Sarcolemmal excitability as investigated with M-waves after eccentric exercise in humans.

It has been shown that intensive eccentric muscle actions lead to prolonged loss of muscle force and sarcolemmal damage. This may lead to a reduction in the excitability of the sarcolemma and contribute to the functional deficit. Experiments were carried out to test sarcolemmal excitability after eccentric elbow flexor exercise in humans. Electrically elicited surface compound muscle action potential (M-wave) properties from 30s stimulation trains (20Hz) were analyzed in biceps brachii muscle immediately after, 1h and 48h after the exercise. M-wave area, amplitude, root mean square and duration were reduced immediately after the eccentric exercise. However, no such reduction could be observed 48h after the exercise, although the maximal voluntary isometric and eccentric torques were still depressed by 12.2+/-9% (P<0.001) and 17.7+/-9% (P<0.001), respectively. Acute increase in plasma concentrations of K(+) and Ca(2+) were also observed after the eccentric exercise. These findings suggest that eccentric exercise may acutely decrease sarcolemmal excitability, which seems to be partially related to increased extracellular ion concentrations. However, disturbance of sarcolemmal excitability is not the major factor determining eccentric exercise induced prolonged loss of muscle strength, because no prolonged impairment was observed in any of the studied M-wave parameters.     

Effects of 8 wk of voluntary unloaded wheel running on K+ tolerance and excitability of soleus muscles in rat

During intense exercise, efflux of K(+) from working muscles increases extracellular K(+) ([K(+)](o)) to levels that can compromise muscle excitability and hence cause fatigue. In this context, the reduction in the exercise-induced elevation of [K(+)](o) observed after training in humans is suggested to contribute to the increased performance after training. Although a similar effect could be obtained by an increase in the tolerance of muscle to elevated [K(+)](o), this possibility has not been investigated. To examine this, isolated soleus muscles from sedentary (sedentary) rats and from rats that had voluntarily covered 13.1 ± 0.7 km/day in an unloaded running wheel for 8 wk (active) were compared. In muscles from active rats, the loss of force induced by exposure to an elevated [K(+)](o) of 9 mM was 42% lower than in muscles from sedentary rats (P < 0.001). This apparent increase in K(+) tolerance in active rats was associated with an increased excitability as evident from a 33% reduction in the electrical current needed to excite individual muscle fibers (P < 0.0009). Moreover, muscles from active rats had lower Cl(-) conductance, higher maximal rate of rise of single-fiber action potentials (AP), and higher Na(+)/K(+) pump content. When stimulated intermittently at 6.5 mM K(+), muscles from active rats displayed better endurance than muscles from sedentary rats, whereas no difference was found when the muscles were stimulated continuously at 30 or 120 Hz. We conclude that voluntary running increases muscle excitability, leading to improved tolerance to elevated [K(+)](o).     

Caffeine intake improves intense intermittent exercise performance and reduces muscle interstitial potassium accumulation

The effect of oral caffeine ingestion on intense intermittent exercise performance and muscle interstitial ion concentrations was examined. The study consists of two studies (S1 and S2). In S1, 12 subjects completed the Yo-Yo intermittent recovery level 2 (Yo-Yo IR2) test with prior caffeine (6 mg/kg body wt; CAF) or placebo (PLA) intake. In S2, 6 subjects performed one low-intensity (20 W) and three intense (50 W) 3-min (separated by 5 min) one-legged knee-extension exercise bouts with (CAF) and without (CON) prior caffeine supplementation for determination of muscle interstitial K(+) and Na(+) with microdialysis. In S1 Yo-Yo IR2 performance was 16% better (P < 0.05) in CAF compared with PLA. In CAF, plasma K(+) at the end of the Yo-Yo IR2 test was 5.2 ± 0.1 mmol/l with no difference between the trials. Plasma free fatty acids (FFA) were higher (P < 0.05) in CAF than PLA at rest and remained higher (P < 0.05) during exercise. Peak blood glucose (8.0 ± 0.6 vs. 6.2 ± 0.4 mmol/l) and plasma NH(3) (137.2 ± 10.8 vs. 113.4 ± 13.3 μmol/l) were also higher (P < 0.05) in CAF compared with PLA. In S2 interstitial K(+) was 5.5 ± 0.3, 5.7 ± 0.3, 5.8 ± 0.5, and 5.5 ± 0.3 mmol/l at the end of the 20-W and three 50-W periods, respectively, in CAF, which were lower (P < 0.001) than in CON (7.0 ± 0.6, 7.5 ± 0.7, 7.5 ± 0.4, and 7.0 ± 0.6 mmol/l, respectively). No differences in interstitial Na(+) were observed between CAF and CON. In conclusion, caffeine intake enhances fatigue resistance and reduces muscle interstitial K(+) during intense intermittent exercise.     

