Muscle metabolism during heavy-intensity exercise after acute acetazolamide administration.
(57/1198)
Carbonic anhydrase (CA) inhibition is associated with a lower plasma lactate concentration ([La(-)](pl)), but the mechanism for this association is not known. The effect of CA inhibition on muscle high-energy phosphates [ATP and phosphocreatine (PCr)], lactate ([La(-)](m)), and glycogen was examined in seven men [28 +/- 3 (SE) yr] during cycling exercise under control (Con) and acute CA inhibition with acetazolamide (Acz; 10 mg/kg body wt iv). Subjects performed 6-min step transitions in work rate from 0 W to a work rate corresponding to approximately 50% of the difference between the O(2) uptake at the ventilatory threshold and peak O(2) uptake. Muscle biopsies were taken from the vastus lateralis at rest, at 30 min postinfusion, at end exercise (EE), and at 5 and 30 min postexercise. Arterialized venous blood was sampled from a dorsal hand vein and analyzed for [La(-)](pl). ATP was unchanged from rest values; no difference between Con and Acz was observed. The fall in PCr from rest [72 +/- 3 and 73 +/- 3.6 (SE) mmol/kg dry wt for Con and Acz, respectively] to EE (51 +/- 4 and 46 +/- 5 mmol/kg dry wt for Con and Acz, respectively) was similar in Con and Acz. At EE, glycogen (mmol glucosyl units/kg dry wt) decreased to similar values in Con and Acz (307 +/- 16 and 300 +/- 19, respectively). At EE, no difference was observed in [La(-)](m) between conditions (46 +/- 6 and 43 +/- 5 mmol/kg dry wt for Con and Acz, respectively). EE [La(-)](pl) was higher during Con than during Acz (11.4 +/- 1.0 vs. 8.2 +/- 0.6 mmol/l). The similar [La(-)](m) but lower [La(-)](pl) suggests that the uptake of La(-) by other tissues is enhanced after CA inhibition. (+info)
Pinacidil suppresses contractility and preserves energy but glibenclamide has no effect during muscle fatigue.
(58/1198)
The effects of 10 microM glibenclamide, an ATP-sensitive K(+) (K(ATP)) channel blocker, and 100 microM pinacidil, a channel opener, were studied to determine how the K(ATP) channel affects mouse extensor digitorum longus (EDL) and soleus muscle during fatigue. Fatigue was elicited with 200-ms-long tetanic contractions every second. Glibenclamide did not affect rate and extent of fatigue, force recovery, or (86)Rb(+) fractional loss. The only effects of glibenclamide during fatigue were: an increase in resting tension (EDL and soleus), a depolarization of the cell membrane, a prolongation of the repolarization phase of action potential, and a greater ATP depletion in soleus. Pinacidil, on the other hand, increased the rate but not the extent of fatigue, abolished the normal increase in resting tension during fatigue, enhanced force recovery, and increased (86)Rb(+) fractional loss in both the EDL and soleus. During fatigue, the decreases in ATP and phosphocreatine of soleus muscle were less in the presence of pinacidil. The glibenclamide effects suggest that fatigue, elicited with intermittent contractions, activates few K(ATP) channels that affect resting tension and membrane potentials but not tetanic force, whereas opening the channel with pinacidil causes a faster decrease in tetanic force, improves force recovery, and helps in preserving energy. (+info)
Energy state, pH, and vasomotor tone during hypoxia in precontracted pulmonary and femoral arteries.
(59/1198)
To assess effects of smooth muscle energy state and intracellular pH (pH(i)) on pulmonary arterial tone during hypoxia, we measured ATP, phosphocreatine, P(i), and pH(i) by (31)P-NMR spectroscopy and isometric tension in phenylephrine-contracted rings of porcine proximal intrapulmonary arteries. Hypoxia caused early transient contraction followed by relaxation and late sustained contraction. Energy state and pH(i) decreased during relaxation and recovered toward control values during late contraction. Femoral arterial rings had higher energy state and lower pH(i) under baseline conditions and did not exhibit late contraction or recovery of energy state and pH(i) during hypoxia. In pulmonary arteries, glucose-free conditions abolished late hypoxic contraction and recovery of energy state and pH(i), but endothelial denudation abolished only late hypoxic contraction. NaCN had little effect at 0. 1 and 1.0 mM but caused marked vasorelaxation and decreases in energy state and pH(i) at 10 mM. These results suggest that 1) regulation of tone, energy state, and pH(i) differed markedly in pulmonary and femoral arterial smooth muscle, 2) hypoxic relaxation was mediated by decreased energy state or pH(i) due to hypoxic inhibition of oxidative phosphorylation, 3) recovery of energy state and pH(i) in hypoxic pulmonary arteries was due to accelerated glycolysis mediated by mechanisms intrinsic to smooth muscle, and 4) late hypoxic contraction in pulmonary arteries was mediated by endothelial factors that required hypoxic recovery of energy state and pH(i) for transduction in smooth muscle or extracellular glucose for production and release by endothelium. (+info)
Free [ADP] and aerobic muscle work follow at least second order kinetics in rat gastrocnemius in vivo.
