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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypoxic, hypercapnic acidosis (HHA) decreases tension and enhances fatigue in hamster diaphragm in vitro. We hypothesized that theophylline would decrease the harmful effect of HHA. Hamster diaphragm strips were studied in Krebs solution aerated with 21% O2 and 12% CO2. The force-frequency responses and the tension and relaxation of brief, submaximal contractions were studied. Mild fatigue was produced by a series of 45 submaximal contractions, after which recovery of force was followed for 15 min. Theophylline (0.55 mM) was added at the time of exposure to HHA (early theophylline) in half the strips and at the end of the fatigue run (late theophylline) in the others. In contrast to our hypothesis, early theophylline had a limited effect on force production in unfatigued HHA diaphragm strips and resulted in lower force production in the recovery period. Late theophylline improved force in the recovery period for low-frequency contractions. Thus the effect of theophylline in the setting of HHA depended on the time it was added and was beneficial only if added after the muscle stopped contracting.
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PMID:The effect of theophylline on hypoxic, hypercapnic hamster diaphragm muscle in vitro. 202 50

The traditional role of theophylline as a bronchodilator has been expanded by recent findings that suggest this drug has more than smooth muscle relaxant properties. Several investigators indicate that theophylline has an inotropic effect on respiratory muscle, causing enhanced muscular contraction and prevention of muscle fatigue. In animal studies, the drug enhanced respiratory muscle contraction by 15-20%, with levels in the upper end of the therapeutic range (15-20 mg/L). Results of studies in healthy volunteers and patients with lung disease, however, are conflicting. Five clinical trials demonstrated increased diaphragmatic contractility, whereas seven trials showed no effect, with five referring to the diaphragm and the remaining two to the sternomastoid muscle. Disparity in outcomes may be attributed to differences in patient populations, study designs, and techniques used to determine diaphragmatic contractility. Few long-term trials exist that document significant clinical benefit. Theophylline may prove to be of value in selected populations, such as adults with hypercapnic obstructive lung disease.
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PMID:The effect of theophylline on respiratory muscle contractility and fatigue. 220 60

Theophylline improves diaphragmatic contractility of the respiratory muscles both in isolated muscle preparations, as well as in animals and normal human beings. Furthermore, theophylline restores diaphragmatic fatigue and prevents fatigue of the diaphragm when given prophylactically. Finally, it was recently shown that theophylline improves diaphragmatic function in COPD patients, all of whom were CO2 retainers (PaCO2 53 +/- 3 mm Hg) and hypoxemic (PaO2 57 +/- 8 mm Hg). Patients improved transdiaphragmatic pressure and were less susceptible to fatigue. Presently the mechanisms of action of theophylline regarding its effects on diaphragmatic function are not fully elucidated. Experimental evidence, however, suggests that theophylline may have an effect on transmembrane calcium movements by blocking adenosine receptors.
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PMID:Effect of theophylline on respiratory muscle function. 241 Feb 4

The influence of theophylline and the related drug caffeine on the mechanical performance of fatigued muscle fibre isolated from semitendinosus muscle of Rana temporaria (2.5-6.7 degrees C) was investigated. The fibre was stimulated supramaximally to produce I s fused tetani and 2 s and 10 s partially fused tetani at intervals of 10 min. Fatigue was produced by shortening the contraction interval to 15 and 30 s. This caused a 15-20% decline in the maximum tension during fused tetanus and a 40-50% decline during partially fused tetanus. Theophylline and caffeine (0.1-0.5 mM) did not change the maximum tension developed by the fatigued fibre during fused tetanization. Both drugs, however, markedly increased the tension output of the fatigued muscle fibre during partially fused tetanus. It was observed that the increase in partially fused tetanic tension by theophylline and caffeine was associated with an increase in the degree of fusion. This later effect was even more pronounced in the presence of diethyl-stilboestrol. It is concluded that these drugs may not reverse the metabolic changes caused by fatigue, since they are unnable to increase fused tetanic force of a fatigued muscle fibre. The increase in partially fused tetanic tension of a fatigued muscle fibre by these drugs is probably due to enhancement of the activator calcium release from the sarcoplasmic reticulum in response to stimulation.
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PMID:Fatigue in frog skeletal muscle fibres and effects of methylxanthine derivatives. 387 23