Activity-induced recovery of excitability in K(+)-depressed rat soleus muscle

Increased extracellular K(+) concentration ([K(+)](o)) can reduce excitability and force in skeletal muscle. Here we examine the effects of muscle activation on compound muscle action potentials (M waves), resting membrane potential, and contractility in isolated rat soleus muscles. In muscles incubated for 60 min at 10 mM K(+), tetanic force and M wave area decreased to 23 and 24%, respectively, of the control value. Subsequently, short (1.5 s) tetanic stimulations given at 1-min intervals induced recovery of force and M wave area to 81 and 90% of control levels, respectively, within 15 min (P < 0.001). The recovery of force and M wave was associated with a partial repolarization of the muscle fibers. Experiments with tubocurarine suggest that the force recovery was related to activation of muscle Na(+)-K(+) pumps caused by the release of some compound from sensory nerves in response to muscle activity. In conclusion, activity produces marked recovery of excitability in K(+)-depressed muscle, and this may protect muscles against fatigue caused by increased [K(+)](o) during exercise.     

Increased excitability of acidified skeletal muscle: role of chloride conductance

Generation of the action potentials (AP) necessary to activate skeletal muscle fibers requires that inward membrane currents exceed outward currents and thereby depolarize the fibers to the voltage threshold for AP generation. Excitability therefore depends on both excitatory Na+ currents and inhibitory K+ and Cl- currents. During intensive exercise, active muscle loses K+ and extracellular K+ ([K+]o) increases. Since high [K+]o leads to depolarization and ensuing inactivation of voltage-gated Na+ channels and loss of excitability in isolated muscles, exercise-induced loss of K+ is likely to reduce muscle excitability and thereby contribute to muscle fatigue in vivo. Intensive exercise, however, also leads to muscle acidification, which recently was shown to recover excitability in isolated K(+)-depressed muscles of the rat. Here we show that in rat soleus muscles at 11 mM K+, the almost complete recovery of compound action potentials and force with muscle acidification (CO2 changed from 5 to 24%) was associated with reduced chloride conductance (1731 +/- 151 to 938 +/- 64 microS/cm2, P < 0.01) but not with changes in potassium conductance (405 +/- 20 to 455 +/- 30 microS/cm2, P < 0.16). Furthermore, acidification reduced the rheobase current by 26% at 4 mM K+ and increased the number of excitable fibers at elevated [K+]o. At 11 mM K+ and normal pH, a recovery of excitability and force similar to the observations with muscle acidification could be induced by reducing extracellular Cl- or by blocking the major muscle Cl- channel, ClC-1, with 30 microM 9-AC. It is concluded that recovery of excitability in K(+)-depressed muscles induced by muscle acidification is related to reduction in the inhibitory Cl- currents, possibly through inhibition of ClC-1 channels, and acidosis thereby reduces the Na+ current needed to generate and propagate an AP. Thus short term regulation of Cl- channels is important for maintenance of excitability in working muscle.     

