Hypoxia potentiates exercise-induced sympathetic neural activation in humans.

Our purpose was to test the hypothesis that hypoxia potentiates exercise-induced sympathetic neural activation in humans. In 15 young (20-30 yr) healthy subjects, lower leg muscle sympathetic nerve activity (MSNA, peroneal nerve; microneurography), venous plasma norepinephrine (PNE) concentrations, heart rate, and arterial blood pressure were measured at rest and in response to rhythmic handgrip exercise performed during normoxia or isocapnic hypoxia (inspired O2 concn of 10%). Study I (n = 7): Brief (3-4 min) hypoxia at rest did not alter MSNA, PNE, or arterial pressure but did induce tachycardia [17 +/- 3 (SE) beats/min; P less than 0.05]. During exercise at 50% of maximum, the increases in MSNA (346 +/- 81 vs. 207 +/- 14% of control), PNE (175 +/- 25 vs. 120 +/- 11% of control), and heart rate (36 +/- 2 vs. 20 +/- 2 beats/min) were greater during hypoxia than during normoxia (P less than 0.05), whereas the arterial pressure response was not different (26 +/- 4 vs. 25 +/- 4 mmHg). The increase in MSNA during hypoxic exercise also was greater than the simple sum of the separate responses to hypoxia and normoxic exercise (P less than 0.05). Study II (n = 8): In contrast to study I, during 2 min of exercise (30% max) performed under conditions of circulatory arrest and 2 min of postexercise circulatory arrest (local ischemia), the MSNA and PNE responses were similar during systemic hypoxia and normoxia. Arm ischemia without exercise had no influence on any variable during hypoxia or normoxia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Muscle mechanoreflex augments arterial baroreflex-mediated dynamic sympathetic response to carotid sinus pressure

Although the muscle mechanoreflex is one of the pressor reflexes during exercise, its interaction with dynamic characteristics of the arterial baroreflex remains to be quantitatively analyzed. In anesthetized, vagotomized, and aortic-denervated rabbits (n = 7), we randomly perturbed isolated carotid sinus pressure (CSP) using binary white noise while recording renal sympathetic nerve activity (SNA) and arterial pressure (AP). We estimated the transfer functions of the baroreflex neural arc (CSP to SNA) and peripheral arc (SNA to AP) under conditions of control and muscle stretch of the hindlimb (5 kg of tension). The muscle stretch increased the dynamic gain of the neural arc while maintaining the derivative characteristics [gain at 0.01 Hz: 1.0 +/- 0.2 vs. 1.4 +/- 0.6 arbitrary units (au)/mmHg, gain at 1 Hz: 1.7 +/- 0.6 vs. 2.7 +/- 1.4 au/mmHg; P < 0.05, control vs. stretch]. In contrast, muscle stretch did not affect the peripheral arc. In the time domain, muscle stretch augmented the steady-state response at 50 s (-1.1 +/- 0.3 vs. -1.7 +/- 0.7 au; P < 0.05, control vs. stretch) and negative peak response (-2.1 +/- 0.5 vs. -3.1 +/- 1.5 au; P < 0.05, control vs. stretch) in the SNA step response. A simulation experiment using the results indicated that the muscle mechanoreflex would accelerate the closed-loop AP regulation via the arterial baroreflex.     

Kinetics of oxygenation in inactive forearm muscle during ramp leg cycling

This study was carried out to determine whether hemodynamics in inactive forearm muscle during ramp leg cycling is affected from the ventilatory threshold (VT) and respiratory compensation point (RCP), at which the rate of increase in ventilation (VE) against power output begins to increase abruptly. Change in hemodynamics was evaluated by change in oxygenation index (difference between concentrations of oxygenated hemoglobin and deoxygenated hemoglobin, HbD) measured using near-infrared spectrometry (NIRS). Each subject (n=9) performed 4-min constant-work-rate leg cycling and subsequent ramp leg cycling at an increasing rate of 10 watts.min(-1) in power output. The work rates at VT, RCP and peak oxygen uptake (VO(2 peak)) were 107 +/- 11, 172 +/- 21 and 206 +/- 20 watts, respectively. The rates of increase in VE between 10-watt leg cycling, VT, RCP and VO(2 peak) were 0.19 +/- 0.03, 0.44 +/- 0.07 and 1.32 +/- 0.47 l.min(-1).watts(-1), respectively. In one subject, HbD started to decrease during ramp exercise from the VT, and the rate of decrease increased at a high intensity of exercise. In eight subjects, although no decrease in HbD from the VT was observed, HbD showed a sudden drop at a high intensity of exercise. The work rate at which HbD began to decrease at a high intensity of exercise was 174 +/- 23 watts. This work rate was not significantly different from that at the RCP and was significantly correlated with that at the RCP (r=0.72, P<0.05). The results suggest that the abrupt increase in VE from the RCP affects hemodynamics, resulting in a decrease in HbD in inactive forearm muscle.     