Theophylline enhances the force of diaphragmatic contraction and delays fatigue. The mechanism is not known, but recent evidence suggests it may act at the cell membrane. To test this hypothesis, we studied the effect of theophylline on resting membrane potential and tension in hamster diaphragm cells. Muscle strips were obtained from five adult hamsters and placed in Krebs solution, aerated with 95% O2, 5% CO2. Resting membrane potential was measured using 3-M KCl-filled glass microelectrodes; 15-22 fibers in each strip were sampled. Force frequency curves (twitch to 100 Hz) were obtained. The muscle bath was then changed to one containing 100 mg/liter (0.55) theophylline. Resting membrane potential was -76 +/- 3 mV (mean +/- S.D.) in Krebs solution and increased to -85 +/- 3 mV (P less than 0.01) with added theophylline. Tension increased from 5% (at 100 Hz) to 20% (at 10 Hz) with theophylline. Hyperpolarization indicates an increase in intracellular to extracellular potassium concentration. Net potassium outflow occurs with each contraction, causing the cell membrane to become depolarized with repeated contractions, ultimately leading to fatigue. The hyperpolarization of the skeletal muscle cell membrane observed with theophylline may play an important role in prolonging time to fatigue.
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PMID:Effect of theophylline on membrane potential and contractile force in hamster diaphragm muscle in vitro. 394 72

We studied the effects of theophylline on diaphragmatic strength and fatigue in 15 patients with severe chronic obstructive pulmonary disease. Diaphragmatic strength was assessed by measurement of the transdiaphragmatic pressure generated at functional residual capacity during a maximal inspiratory effort against closed airways. Diaphragmatic fatigue was induced by resistive loaded breathing. The electrical activity of the diaphragm was recorded with an esophageal electrode during the fatigue runs, and the high-low ratio of the electrical signal was analyzed to assess diaphragmatic fatigue. Studies were performed before and after 7 and 30 days of theophylline administration (mean plasma level, 13 +/- 2 mg per liter). A control group received a placebo instead of theophylline. Theophylline increased maximal transdiaphragmatic pressure by 16 per cent after 7 days of administration (P less than 0.01), and this increase persisted after 30 days. No significant change in maximal transdiaphragmatic pressure was observed in the group given the placebo. Theophylline also suppressed diaphragmatic fatigue in all patients who received it. We conclude that theophylline has a potent and long-lasting effect on diaphragmatic strength and fatigue in patients with fixed airway obstruction.
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PMID:Effects of theophylline on diaphragmatic strength and fatigue in patients with chronic obstructive pulmonary disease. 673 52

It is a well known fact that theophylline enhances the force of diaphragmatic contraction and delays fatigue. The action of caffeine which is a methylxanthine analogue on skeletal muscle are complex. It was claimed in few studies that the caffeine was more effective on the diaphragmatic contractility than the theophylline. The aim of this study is to compare the effects of theophylline and caffeine on the tension generated by fresh and fatigued diaphragmatic muscle. Studies were performed in vitro on diaphragmatic muscle strips of rats activated by electrical stimuli applied via the phrenic nerve. Isometric twitch characteristics (twitch tension, contraction and 1/2 relaxation time) were measured. Force-frequency responses were generated using twitches and tetanic contractions produced by stimulating the phrenic nerve with 0.2 ms pulses at 10, 20, 50 and 100 Hz for 1 s with 30 s intervals. Moderate fatigue was then induced by repeated submaximal contractions (25 Hz, 160 ms, at the rate of 1/s for 45 contractions). In fresh muscle 1 mM theophylline and 1 mM caffeine increased diaphragmatic tension 40.98 +/- 8.50% and 82.30 +/- 12.21% of the initial value respectively. Theophylline did not alter contraction time but prolonged 1/2 relaxation time, whereas caffeine had no effect on any one. Theophylline induced force production in all frequencies. Caffeine caused an increase in force only in < 20 Hz, but a decrease in 50 and 100 Hz. In brief submaximal fatigue, both 1 mM theophylline and 1 mM caffeine partly prevented fatigue (effect of caffeine was more potent). This study suggests that caffeine has a greater effect than theophylline on the muscle. Possible mechanism(s) of action of theophylline and caffeine on diaphragmatic contractility and fatigue were discussed. It may well be the fact that they might have different mechanisms of action on the isolated rat diaphragm.
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PMID:The effects of theophylline and caffeine on the isolated rat diaphragm. 858 May 22

Theophylline alleviates central and obstructive apneas of prematurity, and may improve adult obstructive sleep apnea. One mechanism of action appears to be a stimulatory effect on the motor output to upper airway dilator muscles. The purpose of the present study was to determine whether theophylline might have a second mechanism of action, namely that of improving the force and/or endurance of the pharyngeal dilator musculature. Rat sternohyoid muscle strips were studied in vitro and compared to diaphragm strips. The isometric twitch force and twitch kinetics of neither muscle were altered by theophylline (100 mg/l). Theophylline significantly slowed the rate at which the diaphragm fatigued during intermittent 40-Hz stimulation (p < 0.001). In contrast, theophylline produced no improvement in the fatigue resistance of the sternohyoid muscle. The degree of force potentiation during the early portion of the fatigue protocol was not altered by theophylline for either muscle. These results suggest that the mechanism by which theophylline improves obstructive apnea is unlikely to be due to a beneficial effect on pharyngeal dilator muscle force or endurance.
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PMID:Effects of theophylline on pharyngeal dilator and diaphragm muscle contractile properties. 896 72