Effects of calcitonin gene-related peptide on rat soleus muscle excitability: mechanisms and physiological significance

Intense exercise causes a large loss of K(+) from contracting muscles. The ensuing elevation of extracellular K(+) ([K(+)](o)) has been suggested to cause fatigue by depressing muscle fiber excitability. In isolated muscles, however, repeated contractions confer some protection against this effect of elevated K(+). We hypothesize that this excitation-induced force-recovery is related to the release of the neuropeptide calcitonin gene-related peptide (CGRP), which stimulates the muscular Na(+)-K(+) pumps. Using the specific CGRP antagonist CGRP-(8-37), we evaluated the role of CGRP in the excitation-induced force recovery and examined possible mechanisms. Intact rat soleus muscles were stimulated to evoke short tetani at regular intervals. Increasing extracellular K(+) ([K(+)](o)) from 4 to 11 mM decreased force to approximately 20% of initial force (P < 0.001). Addition of exogenous CGRP (10(-9) M), release of endogenous CGRP with capsaicin, or repeated electrical stimulation recovered force to 50-70% of initial force (P < 0.001). In all cases, force recovery could be almost completely suppressed by CGRP-(8-37). At 11 mM [K(+)](o), CGRP (10(-8) M) did not alter resting membrane potential or conductance but significantly improved action potentials (P < 0.001) and increased the proportion of excitable fibers from 32 to 70% (P < 0.001). CGRP was shown to induce substantial force recovery with only modest Na(+)-K(+) pump stimulation. We conclude that the excitation-induced force recovery is caused by a recovery of excitability, induced by local release of CGRP. The data suggest that the recovery of excitability partly was induced by Na(+)-K(+) pump stimulation and partly by altering Na(+) channel function.     

Four weeks of normobaric "live high-train low" do not alter muscular or systemic capacity for maintaining pH and K⁺ homeostasis during intense exercise

It was investigated if athletes subjected to 4 wk of living in normobaric hypoxia (3,000 m; 16 h/day) while training at 800-1,300 m ["live high-train low" (LHTL)] increase muscular and systemic capacity for maintaining pH and K(+) homeostasis as well as intense exercise performance. The design was double-blind and placebo controlled. Mean power during 30-s all-out cycling was similar before and immediately after LHTL (650 ± 31 vs. 628 ± 32 W; n = 10) and placebo exposure (658 ± 22 vs. 660 ± 23 W; n = 6). Supporting the performance data, arterial plasma pH, lactate, and K(+) during submaximal and maximal exercise were also unaffected by the intervention in both groups. In addition, muscle buffer capacity (in mmol H(+)·kg dry wt(-1)·pH(-1)) was similar before and after in both the LHTL (140 ± 12 vs. 140 ± 16) and placebo group (145 ± 2 vs. 140 ± 3). The expression of sarcolemmal H(+) transporters (Na(+)/H(+) exchanger 1, monocarboxylate transporters 1 and 4), as well as expression of Na(+)-K(+) pump subunits-α(1), -α(2), and -β(1) was also similar before and after the intervention. In conclusion, muscular and systemic capacity for maintaining pH and K(+) balance during exercise is similar before and after 4 wk of placebo-controlled normobaric LHTL. In accordance, 30-s all-out sprint ability was similar before and after LHTL.     

Effects of forearm bier block with bretylium on the hemodynamic and metabolic responses to handgrip

We tested the hypothesis that a reduction in sympathetic tone to exercising forearm muscle would increase blood flow, reduce muscle acidosis, and attenuate reflex responses. Subjects performed a progressive, four-stage rhythmic handgrip protocol before and after forearm bier block with bretylium as forearm blood flow (Doppler) and metabolic (venous effluent metabolite concentration and (31)P-NMR indexes) and autonomic reflex responses (heart rate, blood pressure, and sympathetic nerve traffic) were measured. Bretylium inhibits the release of norepinephrine at the neurovascular junction. Bier block increased blood flow as well as oxygen consumption in the exercising forearm (P < 0.03 and P < 0.02, respectively). However, despite this increase in flow, venous K(+) release and H(+) release were both increased during exercise (P < 0.002 for both indexes). Additionally, minimal muscle pH measured during the first minute of recovery with NMR was lower after bier block (6.41 +/- 0.08 vs. 6.20 +/- 0.06; P < 0.036, simple effects). Meanwhile, reflex effects were unaffected by the bretylium bier block. The results support the conclusion that sympathetic stimulation to muscle during exercise not only limits muscle blood flow but also appears to limit anaerobiosis and H(+) release, presumably through a preferential recruitment of oxidative fibers.     

