Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several disturbances of cellular Ca2+ metabolism have been described in essential hypertension and in the spontaneously hypertensive rat. Possibly the elevation of intracellular free Ca2+ concentration in arterial smooth muscle cells is one important step in the pathogenesis of primary hypertension. In most studies a decreased energy-dependent Ca2+ transport has been proposed as a mechanism. However, disturbances in cellular Ca2+ metabolism, which can be exclusively ascribed to essential hypertension, have not yet been found. The cause of altered cellular Ca2+ transport in primary hypertension may either be a genetically determined defect of membrane transport or a still-unidentified humoral factor.
 ...
PMID:Cellular calcium metabolism in primary hypertension. 243 55

A "fatigue" of acetylcholine (ACh) release is described in cholinergic synaptosomes stimulated with the calcium ionophore A23187 or gramicidin. A small conditioning calcium entry, which did not trigger a large ACh release, led to a decrease of transmitter release elicited by a second large calcium influx. This fatigue was half-maximal at approximately 30 microM external calcium and developed in a few minutes. In contrast, activation of release by calcium was very rapid and was half-maximal at approximately 0.5 mM external calcium. Activation and desensitization of release could be attributed to the recently identified presynaptic membrane protein, the "mediatophore." Proteoliposomes equipped with purified mediatophore showed a calcium-dependent activation and "fatigue" of ACh release similar to that of synaptosomes. It was found that the ionophore A23187 rapidly equilibrated internal and external calcium concentrations in proteoliposomes. Thus, the external calcium concentration gave the internal concentration required for activation or desensitization of proteoliposomal ACh release. The mediatophore showed remarkable calcium binding properties (20 sites/molecule) with a KD of 25 microM. The physiological implications of desensitization on the organization of release sites are discussed.
 ...
PMID:Calcium-induced desensitization of acetylcholine release from synaptosomes or proteoliposomes equipped with mediatophore, a presynaptic membrane protein. 244 Sep 93

The protective effect of calcium antagonists on ischemic heart has been attributed to decreased energy expenditure. We administered one of the newer calcium antagonists, DL-bepridil (0.1-10 microM), to Langendorff rat hearts 10 or 15 min before ischemia (flow reduction approximately 80%). Vasodilation during normoxia was already observed with 0.3 microM DL-bepridil (flow increase 34%, p less than 0.005). This concentration decreased normoxic contractility and ischemic purine release, a marker for ATP breakdown. In the absence of bepridil, purine release of hearts that were made ischemic was 8.5-fold higher than that of normoxic control hearts. With 1 microM bepridil, the ischemic purine efflux was suppressed by 55% (p less than 0.05), with negative inotropy (p greater than 0.05) during normoxia. At 3 and 10 microM, bepridil decreased normoxic contractility by 40 and 75%, respectively (p less than 0.001), concomitant with a decrease in ischemic purine release by 80 and 76%, respectively (p less than 0.01). At the end of ischemia, myocardial ATP and creatine phosphate had decreased by 22 and 55%, respectively (p less than 0.05), and ADP, AMP, and creatine had increased 1.5-3.5-fold (p less than 0.05). Bepridil (3 microM) normalized the adenine nucleotide values; creatine and creatine phosphate approached control levels. The dose-dependent protection of the ischemic heart by bepridil appears to arise from its negative inotropic action during normoxia.
 ...
PMID:Protection by bepridil against myocardial ATP-catabolism is probably due to negative inotropy. 244 Nov 54

The specific locus of impairment in excitation-contraction coupling that is associated with skeletal muscle fatigue has not been identified. In the present study the phenomena of staircase and fatigue were studied in the rat gastrocnemius muscle in situ, and the effect of caffeine (50 mg kg-1) given prior to or during 5 minutes of stimulation was observed. A 10 Hz indirect stimulation resulted in a staircase response that proceeded for 10.4 +/- 1.6 (mean +/- SD) seconds, reaching a peak force value that was 70-75% higher than the initial contraction. After 5 minutes of stimulation and 20 minutes of rest, the staircase response was longer (17 +/- 3.1 seconds) and proceeded more slowly when the stimulation regimen was repeated. Caffeine accelerated the fatigue and reversed the effect of fatigue on the staircase response. Since caffeine enhances the release of Ca2+ from terminal cisternae, it is postulated that the accelerated fatigue in the presence of caffeine is indicative of a reduced availability of Ca2+ for release. This hypothesis would also explain the slower progression of staircase in the fatigued muscle.
 ...
PMID:Staircase, fatigue, and caffeine in skeletal muscle in situ. 244 31