The efficacy of the methylxanthine, theophylline, as a respiratory stimulant has been demonstrated previously in an animal model of spinal cord injury. In this model, an upper cervical (C2) spinal cord hemi paralyzes the ipsilateral hemidiaphragm. Theophylline restores respiratory-related activity in the paralyzed hemidiaphragm via activation of a latent respiratory motor pathway. Antagonism of central adenosine A1 receptors mediates this action. Theophylline also enhances respiratory frequency, f, defined as breaths per minute. Thus, long-term use may result in respiratory muscle or motoneuron fatigue particularly after spinal cord injury. We assessed the effects of an adenosine A1 receptor agonist, N6-p-sulfophenyladenosine (p-SPA) on theophylline's action in our model under standardized recording conditions. Four groups of rats, classified as hemisected/nonhemisected with the carotid bodies denervated (H-CBD or NH-CBD), and hemisected/nonhemisected with the carotid bodies intact (H-CBI or NH-CBI ) were used in the study. Eight days after recovery from carotid denervation, a left C2 hemi was performed in H-CBD rats. C2 hemi was also performed in H-CBI animals, and 24 h later, electrophysiologic experiments on respiratory activity were conducted in both groups of animals. Two groups using nonhemisected controls were also employed as described above. In H-CBD rats, theophylline significantly (P < 0.05) enhanced f and induced respiratory-related activity in the previously quiescent left phrenic nerve. In NH-CBD rats, theophylline significantly enhanced f. In both H-CBD and NH-CBD rats, p-SPA (0.25 mg/kg) did not significantly change theophylline-induced effects. In H-CBI rats, theophylline significantly (P < 0.05) enhanced f and induced activity in the previously quiescent left phrenic nerve. In H-CBI rats, p-SPA reduced the values to pre-theophylline discharge levels. Recovered activity was not obliterated with the agonist. In NH-CBI rats, p-SPA reduced theophylline-induced effects to pre-drug discharge levels. Adenosine A1 and A2A receptor immunoreactivity was detected in the carotid bodies. The significance of our findings is that theophylline-induced effects can be normalized to pre-drug levels by the selective activation of peripheral adenosine A1 receptors. The therapeutic benefits of theophylline, i.e., recovered respiratory function after paralysis, however, persists. The potential therapeutic impact is that respiratory muscle fatigue associated with long-term theophylline use may be minimized by a novel therapeutic approach.
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PMID:Recovery of respiratory function following C2 hemi and carotid body denervation in adult rats: influence of peripheral adenosine receptors. 1558 16

Theophylline increases the heart rate in patients with normal sinus rhythm and in patients with sick sinus syndrome. This effect is probably connected to the blockade of adenosine receptors by theophylline. This study evaluated the efficacy of theophylline in 34 elderly patients with symptomatic sinus bradycardia (age 68 +/- 11 years). A resting electrocardiogram, a 24-hour recording and treadmill test were performed both before and after administration of slow-release theophylline (700 mg/day). The drug increased resting heart rate (from 43 +/- 6 to 63 +/- 16 beats/min, p < 0.01), mean 24 hour heart rate (from 49 +/- 7 to 65 +/- 17 beats/min, p < 0.01), and minimal 24 hour heart rate (from 34 +/- 5 to 44 +/- 10 beats/min, p < 0.05 ). Cardiac pauses longer than 2.5 seconds were present in 8 patients during control recordings, and disappeared after theophylline. Twenty-six patients were followed for a period of 20 +/- 5 months. Suppression of symptoms was achieved in 24 of them. Asthenia and easy fatigue were reduced markedly by the drug. During long term therapy, the sinus rate was similar to that observed at the steady-state evaluation. In 6 of the 34 patients theophylline had to be discontinued because of gastric intolerance (in 4 cases at the end of the steady-state evaluation and in 2 during long-term therapy). These data suggest that oral theophylline can represent an effective therapy in some elderly patients with symptomatic sinus bradycardia and can avoid or delay the need of a permanent pacemaker.
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PMID:Clinical effects of oral theophylline in elderly patients with sick sinus syndrome. 1865 35


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