Relationship of CSF pH, O2, and CO2 responses in metabolic acidosis and alkalosis in humans

The effect of induced metabolic acidosis (48 h of NH4Cl ingestion, BE - 10.6 +/- 1.1) and alkalosis (43 h of NaHCO3- ingestion BE 8.8 +/- 1.6) on arterial and lumber CSF pH, Pco2, and HCO3- and ventilatory responses to CO2 and to hypoxia was assessed in five healthy men. In acidosis lumbar CSF pH rose 0.033 +/- 0.02 (P less than 0.05). In alkalosis CSF pH was unchanged. Ventilatory response lines to CO2 at high O2 were displaced to the left in acidosis (9.0 +/- 1.4 Torr) and to the right in alkalosis (4.5 +/- 1.5 Torr) with no change in slope. The ventilatory response to hypoxia (delta V40) was increased in acidosis (P less than 0.05) and it was decreased in four subjects in alkalosis (P, not significant). We conclude that the altered ventilatory drives of steady-state metabolic imbalance are mediated by peripheral chemoreceptors, and in acidosis the medullary respiratory chemoreceptor drive is decreased.     

Exercise-induced regulation of muscular Na+-K+ pump, FXYD1, and NHE1 mRNA and protein expression: importance of training status, intensity, and muscle type

It is investigated if exercise-induced mRNA changes cause similar protein expression changes of Na(+)-K(+) pump isoforms (α(1), α(2), β(1), β(2)), FXYD1, and Na(+)/K(+) exchanger (NHE1) in rat skeletal muscle. Expression was evaluated (n = 8 per group) in soleus and extensor digutorum longus after 1 day, 3 days, and 3 wk (5 sessions/wk) of either sprint (4 × 3-min sprint + 1-min rest) or endurance (20 min) running. Two hours after exercise on day 1, no change in protein expression was apparent in either training group or muscle, whereas sprint exercise increased the mRNA of soleus α(2) (4.9 ± 0.8-fold; P < 0.05), β(2) (13.2 ± 4.4-fold; P < 0.001), and NHE1 (12.0 ± 3.1-fold; P < 0.01). Two hours after sprint exercise, protein expression normalized to control samples was higher on day 3 than day 1 for soleus α(1) (41 ± 18% increase vs. 15 ± 8% reduction; P < 0.05), α(2) (64 ± 35% increase vs. 37 ± 12% reduction; P < 0.05), β(1) (17 ± 21% increase vs. 14 ± 29% reduction; P < 0.05), and FXYD1 (35 ± 16% increase vs. 13 ± 10% reduction; P < 0.05). In contrast, on day 3, soleus α(1) (0.1 ± 0.1-fold; P < 0.001), α(2) (0.2 ± 0.1-fold; P < 0.001), β(1) (0.4 ± 0.1-fold; P < 0.05), and β(2)-mRNA (2.9 ± 1.7-fold; P < 0.001) expression was lower than after exercise on day 1. After 3 wk of training, no change in protein expression relative to control existed. In conclusion, increased expression of Na(+)-K(+) pump subunits, FXYD1 and NHE1 after 3 days exercise training does not appear to be an effect of increased constitutive mRNA levels. Importantly, sprint exercise can reduce mRNA expression concomitant with increased protein expression.     