Differences in muscle sympathetic nerve response to isometric exercise in different muscle groups

The aim of this study was to examine the effects of muscle fibre composition on muscle sympathetic nerve activity (MSNA) in response to isometric exercise. The MSNA, recorded from the tibial nerve by a microneurographic technique during contraction and following arterial occlusion, was compared in three different muscle groups: the forearm (handgrip), anterior tibialis (foot dorsal contraction), and soleus muscles (foot plantar contraction) contracted separately at intensities of 20%, 33% and 50% of the maximal voluntary force. The increases in MSNA relative to control levels during contraction and occlusion were significant at all contracting forces for handgrip and at 33% and 50% of maximal for dorsal contraction, but there were no significant changes, except during exercise at 50%, for plantar contraction. The size of the MSNA response correlated with the contraction force in all muscle groups. Pooling data for all contraction forces, there were different MSNA responses among muscle groups in contraction forces (P = 0.0001, two-way analysis of variance), and occlusion periods (P = 0.0001). The MSNA increases were in the following order of magnitude: handgrip, dorsal, and plantar contractions. The order of the fibre type composition in these three muscles is from equal numbers of types I and II fibres in the forearm to increasing number of type I fibres in the leg muscles. The different MSNA responses to the contraction of different muscle groups observed may have been due in part to muscle metaboreflex intensity influenced by their metabolic capacity which is related to by their metabolic capacity which is related to the fibre type.     

Human postural response to lower leg muscle vibration of different duration

Body lean response to bilateral vibrations of soleus muscles were investigated in order to understand the influence of proprioceptive input from lower leg in human stance control. Proprioceptive stimulation was applied to 17 healthy subjects by two vibrators placed on the soleus muscles. Frequency and amplitude of vibration were 60 Hz and 1 mm, respectively. Vibration was applied after a 30 s of baseline. The vibration duration of 10, 20, 30 s respectively was used with following 30 s rest. Subjects stood on the force platform with eyes closed. Postural responses were characterized by center of pressure (CoP) displacements in the anterior-posterior (AP) direction. The CoP-AP shifts as well as their amplitudes and velocities were analyzed before, during and after vibration. Vibration of soleus muscles gradually increased backward body tilts. There was a clear dependence of the magnitude of final CoP shift on the duration of vibration. The amplitude and velocity of body sway increased during vibration and amplitude was significantly modulated by duration of vibration as well. Comparison of amplitude and velocity of body sway before and after vibration showed significant post-effects. Presented findings showed that somatosensory stimulation has a long-term, direction-specific influence on the control of postural orientation during stance. Further, the proprioceptive input altered by soleus muscles vibration showed significant changes in postural equilibrium during period of vibration with interesting post-effects also.     

Exercise training augments the dynamic heart rate response to vagal but not sympathetic stimulation in rats

We examined the transfer function of autonomic heart rate (HR) control in anesthetized sedentary and exercise-trained (16 wk, treadmill for 1 h, 5 times/wk at 15 m/min and 15-degree grade) rats for comparison to HR variability assessed in the conscious resting state. The transfer function from sympathetic stimulation to HR response was similar between groups (gain, 4.2 ± 1.5 vs. 4.5 ± 1.5 beats·min(-1)·Hz(-1); natural frequency, 0.07 ± 0.01 vs. 0.08 ± 0.01 Hz; damping coefficient, 1.96 ± 0.55 vs. 1.69 ± 0.15; and lag time, 0.7 ± 0.1 vs. 0.6 ± 0.1 s; sedentary vs. exercise trained, respectively, means ± SD). The transfer gain from vagal stimulation to HR response was 6.1 ± 3.0 in the sedentary and 9.7 ± 5.1 beats·min(-1)·Hz(-1) in the exercise-trained group (P = 0.06). The corner frequency (0.11 ± 0.05 vs. 0.17 ± 0.09 Hz) and lag time (0.1 ± 0.1 vs. 0.2 ± 0.1 s) did not differ between groups. When the sympathetic transfer gain was averaged for very-low-frequency and low-frequency bands, no significant group effect was observed. In contrast, when the vagal transfer gain was averaged for very-low-frequency, low-frequency, and high-frequency bands, exercise training produced a significant group effect (P < 0.05 by two-way, repeated-measures ANOVA). These findings suggest that, in the frequency domain, exercise training augments the dynamic HR response to vagal stimulation but not sympathetic stimulation, regardless of the frequency bands.     