The role of dietary calcium in essential hypertension remains controversial. Various studies have found on the one hand a weak negative correlation between blood pressure and Ca2+ intake in special groups, and on the other hand a positive correlation between serum Ca2+ concentration and blood pressure. Several disturbances of cellular Ca2+ metabolism have been described in essential hypertension and in the spontaneously hypertensive rat. Possibly the elevation of intracellular free Ca2+ concentration in arterial smooth muscle cells is one important step in the pathogenesis of primary hypertension. In most studies a decreased energy-dependent Ca2+ transport has been proposed as a mechanism. However, disturbances in cellular Ca2+ metabolism, which can be exclusively ascribed to essential hypertension, have not yet been found. The cause of altered cellular Ca2+ transport in primary hypertension may either be a genetically determined defect of membrane transport or a still unidentified humoral factor.
 ...
PMID:Calcium and primary hypertension. 244 13

The Cardiac Arrhythmia Pilot Study tested the feasibility of performing a large-scale study to evaluate the effect of therapy of ventricular arrhythmias after acute myocardial infarction (AMI). Ten clinical sites identified patients with greater than or equal to 10 ventricular premature complexes (VPCs)/hour, recorded 6 to 60 days after AMI in patients with an ejection fraction greater than 0.20. Patients were randomized to receive 1 of 5 agents: encainide, flecainide, imipramine, moricizine or placebo. Successful therapy was defined as greater than or equal to 70% suppression of VPCs and greater than 90% suppression of runs of ventricular tachycardia. Randomization to a second agent occurred if a patient did not achieve adequate suppression with the initial agent. Patients initially randomized to placebo continued to receive placebo. Patients were evaluated at 3-month intervals for the next year. Of 30,763 patients screened, 10,734 (35%) were younger than 70 years old and had a qualifying AMI. A Holter recording was obtained in 3,957 patients, of whom 871 (22%) had qualifying arrhythmias and 687 were eligible. Of the 687 eligible patients, 502 (73%) were randomized. Mean age of enrolled patients was 59 years. One-half of patients were randomized within 1 month after AMI. Mean ejection fraction was 0.45, with 175 (35%) patients having an ejection fraction less than 0.40. On baseline drug-free recording, 173 (35%) patients had less than 30 VPCs/hour; 149 (30%) between 30 and 100/hour and 180 (36%) greater than or equal to 100/hour. At least 1 run of ventricular tachycardia was seen in 172 (34%) patients. Drugs taken at baseline were similar in all groups with 116 (23%) patients taking digitalis, 161 (32%) taking diuretics, 203 (41%) taking beta blockers and 200 (40%) taking calcium antagonists. Slightly more patients, 53 (51%), randomized to flecainide were taking calcium antagonists. No significant relation was noted between baseline VPC frequency and ejection fraction, but baseline VPC frequency was correlated with heart rate, arrhythmia noted before AMI and right bundle branch block. As expected, a high ejection fraction correlated with lower peak creatine kinase values, an inferior location of the infarct and fewer signs of congestive heart failure. At baseline, at least 1 adverse symptom was volunteered by 192 (39%) patients. The most common symptoms were unusual tiredness or fatigue, heart beating fast or skipping beats or headache. In this study, over 20 age- and AMI-eligible patients were identified to obtain each randomized patient. The randomization process successfully distributed baseline variables across drug groups.
 ...
PMID:Recruitment and baseline description of patients in the Cardiac Arrhythmia Pilot Study. The Cardiac Arrhythmia Pilot Study (CAPS) investigators. 245 14

Ca2+-dependent slow action potentials (AP) were investigated in diaphragm muscles of alloxan-diabetic mice in comparison with normal muscles. Slow APs observed in diabetic muscles were significantly decreased in amplitude and duration. The slow APs which were generated at a stimulation frequency of once every 15 sec decayed more rapidly in diabetic muscles. Fatigue, however, developed regardless of the presence of verapamil (10 microM) in contrast to the quicker development of fatigue in normal muscles in response to verapamil.
 ...
PMID:Alloxan-diabetic state-induced suppression of Ca2+-dependent slow action potentials in mouse diaphragm muscle. 246 72

1. Single muscle fibres were dissected from Xenopus lumbrical muscles and microinjected with the photoprotein aequorin in order to measure the myoplasmic free calcium concentration ([Ca2+]i). Fatigue was produced by repeated intermittent tetanic stimulation continued until tension had declined to approximately 50% of the initial level. Fibres were then allowed to recover by giving tetani at less frequent intervals. Aequorin light (a measure of [Ca2+]i) and tension were measured during fatiguing stimulation and recovery. 2. During fatiguing stimulation, tetanic tension declined steadily, but peak aequorin light first increased before declining substantially. The largest light signal was about 155% of initial control while at the end of fatiguing stimulation the tetanic light fell to about 14% of control. 3. Fibres showed a characteristic slowing of relaxation in the fatigued state. This was associated with a slowing of the rate of decline of the aequorin light signal. 4. Intracellular acidosis produced by equilibrating the Ringer solution with either 5 or 15% CO2 caused an increase in the light signal associated with a tetanus. Carbon dioxide also caused a reduction of tension and a slowing of relaxation. 5. In vivo pCa-tension curves were constructed by exposing the fibres to a series of K+ concentrations which produced contractures of different sizes. Light and tension were measured during periods when both were relatively stable and the light signal was subsequently converted to pCa. 6. Exposure of fibres to 5 or 15% CO2 caused the pCa-tension curve to be shifted to the right of the control curve. This indicates a reduced Ca2+ sensitivity of the contractile proteins, which is in agreement with results from skinned fibre studies. 7. The pCa-tension points obtained from tetani during the early part of fatiguing stimulation also deviated to the right of the control pCa-tension curve, suggesting a reduced Ca2+ sensitivity of the contractile proteins. At the end of fatiguing stimulation, however, pCa-tension points did not differ greatly from the control pCa-tension curve, suggesting that Ca2+ sensitivity was approximately normal. Thus the reduced [Ca2+]i during tetani at the end of fatiguing stimulation (when tension was reduced to approximately 50%) could explain all of the reduction in tension. 8. After fatiguing stimulation, tension and light recovered monotonically in some fibres; however, in the majority of fibres, tension and light showed a secondary decline followed by a slower recovery (post-contractile depression). 9. During post-contractile depression, caffeine contractures or tetani in the presence of caffeine gave increased aequorin light signals and the tension developed was close to that produced in an unfatigued tetanus.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Intracellular calcium and tension during fatigue in isolated single muscle fibres from Xenopus laevis. 251 88