Effect of pH on metabolic and cardiorespiratory responses during progressive exercise

Six healthy male subjects performed three exercise tests in which the power output was increased by 100 kpm/min each minute until exhaustion. The studies were carried out after oral administration of CaCO3 (control), NH4Cl (metabolic acidosis), and NaHCO3 (metabolic alkalosis). Ventilation (VE), O2 intake (VO2), and CO2 output (VCO2) were monitored continuously. Arterialized-venous blood samples were drawn at specific times and analyzed for pH, PCO2, and lactate concentration. Resting pH (mean +/- SE) was lowest in acidosis (7.29 +/- 0.01) and highest in alkalosis (7.46 +/- 0.02). A lower peak power output (kpm/min) was achieved in acidosis (1,717 +/- 95) compared with control (1,867 +/- 120) alkalosis (1,867 +/- 125). Submaximal VO2 and VCO2 were similar, but peak VO2 and VCO2 were lower in acidosis. Plasma lactate concentration was lower at rest and during exercise in acidosis. Although lactate accumulation was reduced in acidosis, increases in hydrogen ion concentration were similar in the three conditions. We conclude that acid-base changes influence the maximum power output that may be sustained in incremental dynamic exercise and modify plasma lactate appearance, but have little effect on hydrogen ion appearance in plasma.     

Effect of respiratory alkalosis during exercise on blood lactate

A biofeedback model of hyperventilation during exercise was used to assess the independent effects of pH, arterial CO2 partial pressure (PaCO2), and minute ventilation on blood lactate during exercise. Eight normal subjects were studied with progressive upright bicycle exercise (2-min intervals, 25-W increments) under three experimental conditions in random order. Arterialized venous blood was drawn at each work load for measurement of blood lactate, pH, and PaCO2. Results were compared with those from reproducible control tests. Experimental conditions were 1) biofeedback hyperventilation (to increase pH by 0.08-0.10 at each work load); 2) hyperventilation following acetazolamide (which returned pH to control values despite ventilation and PaCO2 identical to condition 1); and 3) metabolic acidosis induced by acetazolamide (with spontaneous ventilation). The results showed an increase in blood lactate during hyperventilation. Blood lactate was similar to control with hyperventilation after acetazolamide, suggesting that the change was due to pH and not to PaCO2 or total ventilation. Exercise during metabolic acidosis (acetazolamide alone) was associated with blood lactate lower than control values. Respiratory alkalosis during exercise increases blood lactate. This is due to the increase in pH and not to the increase in ventilation or the decrease in PaCO2.     

Human neuromuscular fatigue is associated with altered Na+-K+-ATPase activity following isometric exercise.

The purpose of this study was to investigate the hypothesis that reductions in Na+-K+- ATPase activity are associated with neuromuscular fatigue following isometric exercise. In control (Con) and exercised (Ex) legs, force and electromyogram were measured in 14 volunteers [age, 23.4 +/- 0.7 (SE) yr] before and immediately after (PST0), 1 h after (PST1), and 4 h after (PST4) isometric, single-leg extension exercise at ~60% of maximal voluntary contraction for 30 min using a 0.5 duty cycle (5-s contraction, 5-s rest). Tissue was obtained from vastus lateralis muscle before exercise in Con and after exercise in both the Con (PST0) and Ex legs (PST0, PST1, PST4), for the measurements of Na+-K+-ATPase activity, as determined by the 3-O-methylfluorescein phosphatase (3-O-MFPase) assay. Voluntary (maximal voluntary contraction) and elicited (10, 20, 50, 100 Hz) force was reduced 30-55% (P < 0.05) at PST0 and did not recover by PST4. Muscle action potential (M-wave) amplitude and area (measured in the vastus medialis) and 3-O-MFPase activity at PST0-Ex were less than that at PST0-Con (P < 0.05) by 37, 25, and 38%, respectively. M-wave area at PST1-Ex was also less than that at PST1-Con (P < 0.05). Changes in 3-O-MFPase activity correlated to changes in M-wave area across all time points (r = 0.38, P < 0.05, n = 45). These results demonstrate that Na+-K+- ATPase activity is reduced by sustained isometric exercise in humans from that in a matched Con leg and that this reduction in Na+-K+-ATPase activity is associated with loss of excitability as indicated by M-wave alterations.     

