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

The relationship between variations in diaphragmatic contractility and corresponding changes in total tissue levels of 45Ca and adenosine 3',5'-cyclic monophosphate (cAMP) was examined. The contractile performance of perfused contracting rat diaphragms was manipulated with theophylline (10(-4) M), induced fatigue, or both. The increased contractility associated with theophylline was related to significant increases in 45Ca levels without changes in cAMP levels. Fatigue-diminished contractility was associated with increases in both 45Ca and cAMP levels. The increased 45Ca and cAMP levels associated with fatigue persisted, even in the presence of theophylline. Calcium channel blockade with 10(-4) M verapamil blocked the positive inotropic influence of theophylline as well as the theophylline-associated increase in 45Ca levels. Verapamil had no effect on either the fatigue-associated decreases in contractility or the fatigue-enhanced 45Ca uptake. The results of this study strongly suggest that the enhanced contractility associated with theophylline is related to its influence on cellular calcium metabolism. The elevated level of isotopic calcium measured in fatigued muscle probably represents calcium sequestered in the sarcoplasmic reticulum, the result of cAMP-enhanced Ca-adenosine triphosphatase activity.
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PMID:Theophylline, fatigue, and diaphragm contractility: cellular levels of 45Ca and cAMP. 165 Jul 69

Impaired diastolic function of the hypertrophied and stiffened left ventricle is a characteristic feature of hypertrophic cardiomyopathy (Figure 1). Altered left ventricular filling dynamics and reduced left ventricular distensibility or increased left ventricular diastolic chamber stiffness are associated with reduced left ventricular stroke volume, increased left ventricular filling pressures and compressive effects on the coronary microcirculation. These factors contribute importantly to the clinical presentation of many patients, including symptoms of fatigue, dyspnea and angina pectoris. Reduced distensibility results both from factors determining the passive elastic properties of the ventricular chamber (including severity of hypertrophy, fibrosis and cellular disarray) and from factors influencing the rate and extent of active left ventricular relaxation (Figure 2). The factors contributing to impaired relaxation in hypertrophic cardiomyopathy are mediated via either inactivation dependent or load-dependent mechanisms. In laboratory animals, compromise of myocardial inactivation results in a persistent increase in intracellular calcium concentration and in prolonged interaction of the contractile proteins. Additionally, there is evidence for an increased number of active receptors for calcium antagonists and, lastly, for myocardial ischemia (Figure 3). Load-dependent mechanisms include diminished wall tension at the opening of the mitral valve, changes in afterload, contractility and coronary flow. Other factors are nonuniform and asynchronous regional ventricular function due to differing increases in thickness of the ventricular walls and ischemia (Figure 4). Calcium channel blockers exert a favorable influence on left ventricular relaxation and filling (Figure 5); verapamil and diltiazem are preferable to nifedipine. Verapamil increases left ventricular stroke volume without an increase in the end-diastolic pressure (Figure 6), reduces regional asynchrony if present, and leads to a more homogeneous regional diastolic filling (Figure 4).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Left ventricular diastolic function in hypertrophic cardiomyopathy. 202 81

The interaction between oral verapamil and propranolol may involve negative chronotropic, inotropic or dromotropic effects. The immediate effects of orally administered verapamil (120 mg) and propranolol (80 mg), alone and combined, on submaximal exercise hemodynamics and on pharmacokinetics were studied in eight healthy male volunteers in a randomized, double-blind, crossover manner. Maximum effects on heart rate, systolic blood pressure, PR interval and rate-adjusted PR prolongation were greatest with the combined administration of verapamil and propranolol. The combination caused a high frequency of adverse drug events, predominantly exercise fatigue. Verapamil increased the AUC and Cmax and shortened the tmax of propranolol. Propranolol decreased the AUC and Cmax of verapamil. The greater reduction of heart rate with the combination of verapamil and propranolol was only partially explained by higher plasma concentrations of propranolol. The combination of propranolol and verapamil produced clinically important synergistic adverse effects during exercise. Negative dromotropic effects occurred primarily by direct AV node inhibition and were more important than previously recognized.
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PMID:Synergistic adverse hemodynamic interaction between oral verapamil and propranolol. 279 49