This study involved 113 patients (mean age 50 +/- 14 years) with diastolic blood pressure above 95 mmHg. The patients abstained from taking any antihypertensive drug and received a placebo for one week before entering felodipine, a new calcium antagonist (5 mg x2/day for 2 weeks, then 10 mg x2/day) or atenolol (100 mg/day). There was no significant difference between the two treatment groups. Atenolol tended to be more effective in young subjects and felodipine in subjects aged 60 years or more. Heart rate was more reduced by atenolol than by felodipine (P less than 0.01). Undesirable side-effects were recorded by means of an open questionnaire. Their incidence was 23 per cent during the week under placebo and 84 per cent and 80 per cent respectively during treatment with felodipine or atenolol. The most frequent side-effects were oedema of the ankles and headache under felodipine, fatigue and headache under atenolol. Alkaline phosphatase levels were higher in the felodipine group (P less than 0.05), and a slight rise in blood potassium level (0.2 mmol/l) was noted in the atenolol group (P = 0.001), but these values remained within normal limits.
 ...
PMID:[Treatment of essential hypertension with felodipine or atenolol as first line therapy. Comparative double-blind randomized study]. 252 34

1. Maximal calcium-activated force (Fmax) and calcium sensitivity were markedly decreased in detergent-skinned fibres from skeletal and cardiac muscle by solutions that mimicked the total milieu changes associated with fatigue and hypoxia. Further experiments determined the relative contribution of each of the individual changes in milieu. 2. Both Ca2+ sensitivity and Fmax of skeletal and cardiac fibres were decreased with increased [H+] or inorganic phosphate (Pi). These effects were greater in cardiac muscle. 3. Decreasing MgATP over the range observed with fatigue and hypoxia (6.8-4.7 mM) had no effect on Fmax or Ca2+ sensitivity of either muscle type. 4. Decreasing phosphocreatine (PCr: 15-1 mM) increased Fmax but had little effect on Ca2+ sensitivity in both muscle types. In cardiac fibres, the effect on Fmax could be mimicked by inhibition of endogenous creatine kinase. 5. ADP (0.7 mM) increased Fmax and Ca2+ sensitivity, while AMP (0.06 mM) slightly increased Fmax but had no effect on Ca2+ sensitivity of either skeletal or cardiac fibres. 6. Creatine (25 mM) had no significant effect on either Ca2+ sensitivity or Fmax of skeletal and cardiac muscle fibres. At higher levels (50 mM), however, creatine depressed Fmax and slightly altered Ca2+ sensitivity. 7. Thiophosphorylation of myosin P light chains (phosphorylatable light chains of myosin) in rabbit psoas fibres had no effect on Ca2+ sensitivity, yet slightly but significantly increased Fmax under fatigue conditions. 8. Reducing the affinity for ATP hydrolysis (by adding ADP, AMP and creatine) over the range calculated for fatigue/hypoxia (60-45 kJ/mol) produced the enhancement in Fmax expected from added ADP and AMP in cardiac but not skeletal muscle, indicating that changes in affinity influence Fmax of skeletal muscle. Reducing affinity produced little change in Ca2+ sensitivity of skeletal muscle. In contrast, the change produced in cardiac muscle was greater than that expected from addition of ADP and AMP; i.e. decreasing affinity increases calcium sensitivity of the heart. 9. Simple summation of all significant changes expected from each constituent altered by fatigue/hypoxia adequately predicted the observed changes in Fmax and Ca2+ sensitivity in both cardiac and skeletal muscle fibres with but one exception (the change in Ca2+ sensitivity of skeletal muscle at pH 7 was slightly overestimated).
 ...
PMID:Changes of intracellular milieu with fatigue or hypoxia depress contraction of skinned rabbit skeletal and cardiac muscle. 260 Aug 30


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>