Mediators of alkalosis-induced relaxation of piglet pulmonary veins

Pulmonary venous constriction leads to significant pulmonary hypertension and increased edema formation in several models using newborns. Although alkalosis is widely used in treating neonatal and pediatric pulmonary hypertension, its effects on pulmonary venous tone have not previously been directly measured. This study sought to determine whether alkalosis caused pulmonary venous relaxation and, if so, to identify the mediator(s) involved. Pulmonary venous rings (500-microm external diameter) were isolated from 1-wk-old piglets and precontracted with the thromboxane mimetic U-46619. Responses to hypocapnic alkalosis were then measured under control conditions after inhibition of endothelium-derived modulator activity or K(+) channels. In control rings, alkalosis caused a 34.4 +/- 4.8% decrease in the U-46619-induced contraction. This relaxation was significantly blunted in rings without functional endothelium and in rings treated with nitric oxide synthase or guanylate cyclase inhibitors. However, neither cyclooxygenase inhibition nor voltage-dependent, calcium-dependent, or ATP-dependent K(+)-channel inhibitors altered alkalosis-induced relaxation. These data suggest that alkalosis caused significant dilation of piglet pulmonary veins that was mediated by the nitric oxide-cGMP pathway.     

NaHCO3-induced alkalosis reduces the phosphocreatine slow component during heavy-intensity forearm exercise.

During heavy-intensity exercise, the mechanisms responsible for the continued slow decline in phosphocreatine concentration ([PCr]) (PCr slow component) have not been established. In this study, we tested the hypothesis that a reduced intracellular acidosis would result in a greater oxidative flux and, consequently, a reduced magnitude of the PCr slow component. Subjects (n = 10) performed isotonic wrist flexion in a control trial and in an induced alkalosis (Alk) trial (0.3g/kg oral dose of NaHCO3, 90 min before testing). Wrist flexion, at a contraction rate of 0.5 Hz, was performed for 9 min at moderate- (75% of onset of acidosis; intracellular pH threshold) and heavy-intensity (125% intracellular pH threshold) exercise. 31P-magnetic resonance spectroscopy was used to measure intracellular [H+], [PCr], [Pi], and [ATP]. The initial recovery data were used to estimate the rate of ATP synthesis and oxidative flux at the end of heavy-intensity exercise. In repeated trials, venous blood sampling was used to measure plasma [H+], [HCO3-], and [Lac-]. Throughout rest and exercise, plasma [H+] was lower (P < 0.05) and [HCO3-] was elevated (P < 0.05) in Alk compared with control. During the final 3 min of heavy-intensity exercise, Alk caused a lower (P < 0.05) intracellular [H+] [246 (SD 117) vs. 291 nmol/l (SD 129)], a greater (P < 0.05) [PCr] [12.7 (SD 7.0) vs. 9.9 mmol/l (SD 6.0)], and a reduced accumulation of [ADP] [0.065 (SD 0.031) vs. 0.098 mmol/l (SD 0.059)]. Oxidative flux was similar (P > 0.05) in the conditions at the end of heavy-intensity exercise. In conclusion, our results are consistent with a reduced intracellular acidosis, causing a decrease in the magnitude of the PCr slow component. The decreased PCr slow component in Alk did not appear to be due to an elevated oxidative flux.     

