Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: KEGG:D06103 (Theophylline)
2,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adenosine has been suggested to have a role in regulation of the tone of the cardiac resistance vessels. To elucidate the coronary vasoregulatory role of endogenous adenosine in man, we studied the effects of adenosine receptor antagonism by theophylline on coronary blood flow at rest and during light exercise. However, theophylline may also exert pharmacological effects not related to adenosine antagonism. To clarify the contribution of endogenous adenosine in coronary hyperaemia, the effect of theophylline was compared to that of enprofylline, a xanthine which exerts similar pharmacological effects as theophylline while lacking antagonistic action at adenosine receptors. Twenty healthy subjects (10 males) aged 22-39 years were examined. Coronary sinus (CS) blood flow and blood oxygen content were determined at rest and during supine bicycle exercise, at a load of 50 watts, for 10 min. Thereafter, stepwise infusion of adenosine (30 to 60 micrograms/kg/min into the subclavian vein) was performed. Theophylline or enprofylline treatment was instituted randomly and double-blind (10 in each group), and the procedures (i.e. determinations at rest, during exercise and during infusion of adenosine) were repeated. In all 20 subjects, basal CS flow was 70 +/- 6 ml/min and the cardiac oxygen extraction ((A-CS)O2D) was 123 +/- 3 ml/l. During exercise, CS flow and (A-CS)O2D increased to 135 +/- 17 ml/min and 132 +/- 3 ml/l, respectively. Adenosine increased CS flow dose dependently to 161 +/- 27 ml/min, while (A-CS)O2D decreased to 66 +/- 7 ml/l. The vasodilatory effect of adenosine was readily counteracted by theophylline, the increase in CS flow being 33% vs. 133% in the control situation. Enprofylline, on the other hand, enhanced the response to exogenous adenosine. Theophylline, at a dose lacking effect on heart rate and blood pressure, decreased CS flow at rest by 14% (P < 0.05) and during exercise by 18% (P < 0.05). ((A-CS)O2D increased by 14% at rest and during exercise (P < 0.001). Enprofylline, on the other hand, was without effect. The differences in responses between theophylline and enprofylline with respect to coronary flow and oxygen extraction were significant both at rest and during exercise. It is concluded that theophylline increases coronary vascular resistance, while enprofylline, lacking adenosine antagonistic properties, was without such effect. This indicates a physiological role of adenosine in regulation of coronary flow.
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PMID:A role for adenosine in coronary vasoregulation in man. Effects of theophylline and enprofylline. 859 May 56

We tested the hypothesis that adenosine is involved in regulating substrate metabolism during exercise. Seven trained cyclists were studied during 30 minutes of exercise at approximately 75% maximal oxygen uptake (VO2max). Lipid metabolism was evaluated by infusing [2H5]glycerol and [1-13C]palmitate, and glucose kinetics were evaluated by infusing [6,6-2H]glucose. Fat and carbohydrate oxidation were also measured by indirect calorimetry. The same subjects performed two identical exercise tests, but in one trial theophylline, a potent adenosine receptor antagonist, was infused for 1 hour before and throughout exercise. Theophylline did not increase whole-body lipolysis (glycerol rate of appearance [Ra]) or free fatty acid (FFA) release during exercise, but fat oxidation was lower than control values (9.5 +/- 3.0 v 18.0 +/- 4.2 micromol x min(-1) x kg(-1), P < .01). Glucose Ra was not affected by theophylline infusion, but glucose uptake was lower (31.6 +/- 4.1 v 40.4 +/- 5.0 micromol x min(-1) x kg(-1), P < .05) and glucose concentration was higher (6.4 +/- 0.6 v 5.8 +/- 0.4 mmol/L, P < .05) than in the control trial. Total carbohydrate oxidation (302.3 +/- 26.2 v 265.5 +/- 11.7 micromol x min(-1) x kg(-1), P < .06), estimated muscle glycogenolysis (270.7 +/- 23.1 v 225.1 +/- 9.7 micromol x min(-1) x kg(-1), P < .05), and plasma lactate concentration (7.9 +/- 1.6 v 5.9 +/- 1.1 mmol/L, P < .001) were also higher during the theophylline trial. These data suggest that adenosine may play a role in stimulating glucose uptake and restraining glycogenolysis but not in limiting lipolysis during exercise.
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PMID:Effect of theophylline on substrate metabolism during exercise. 878 4