New knowledge of the pathophysiology of coronary disease has helped determine the therapy for angina pectoris. Calcium antagonists have the advantage of being direct coronary vasodilators as well as decreasing overall demand by systemic vasodilatation. Verapamil has the same anti-anginal effect during exercise as beta-adrenoceptor blockers but has the advantage of increasing rather than decreasing the cardiac output and so fatigue both at rest and exercise commonly seen with beta-adrenoceptor blockers is not found with verapamil. The longterm incidence of side-effects with verapamil are few and it can be used as a single anti-anginal therapy in a three times daily dosage. Left ventricular function where normal and near-normal is not depressed. Tolerance to therapy has not been recorded. The anti-anginal effects have been shown to remain effective over at least a 5 year period. Verapamil should be considered as initial therapy for patients with stable angina pectoris.
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PMID:Verapamil in angina pectoris. 287 28

We compared verapamil and propranolol hydrochloride for monotherapy of hypertension. Verapamil lowered blood pressure (BP) more effectively than propranolol in black and white patients. Verapamil was equally effective in blacks and whites, whereas propranolol was more effective in whites. Heart rate was reduced by 6.0 beats per minute by verapamil, and by 13.6 beats per minute by propranolol. In blacks, verapamil lowered systolic BP 16.9 vs 8.1 mm Hg for propranolol; verapamil reduced diastolic BP 12.8 vs 8.6 mm Hg for propranolol. In whites, verapamil lowered systolic BP 19.0 vs 12.7 mm Hg for propranolol; verapamil reduced diastolic BP 16.7 vs 12.3 mm Hg for propranolol. Increases in systolic BP were observed in 22% and 3.4% of patients receiving propranolol and verapamil, respectively. The PR interval was increased from 163.5 to 174.9 ms for verapamil vs 160.3 to 164.4 ms for propranolol. Constipation (15%) and headaches (10%) were most frequent complaints for verapamil vs fatigue (18%) and dizziness (7%) for propranolol. Changes in blood biochemistry values were of small magnitude. We conclude that verapamil monotherapy is a safe and effective means of achieving BP control in patients with essential hypertension.
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PMID:A comparison of verapamil and propranolol for the initial treatment of hypertension. Racial differences in response. 353 60

Oxygen utilization, arterial and venous blood gas levels, hemodynamic values and exercise tolerance were compared before and after administration of propranolol and verapamil in 10 patients with stable angina pectoris. During exercise, propranolol decreased cardiac output (CO) by 22%; O2 extraction was increased and O2 consumption (VO2) did not change. With verapamil treatment, CO modestly increased (7%), O2 extraction decreased and VO2 did not change. In contrast to O2 utilization, the drugs produced opposite changes in mixed venous and arterial blood gas levels. Propranolol decreased mixed venous pH, increased CO2 tension and decreased the pH of arterial blood. Verapamil increased venous pH and decreased CO2 tension; pH of arterial blood did not change. The drugs yielded similar levels of antianginal efficacy, but patients exercised longer during verapamil therapy and were less fatigued. The hemodynamic and metabolic differences suggest that muscle perfusion during exercise influences the onset of fatigue and may help determine the choice of therapy.
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PMID:Effect of propranolol and verapamil on oxygen utilization, acidosis and fatigue during exercise in stable angina pectoris. 361 85

Verapamil, a papaverine calcium channel blocker, has been used effectively and safely in the treatment of angina pectoris and auricular arrhythmias, and more recently in the treatment of mania. Many antipsychotic drugs show calcium channel blocking effects similar to verapamil's. A 41 year old male schizophrenic, only partially responsive to haloperidol decanoate and oral haloperidol, was given increasing doses of verapamil concomitantly, and monitored clinically and by the BPRS, electrocardiogramme, and other laboratory measures. The patient's total BPRS score dropped from 79 to 41 and remained stable, after initial worsening at lower doses, at verapamil 80 mg po qid. Mild fatigue was the only side effect. Further investigation of verapamil in the treatment of schizophrenia is warranted.
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PMID:Verapamil in refractory schizophrenia: a case report. 362 27