Exertional dyspnea in mitochondrial myopathy: clinical features and physiological mechanisms

Exertional dyspnea limits exercise in some mitochondrial myopathy (MM) patients, but the clinical features of this syndrome are poorly defined, and its underlying mechanism is unknown. We evaluated ventilation and arterial blood gases during cycle exercise and recovery in five MM patients with exertional dyspnea and genetically defined mitochondrial defects, and in four control subjects (C). Patient ventilation was normal at rest. During exercise, MM patients had low Vo(2peak) (28 ± 9% of predicted) and exaggerated systemic O(2) delivery relative to O(2) utilization (i.e., a hyperkinetic circulation). High perceived breathing effort in patients was associated with exaggerated ventilation relative to metabolic rate with high VE/VO(2peak), (MM = 104 ± 18; C = 42 ± 8, P ≤ 0.001), and Ve/VCO(2peak)(,) (MM = 54 ± 9; C = 34 ± 7, P ≤ 0.01); a steeper slope of increase in ΔVE/ΔVCO(2) (MM = 50.0 ± 6.9; C = 32.2 ± 6.6, P ≤ 0.01); and elevated peak respiratory exchange ratio (RER), (MM = 1.95 ± 0.31, C = 1.25 ± 0.03, P ≤ 0.01). Arterial lactate was higher in MM patients, and evidence for ventilatory compensation to metabolic acidosis included lower Pa(CO(2)) and standard bicarbonate. However, during 5 min of recovery, despite a further fall in arterial pH and lactate elevation, ventilation in MM rapidly normalized. These data indicate that exertional dyspnea in MM is attributable to mitochondrial defects that severely impair muscle oxidative phosphorylation and result in a hyperkinetic circulation in exercise. Exaggerated exercise ventilation is indicated by markedly elevated VE/VO(2), VE/VCO(2), and RER. While lactic acidosis likely contributes to exercise hyperventilation, the fact that ventilation normalizes during recovery from exercise despite increasing metabolic acidosis strongly indicates that additional, exercise-specific mechanisms are responsible for this distinctive pattern of exercise ventilation.     

Effect of downhill running on motoneuron pool excitability.

The purpose of this study was to compare alterations in motoneuron pool excitability after eccentric-biased (ECC-B) downhill running exercise with non-biased (NO-B) level running exercise. Six male subjects (25-34 yr) participated in the study, which included ECC-B exercise (-10% grade) and NO-B exercise (0% grade) at 50% of maximal O2 uptake for 20 min. The control trial consisted of 20 min of quiet rest with all subjects participating in all conditions (repeated measures). Motoneuron pool excitability was measured by the Hoffman reflex (H-wave), which was expressed as a ratio (H/M ratio) of the maximal electrically stimulated muscle action potential (M-wave). NO-B exercise resulted in a 9.3 +/- 2.7% (SE) reduction in the H/M ratio. ECC-B exercise resulted in a 24.6 +/- 5.7% reduction in the ratio (P less than 0.05 for both). The two exercise treatment conditions were also significantly different from one another (P less than 0.05). Twenty-four-hour postexercise H/M ratios were similar to baseline (P greater than 0.05). Postexercise subjective muscle soreness assessment (DOMS) produced significant increases in DOMS of 36 and 166% immediately and 24 h after exercise, respectively, for the ECC-B trial only (P less than 0.001). The data show that ECC-B exercise results in greater postexercise H/M ratio reductions than NO-B exercise and that H/M ratio changes post-ECC-B exercise are not solely associated with DOMS.     

Combined in situ analysis of metabolic and myoelectrical changes associated with electrically induced fatigue.

Electrical muscle stimulation (Mstim) at a low or high frequency is associated with failure of force production, but the exact mechanisms leading to fatigue in this model are still poorly understood. Using 31P magnetic resonance spectroscopy (31PMRS), we investigated the metabolic changes in rabbit tibialis anterior muscle associated with the force decline during Mstim at low (10 Hz) and high (100 Hz) frequency. We also simultaneously recorded the compound muscle mass action potential (M-wave) evoked by direct muscle stimulation, and we analyzed its post-Mstim variations. The 100-Hz Mstim elicited marked M-wave alterations and induced mild metabolic changes at the onset of stimulation followed by a paradoxical recovery of phosphocreatine (PCr) and pH during the stimulation period. On the contrary, the 10-Hz Mstim produced significant PCr consumption and intracellular acidosis with no paradoxical recovery phenomenon and no significant changes in M-wave characteristics. In addition, the force depression was linearly linked to the stimulation-induced acidosis and PCr breakdown. These results led us to conclude that force failure during 100-Hz Mstim only results from an impaired propagation of muscle action potentials with no metabolic involvement. On the contrary, fatigue induced by 10-Hz Mstim is closely associated with metabolic changes with no alteration of the membrane excitability, thereby underlining the central role of muscle energetics in force depression when muscle is stimulated at low frequency. Finally, our results further indicate a reduction of energy cost of contraction when stimulation frequency is increased from 10 to 100 Hz.     