Dissociation of muscle sympathetic nerve activity and leg vascular resistance in humans

We examined the hypothesis that the increase in inactive leg vascular resistance during forearm metaboreflex activation is dissociated from muscle sympathetic nerve activity (MSNA). MSNA (microneurography), femoral artery mean blood velocity (FAMBV, Doppler), mean arterial pressure (MAP), and heart rate (HR) were assessed during fatiguing static handgrip exercise (SHG, 2 min) followed by posthandgrip ischemia (PHI, 2 min). Whereas both MAP and MSNA increase during SHG, the transition from SHG to PHI is characterized by a transient reduction in MAP but sustained elevation in MSNA, facilitating separation of these factors in vivo. Femoral artery vascular resistance (FAVR) was calculated (MAP/MBV). MSNA increased by 59 +/- 20% above baseline during SHG (P < 0.05) and was 58 +/- 18 and 78 +/- 18% above baseline at 10 and 20 s of PHI, respectively (P < 0.05 vs. baseline). Compared with baseline, FAVR increased 51 +/- 22% during SHG (P < 0.0001) but returned to baseline levels during the first 30 s of PHI, reflecting the changes in MAP (P < 0.005) and not MSNA. It was concluded that control of leg muscle vascular resistance is sensitive to changes in arterial pressure and can be dissociated from sympathetic factors.     

Short-term exercise training augments sympathetic vasoconstrictor responsiveness and endothelium-dependent vasodilation in resting skeletal muscle

We tested the hypotheses that 4 wk of exercise training would diminish the magnitude of vasoconstriction in response to sympathetic nerve stimulation and augment endothelium-dependent vasodilation (EDD) in resting skeletal muscle in a training intensity-dependent manner. Sprague-Dawley rats were randomly assigned to sedentary time-control (S), mild- (M; 20 m/min, 5% grade), or heavy-intensity (H; 40 m/min, 5% grade) treadmill exercise groups. Animals trained 5 days/wk for 4 wk with training volume matched between groups. Rats were anesthetized and instrumented for study 24 h after the last training session. Arterial pressure and femoral artery blood flow were measured, and femoral vascular conductance (FVC) was calculated. Lumbar sympathetic chain stimulation was delivered continuously at 2 Hz and in patterns at 20 and 40 Hz. EDD was assessed by the vascular response to intra-arterial bolus injections of ACh. The response (% change FVC) to sympathetic stimulation increased (P < 0.05) in a training intensity-dependent manner at 2 Hz (S: -20.2 ± 9.8%, M: -34.0 ± 6.7%, and H: -44.9 ± 2.0%), 20 Hz (S: -22.0 ± 10.6%, M: -31.2 ± 8.4%, and H: -42.8 ± 5.9%), and 40 Hz (S: H -24.5 ± 8.5%, M: -35.1 ± 8.9%, H: -44.9 ± 6.5%). The magnitude of EDD also increased in a training intensity-dependent manner (P < 0.05). These data demonstrate that short-term exercise training augments the magnitude of vasoconstriction in response to sympathetic stimulation and EDD in resting skeletal muscle in a training intensity-dependent manner.     

Relationship between oxygenation in inactive biceps brachii muscle and hyperventilation during leg cycling

Inactive forearm muscle oxygenation has been reported to begin decreasing from the respiratory compensation point (RCP) during ramp leg cycling. From the RCP, hyperventilation occurs with a decrease in arterial CO2 pressure (PaCO2). The aim of this study was to determine which of these two factors, hyperventilation or decrease in PaCO2, is related to a decrease in inactive biceps brachii muscle oxygenation during leg cycling. Each subject (n = 7) performed a 6-min two-step leg cycling. The exercise intensity in the first step (3 min) was halfway between the ventilatory threshold and RCP (170+/-21 watts), while that in the second step (3 min) was halfway between the RCP and peak oxygen uptake (240+/-28 watts). The amount of hyperventilation and PaCO2 were calculated from gas parameters. The average cross correlation function in seven subjects between inactive muscle oxygenation and amount of hyperventilation showed a negative peak at the time shift of zero (r = -0.72, p<0.001), while that between inactive muscle oxygenation and calculated PaCO2 showed no peak near the time shift of zero. Thus, we concluded that decrease in oxygenation in inactive arm muscle is closely coupled with increase in the amount of hyperventilation.     