(60/1198)
The relationship between free cytosolic [ADP] (and [P(i)]) and steady-state aerobic muscle work in rat gastrocnemius muscle in vivo using (31)P NMR was investigated. Anesthetized rats were ventilated and placed in a custom-built cradle fitted with a force transducer that could be placed into a 7-tesla NMR magnet. Muscle work was induced by supramaximal sciatic nerve stimulation that activated all fibers. Muscles were stimulated at 0.1, 0.2, 0.3, 0.4, 0.5, 0.8, 1.0, and 2.0 Hz until twitch force, phosphocreatine, and P(i) were unchanged between two consecutive spectra acquired in 4-min blocks (8-12 min). Parallel bench experiments were performed to measure total tissue glycogen, lactate, total creatine, and pyruvate in freeze-clamped muscles after 10 min of stimulation at each frequency. Up to 0.5 Hz, there was no significant change in muscle glycogen, lactate, and the lactate/pyruvate ratios between 8-12 min. At 0.8 Hz, there was a 17% fall in glycogen and a 65% rise in the muscle lactate with a concomitant fall in pH. Above this frequency, glycogen fell rapidly, lactate continued to rise, and ATP and pH declined. On the basis of these force and metabolic measurements, we estimated the maximal mitochondrial capacity (V(max)) to be 0.8 Hz. Free [ADP] was then calculated at each submaximal workload from measuring all the reactants of the creatine kinase equilibrium after adjusting the K'(CK) to the muscle temp (30 degrees C), pH, and pMg. We show that ADP (and P(i)) and tension-time integral follow a Hill relationship with at least a second order function. The K(0.5) values for free [ADP] and [P(i)] were 48 microM and 9 mM, respectively. Our data did not fit any form of the Michaelis-Menten equation. We therefore conclude that free cytosolic [ADP] and [P(i)] could potentially control steady-state oxidative phosphorylation in skeletal muscle in vivo. (+info)
31P magnetic resonance spectroscopy study of phosphocreatine recovery kinetics in skeletal muscle: the issue of intersubject variability.
(61/1198)
We have analyzed by (31)P MRS the relationship between kinetic parameters of phosphocreatine (PCr) recovery and end-of-exercise status under conditions of moderate and large acidosis induced by dynamic exercise. Thirteen healthy subjects performed muscular contractions at 0.47 Hz (low frequency, moderate exercise) and 0.85 Hz (high frequency, heavy exercise). The rate constant of PCr resynthesis (k(PCr)) varied greatly among subjects (variation coefficients: 43 vs. 57% for LF vs. HF exercises) and protocols (k(PCr) values: 1.3+/-0.5 min(-1) vs. 0.9+/-0.5 min(-1) for LF vs. HF exercises, P<0.03). The large intersubject variability can be captured into a linear relationship between k(PCr), the amount of PCr consumed ([PCr(2)]) and pH reached at the end of exercise (pH(end)) (k(PCr)=-3.3+0.7 pH(end)-0.03 [PCr(2)]; P=0.0007; r=0.61). This dual relationship illustrates that mitochondrial activity is affected by end-of-exercise metabolic status and allows reliable comparisons between control, diseased and trained muscles. In contrast to k(PCr), the initial rate of PCr recovery and the maximum oxidative capacity were always constant whatever the metabolic conditions of end-of-exercise and can then be additionally used in the identification of dysfunctions in the oxidative metabolic pathway. (+info)
Role of TNF-alpha in myocardial dysfunction after hemorrhagic shock and lower-torso ischemia.