The pharmacokinetics, clinical efficacy, and adverse effects of three calcium-channel blocking agents--verapamil, nifedipine, and diltiazem--are reviewed. Verapamil, nifedipine, and diltiazem are absorbed well after oral dosing, but absolute bioavailability of each is reduced substantially by a first-pass effect. Each drug is metabolized extensively (verapamil and diltiazem to moderately active metabolites) by the liver. A substantial percentage of each drug is bound to plasma proteins, but the binding is of clinical importance only for nifedipine (92--98% protein bound). Intravenous verapamil has become the agent of first choice for treatment of acute paroxysmal supraventricular tachycardia (PSVT); use of chronic oral verapamil therapy for prophylaxis remains controversial. Verapamil and diltiazem have been evaluated with mixed results for atrial flutter and fibrillation. For treatment of myocardial ischemia, calcium-channel blockers may be of some value (possibly in combination with nitrates of B blockers). All three agents have been studied in patients with exertional angina with good results. Calcium-channel blockers appear to be equal with nitrates for treatment of variant angina. Patients with hypertropic cardiomyopathy have been treated with verapamil and nifedipine with promising results. Nifedipine has been effective for treatment of essential hypertension. Adverse effects of calcium-channel blockers have been relatively minor or infrequent. Diltiazem overall has the best side-effect profile, with adverse effects causing discontinuation of therapy in about 2--10% of patients; verapamil in intermediate (8--10%) and nifedipine the worst (17%) in this respect. The most common side effects generally are fatigue, headache, dizziness, skin rash, and peripheral edema. While they generally should be reserved for patients in whom more conventional therapy has failed (except those with PSVT), calcium-channel blockers appear to have a valid role as reserve agents for exertional and variant angina, cardiomyopathy, and hypertension.
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PMID:Update on calcium-channel blocking agents. 635 66

Verapamil (VRP) improves ischemic tolerance of different organs including brain, kidney, liver and heart. We report here on the effects of preischemic VRP treatment on skeletal muscle function following 3 h of tourniquet ischemia and 2 h of reperfusion using a rodent model. Postischemic and contralateral limbs were evaluated. Fast (musculi peronei)- and slow-twitch muscles (musculus soleus) of both limbs were excised and electrically stimulated in vitro. VRP pretreatment was found to significantly decrease tetanic peak tension of both contralateral nonischemic m. soleus and mm. peronei. Furthermore, VRP improved fatigability of slow-twitch muscles of both ischemic and contralateral limbs [increase of fatigue index from 0.04 +/- 0.009 (0 mg/kg) to 0.10 +/- 0.019 (4 mg/kg)], but not of fast-twitch muscles. These data indicate that the effects of VRP on postischemic skeletal muscle function depend on fiber composition.
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PMID:Effects of verapamil on skeletal muscle function following ischemia and reperfusion. 883 64

The effects of low calcium and verapamil on contractility of two muscle fibre types (m. iliofibularis, Rana temporaria) upon different stimulation protocols were been compared. Verapamil (0.02 mmol/l) induced temporal excitation-contraction coupling failure during single tetanic stimulation and enhanced the decline of tetanic force during 30 s repetitive tetanic stimulation in both fatigue-resistant fibres and easily-fatigued fibres. In contrast to verapamil, low extracellular calcium (0.02 mmol/l) only enhanced the decline of tetanic force in fatigue-resistant during repetitive tetanic stimulation but had no effect on easily-fatigued fibres. The effect of verapamil on the decline of tetanic force in fatigue-resistant fibres was more profound in low calcium conditions. Both verapamil and low calcium eliminated twitch facilitation that appeared after prolonged contractile activity in fatigue-resistant fibres. 4mmol/l Ni+2, used as calcium channel antagonist, had effects similar to low calcium medium. It could be concluded that (i) extracellular Ca2+-requirements for excitation-contraction coupling are different in fatigue-resistant and easily-fatigued fibres; (ii) the effects of verapamil on force performance are not entirely dependent upon calcium channel blockade.
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PMID:Different effects of verapamil and low calcium on repetitive contractile activity of frog fatigue-resistant and easily-fatigued muscle fibres. 1051 89


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