Hypoxia augments apnea-induced peripheral vasoconstriction in humans.

Obstructive apnea and voluntary breath holding are associated with transient increases in muscle sympathetic nerve activity (MSNA) and arterial pressure. The contribution of changes in blood flow relative to the contribution of changes in vascular resistance to the apnea-induced transient rise in arterial pressure is unclear. We measured heart rate, mean arterial blood pressure (MAP), MSNA (peroneal microneurography), and femoral artery blood velocity (V(FA), Doppler) in humans during voluntary end-expiratory apnea while they were exposed to room air, hypoxia (10.5% inspiratory fraction of O2), and hyperoxia (100% inspiratory fraction of O2). Changes from baseline of leg blood flow (Q) and vascular resistance (R) were estimated from the following relationships: Q proportional to V(FA), corrected for the heart rate, and R proportional to MAP/Q. During apnea, MSNA rose; this rise in MSNA was followed by a rise in MAP, which peaked a few seconds after resumption of breathing. Responses of MSNA and MAP to apnea were greatest during hypoxia and smallest during hyperoxia (P < 0.05 for both compared with room air breathing). Similarly, apnea was associated with a decrease in Q and an increase in R. The decrease in Q was greatest during hypoxia and smallest during hyperoxia (-25 +/- 3 vs. -6 +/- 4%, P < 0.05), and the increase in R was the greatest during hypoxia and the least during hyperoxia (60 +/- 8 vs. 21 +/- 6%, P < 0.05). Thus voluntary apnea is associated with vasoconstriction, which is in part mediated by the sympathetic nervous system. Because apnea-induced vasoconstriction is most intense during hypoxia and attenuated during hyperoxia, it appears to depend at least in part on stimulation of arterial chemoreceptors.     

Muscle sympathetic nerve responses to static leg exercise.

Previous studies of muscle sympathetic nerve activity (MSNA) during static exercise have employed predominantly the arms. These studies have revealed striking increases in arm and leg MSNA during static handgrip (SHG) and postexercise circulatory arrest (PECA). The purpose of this study was to examine MSNA during static leg exercise (SLE) at intensities and duration commonly used during SHG followed by PECA. During 2 min of SLE (static knee extension) at 10% of maximal voluntary contraction (MVC; n = 18) in the sitting position, mean arterial pressure and heart rate increased significantly. Surprisingly, MSNA in the contralateral leg did not increase above control levels during SLE but rather decreased (23 +/- 5%; P < 0.05) during the 1st min of SLE at 10% MVC. We compared MSNA responses to SHG and SLE (n = 8) at 30% MVC. SHG and SLE elicited comparable increases (P < 0.05) in arterial pressure and heart rate, but SHG elicited significant increases in MSNA, whereas SLE did not. During PECA after SHG and SLE, mean arterial pressure remained significantly above control. However, MSNA was unchanged during PECA after SLE but was significantly greater than control during PECA after SHG. Because previous studies have indicated differences in MSNA responses to the arm and leg, we measured arm and leg MSNA simultaneously in six subjects during SLE at 20% MVC and PECA. During SLE and PECA, MSNA in the contralateral arm and leg did not differ significantly from each other.(ABSTRACT TRUNCATED AT 250 WORDS)     

Endothelial modulation of neural sympathetic vascular tone in canine skeletal muscle