(62/1198)
Ruptured abdominal aortic aneurysm (RAAA) repair, a combination of hemorrhagic shock and lower-torso ischemia, is associated with a 50-70% mortality. Myocardial dysfunction may contribute to the high rate of mortality after aneurysm repair. We attempted to determine whether RAAA repair results in cardiac dysfunction mediated by tumor necrosis factor-alpha (TNF-alpha). We modeled aortic rupture and repair in the rat by inducing hemorrhagic shock to a mean blood pressure of 50 mmHg for 1 h, followed by supramesenteric clamping of the aorta for 45 min. After 90 min of reperfusion, cardiac contractile function was assessed with a Langendorff preparation. Myocardial TNF-alpha, ATP and creatine phosphate (CP) levels, and markers of oxidant stress (F(2)-isoprostanes) were measured. Cardiac function in the combined shock and clamp rats was significantly depressed compared with sham-operated control rats but was similar to that noted in animals subjected to shock alone. Myocardial TNF-alpha concentrations increased 10-fold in the combined shock and clamp rats compared with sham rats, although there was no difference in myocardial ATP, CP, or F(2)-isoprostanes. TNF-alpha neutralization improved cardiac function by 50% in the combined shock and clamp rats. Hemorrhagic shock is the primary insult inducing cardiac dysfunction in this model of RAAA repair. An improvement in cardiac contractile function after immunoneutralization of TNF-alpha indicates that TNF-alpha mediates a significant portion of the myocardial dysfunction in this model. (+info)
Blunted pressor and intramuscular metabolic responses to voluntary isometric exercise in multiple sclerosis.
(63/1198)
To test the hypothesis that a lower mean arterial pressure (MAP) response during voluntary isometric exercise in multiple sclerosis (MS) is related to a dampened muscle metabolic signal, 9 MS and 11 control subjects performed an isometric dorsiflexor contraction at 30% maximal voluntary contraction until target failure (endurance time). We made continuous and noninvasive measurements of heart rate and MAP (Finapres) and of intramuscular pH and P(i) (phosphorus magnetic resonance spectroscopy) in a subset of 6 MS and 10 control subjects. Endurance times and change in heart rate were similar in MS and control subjects. The decrease in pH and increase in P(i) were less throughout exercise in MS compared with control subjects, as was the change in MAP response. Differences in muscle strength accounted for some of the difference in MAP response between groups. Cardiovascular responses during Valsalva and cold pressor tests were similar in MS and control subjects, suggesting that the blunted MAP response during exercise in MS was not due to a generalized dysautonomia. The dampened metabolic response in MS subjects was not explained by inadequate central muscle activation. These data suggest that the blunted pressor response to exercise in MS subjects may be largely appropriate to a blunted muscle metabolic response and differences in contracting muscle mass. (+info)
Effects of loaded breathing and hypoxia on diaphragm metabolism as measured by (31)P-NMR spectroscopy.
(64/1198)
Diaphragm fatigue may contribute to respiratory failure. (31)P-nuclear magnetic resonance spectroscopy is a useful tool to assess energetic changes within the diaphragm during fatigue, as indicated by P(i) accumulation and phosphocreatine (PCr) depletion. We hypothesized that loaded breathing during hypoxia would lead to diaphragm fatigue and inadequate aerobic metabolism. Seven piglets were anesthetized by using halothane inhalation. Diaphragmatic contractility was assessed by transdiaphragmatic pressure (Pdi) at end expiration with the airway occluded. A nuclear magnetic resonance surface coil placed under the right hemidiaphragm measured P(i) and PCr during four conditions: control, inspiratory resistive breathing (IRB), IRB with hypoxia, and recovery (IRB without hypoxia). IRB alone resulted in hypercarbia (32 +/- 7 to 61 +/- 21 Torr) and respiratory acidosis but no change in diaphragm force output or aerobic metabolism. Combined IRB and hypoxia resulted in decreased force output (Pdi decreased by 40%; from 30 +/- 17 to 19 +/- 11 mmHg) and evidence of metabolic stress (ratio of P(i) to PCr increased by 290%; from 0.19 +/- 0.09 to 0.74 +/- 0.27). We conclude that diaphragm fatigue associated with inadequate aerobic oxidative metabolism occurs in the setting of loaded breathing and hypoxia. Conversely, aerobic metabolism and force output of the diaphragm remain unchanged from control during loaded normoxic or hyperoxic breathing despite the onset of respiratory failure. (+info)