase was higher than in leg exercise. The delayed V O2 kinetics in arm exercise might be due to delayed Q kinetics and higher anaerobic glycolysis occurring early during arm exercise.

Non-thermal modification of heat-loss responses during exercise in humans

This review focuses on the characteristics of heat-loss responses during exercise with respect to non-thermal factors. In addition, the effects of physical training on non-thermal heat-loss responses are discussed. When a subject is already sweating the sweating rate increases at the onset of dynamic exercise without changes in core temperature, while cutaneous vascular conductance (skin blood flow) is temporarily decreased. Although exercise per se does not affect the threshold for the onset of sweating, it is possible that an increase in exercise intensity induces a higher sensitivity of the sweating response. Exercise increases the threshold for cutaneous vasodilation, and at higher exercise intensities, the sensitivity of the skin-blood-flow response decreases. Facilitation of the sweating response with increased exercise intensity may be due to central command, peripheral reflexes in the exercising muscle, and mental stimuli, whereas the attenuation of skin-blood-flow responses with decreased cutaneous vasodilation is related to many non-thermal factors. Most non-thermal factors have negative effects on magnitude of cutaneous vasodilation; however, several of these factors have positive effects on the sweating response. Moreover, thermal and non-thermal factors interact in controlling heat-loss responses, with non-thermal factors having a greater impact until core temperature elevations become significant, after which core temperature primarily would control heat loss. Finally, as with thermally induced sweating responses, physical training seems to also affect sweating responses governed by non-thermal factors.

Slowed oxygen uptake kinetics in hypoxia correlate with the transient peak and reduced spatial distribution of absolute skeletal muscle deoxygenation

•  What is the central question of the study? Does a transient overshoot in skeletal muscle deoxygenation (reflecting a kinetic mismatch of microvascular O2 delivery to consumption) and/or its spatial distribution slow the adjustment of oxidative energy provision at the onset of exercise? •  What is the main finding and its importance? Slowed oxidative energy provision at the onset of exercise was correlated with the transient skeletal muscle deoxygenation peak and the reduced spatial distribution, measured by quantitative near‐infrared spectroscopy. It was not correlated with a microvascular O2 delivery‐to‐consumption mismatch per se. This suggests that an absolute, rather than kinetic, mismatch of microvascular O2 delivery and consumption limits the kinetics of muscular oxidative energy provision, but only when muscle deoxygenation reaches some ‘critical’ level.