The effect of nitric oxide synthase (NOS)inhibition and endothelin-A(ET_A)-receptor blockade onneural sympathetic control of vascular tone in the gastrocnemius musclewas examined in anesthetized dogs under conditions of constant flow.Muscle perfusion pressure (MPP) was measured before and after NOSinhibition(N-nitro-L-argininemethyl ester; L-NAME) andET_A-receptor blockade [cyclo-(D-Trp-d-Asp-Pro-D-Val-Leu);BQ-123]. Zero and maximum sympathetic nerve activities wereachieved by sciatic nerve cold block and stimulation, respectively. Ingroup 1 (n = 6), MPP was measured1) before nerve cold block,2) during nerve cold block, and3) during nerve stimulation.Measurements under these conditions were repeated afterL-NAME and then BQ-123. The sameprotocol was followed in group 2 (n = 6) except that the order ofL-NAME and BQ-123 was reversed.MPP and muscle vascular resistance (MVR) increased afterL-NAME and then decreased tocontrol values after BQ-123. MVR decreased after BQ-123 alone and, withthe addition of L-NAME,increased to a level not different from that observed during thecontrol period. MVR fell during nerve cold block. This response was notaffected by administration ofL-NAME followed by BQ-123, butit was attenuated by administration of BQ-123 before L-NAME. The constrictor responseduring sympathetic nerve stimulation was enhanced byL-NAME; no further effect wasobserved with BQ-123, nor was the response affected when BQ-123 wasgiven first. These findings indicate that endothelin contributes to1) basal vascular tone in skeletalmuscle and 2) the increase inskeletal muscle vascular resistance after NOS inhibition. Finally,nitric oxide "buffers" the degree of constriction in skeletalmuscle vasculature during maximal sympathetic stimulation.

     

Influence of muscle mass on sympathetic neural activation during isometric exercise

The primary purpose of this study was to determine whether the sympathetic neural activation induced by isometric exercise is influenced by the size of the contracting muscle mass. To address this, in nine healthy subjects (aged 19-27 yr) we measured heart rate, systolic arterial blood pressure, and muscle sympathetic nerve activity in the leg (MSNA; peroneal nerve) before (control) and during 2.5 min of isometric handgrip exercise (30% of maximal voluntary force). Exercise was performed with the right and left arms separately and with both arms simultaneously (random order). During exercise, heart rate, systolic pressure, and MSNA increased above control under all conditions (P less than 0.05). For each variable, the magnitudes of the increases from control to the end of exercise were significantly greater when exercise was performed with two arms compared with either arm alone (P less than 0.05). In general, the increases in heart rate, systolic pressure, and MSNA elicited during two-arm exercise were significantly less than the simple sums of the responses evoked during exercise of each arm separately. These findings indicate that the magnitude of the sympathetic neural activation evoked during isometric exercise in humans is determined in part by the size of the active muscle mass. In addition, our results suggest that the sympathetic cardiovascular adjustments elicited during exercise of separate limbs are not simply additive but instead exhibit an inhibitory interaction (i.e., neural occlusion).     

Hypoxia and low glucose differentially augments TRAIL-induced apoptotic death

Tumor microenvironment, which is characterized by hypoxia, low-glucose concentrations, high-lactate concentrations, low-extracellular pH, can alter the therapeutic response in tumors. In this study, we investigated whether hypoxia affects TRAIL-induced apoptotic death. When human prostate adenocarcinoma DU-145 cells were treated with 50 ng/mL TRAIL or hypoxia for 4 h, the survival was 45.7 and 32.5%, respectively. The combination of TRAIL and hypoxia synergistically increased cell death. Similar results were observed in human prostate adenocarcinoma LNCaP cells. Western blot analysis showed that the hypoxia augmented TRAIL-induced PARP cleavage as well as the activation of caspase-8 and caspase-3, but not caspase-9. Unlike hypoxia, low glucose promoted caspase-9 activation during TRAIL treatment. These results suggest that hypoxia or low glucose-augmented TRAIL cytotoxicity is mediated through the mitochondria-independent pathway or -dependent pathway, respectively. (Mol Cell Biochem 270: 89–97, 2005)     

Structural changes in locust leg muscle fibres in response to tenotomy and joint immobilization

Tenotomy and immobilization at minimum physiological length resulted in degenerative changes in the ultrastructure of the locust metathoracic flexor tibiae muscle.Degeneration was observed in some muscle fibres 9 days after tenolomy and was progressive, affecting an increasing proportion of fibres at longer times after operation. Changes included disruption and loss of myofilaments, Z-disk streaming, degeneration of sarcoplasmic reticulum, formation of large membranous complexes and changes in number and appearance of mitochondria. Different muscle fibres followed different degenerative pathways. By 73 days very few intact muscle fibres remained.Joint immobilization resulted in similar but much less severe progressive degeneration. Degenerate fibres were largely localized in the distal and medial parts of the muscle. Both immobilized and tenotomized muscles were invaded by large numbers of fat body cells in the later stages of degeneration.Nerve terminals on degenerate tenotomized and immobilized muscle fibres were ultrastructurally normal. Tendinous cells attaching degenerate muscle fibres to the cuticle themselves degenerated.