Extracellular proton depression of peak and late Na⁺ current in the canine left ventricle

Cardiac ischemia reduces excitability in ventricular tissue. Acidosis (one component of ischemia) affects a number of ion currents. We examined the effects of extracellular acidosis (pH 6.6) on peak and late Na(+) current (I(Na)) in canine ventricular cells. Epicardial and endocardial myocytes were isolated, and patch-clamp techniques were used to record I(Na). Action potential recordings from left ventricular wedges exposed to acidic Tyrode solution showed a widening of the QRS complex, indicating slowing of transmural conduction. In myocytes, exposure to acidic conditions resulted in a 17.3 ± 0.9% reduction in upstroke velocity. Analysis of fast I(Na) showed that current density was similar in epicardial and endocardial cells at normal pH (68.1 ± 7.0 vs. 63.2 ± 7.1 pA/pF, respectively). Extracellular acidosis reduced the fast I(Na) magnitude by 22.7% in epicardial cells and 23.1% in endocardial cells. In addition, a significant slowing of the decay (time constant) of fast I(Na) was observed at pH 6.6. Acidosis did not affect steady-state inactivation of I(Na) or recovery from inactivation. Analysis of late I(Na) during a 500-ms pulse showed that the acidosis significantly reduced late I(Na) at 250 and 500 ms into the pulse. Using action potential clamp techniques, application of an epicardial waveform resulted in a larger late I(Na) compared with when an endocardial waveform was applied to the same cell. Acidosis caused a greater decrease in late I(Na) when an epicardial waveform was applied. These results suggest acidosis reduces both peak and late I(Na) in both cell types and contributes to the depression in cardiac excitability observed under ischemic conditions.     

Metabolic determinants of the onset of acidosis in exercising human muscle: a 31P-MRS study.

Onset of intracellular acidosis during muscular exercise has been generally attributed to activation or hyperactivation of nonoxidative ATP production but has not been analyzed quantitatively in terms of H(+) balance, i.e., production and removal mechanisms. To address this issue, we have analyzed the relation of intracellular acidosis to H(+) balance during exercise bouts in seven healthy subjects. Each subject performed a 6-min ramp rhythmic exercise (finger flexions) at low frequency (LF, 0.47 Hz), leading to slight acidosis, and at high frequency (HF, 0.85 Hz), inducing a larger acidosis. Metabolic changes were recorded using (31)P-magnetic resonance spectroscopy. Onset of intracellular acidosis was statistically identified after 3 and 4 min of exercise for HF and LF protocols, respectively. A detailed investigation of H(+) balance indicated that, for both protocols, nonoxidative ATP production preceded a change in pH. For HF and LF protocols, H(+) consumption through the creatine kinase equilibrium was constant in the face of increasing H(+) generation and efflux. For both protocols, changes in pH were not recorded as long as sources and sinks for H(+) approximately balanced. In contrast, a significant acidosis occurred after 4 min of LF exercise and 3 min of HF exercise, whereas the rise in H(+) generation exceeded the rise in H(+) efflux at a nearly constant H(+) uptake associated with phosphocreatine breakdown. We have clearly demonstrated that intracellular acidosis in exercising muscle does not occur exclusively as a result of nonoxidative ATP production but, rather, reflects changes in overall H(+) balance.