Diazepam (2 x 10(-5)-6 x 10(-4) M) induced a concentration-dependent positive inotropic effect on the perfused rat heart which was preceded by a transient concentration-dependent negative inotropic response. The influence of the Ca(2+)-entry blocking drug, flunarizine, and the adenosine receptor blocking drug, theophylline on these inotropic responses was studied. Flunarizine in concentrations of 10(-9)-10(-6) M antagonized the positive inotropic response to diazepam significantly; the negative inotropic response was reduced as well. At the lower concentrations of diazepam the negative inotropic response was completely abolished in the presence of flunarizine. The actions of the Ca(2+)-entry blocker were related to the concentrations used. Theophylline in concentrations up to 5 x 10(-5) M did not interfere with either inotropic response to diazepam. The results suggest that Ca2+ currents in the myocardium are involved with the response of the isolated heart to diazepam. It is concluded that the finding that the negative inotropic effect of diazepam was almost abolished by flunarizine suggests that the site of this response most be associated with Ca(2+)-current mechanisms.
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PMID:Flunarizine but not theophylline modulates inotropic responses of the isolated rat heart to diazepam. 896 Aug 78

This study was designed to examine whether theophylline, an adenosine receptor antagonist, affects cardiac adaptation to ischemia during progression of repetitive balloon inflations of percutaneous transluminal coronary angioplasty (PTCA). Theophylline abolished this cardiac adaptation, suggesting that endogenous adenosine is a key mediator for cardiac adaptation during PTCA.
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PMID:Effect of theophylline on adaptation of the heart to myocardial ischemia during percutaneous transluminal coronary angioplasty in patients with stable angina pectoris. 905 52

The role of adenosine in the modulation of respiration-related neurons was examined using an in vitro brainstem-spinal cord preparation from neonatal rats (0-4 d old). Respiratory activity was recorded from the C4 or C5 ventral roots by suction electrodes and from inspiratory related neurons (I neurons) in the rostral ventrolateral medulla by microelectrodes. The following substances were added to the preparation superfusate, and their effect was evaluated: the adenosine A1 receptor agonist N6-(2-phenylisopropyl)adenosine, R(-)isomer (R-PIA), the adenosine uptake blocker dipyridamole, the adenosine receptor antagonist theophylline, and the specific A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). R-PIA and dipyridamole decreased the activity of I neurons and the C4 respiratory burst rate. Furthermore, these compounds induced a significantly more irregular respiratory rate in three-quarters of preparations from the youngest animals (<48 h old) compared with that of controls. Theophylline or DPCPX reversed the effects of both R-PIA and dipyridamole on respiratory rate, regularity of respiratory rate, inspiratory time, amplitude, and intra-burst frequency of I neurons. Thus, adenosine depresses both the I neurons in the rostral ventrolateral medulla and the respiratory motor output. This depression of I neurons and respiratory rate can be abolished by theophylline primarily through a blockade of medullary adenosine A1 receptors. An age-dependent correlation of the effects of R-PIA and dipyridamole, with a more pronounced decrease in respiratory activity in preparations from younger animals, indicates that adenosinergic modulation of medullary respiration-related neurons changes during the first days of postnatal life.
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PMID:Adenosine modulates inspiratory neurons and the respiratory pattern in the brainstem of neonatal rats. 921 36

The effects of nonselective (theophylline), A1-(DPCPX) or A2A-selective (SCH 58261) adenosine receptor antagonists administered before or after neonatal hypoxia-ischemia (HI) were studied on the extent of brain injury in 7-day-old rats evaluated after 14 days. A possible effect of theophylline (20 mg/kg) on expression of immediate early genes was studied with in situ hybridization. Theophylline (20, 30 or 60 mg/kg) given prior to HI reduced brain damage by 48% (P < 0.001), 36% (P < 0.01) and 34% (P < 0.05), respectively, compared to control rats. This effect was not explained by changes in temperature, cerebral blood flow, blood gas/acid base status or blood glucose during the insult. Theophylline enhanced the upregulation of c-fos and NFGI-A during reperfusion but did not prevent the decrease in adenosine A1 receptor mRNA. Posttreatment with SCH 58261 (0.2 or 2 mg/kg) reduced brain damage by 19% (P < 0.05) and 14% (NS), respectively, compared to control rats which was unrelated to the core temperature. DPCPX (2 or 10 mg/kg) had no effect on the development of brain injury. In conclusion, nonselective and A2A adenosine receptor antagonists reduced brain injury in a model of HI in immature animals.
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PMID:Neonatal cerebral hypoxia-ischemia: the effect of adenosine receptor antagonists. 936 88

Radiocontrast agents (RCA) induce nephrotoxicity characterized by acute renal failure (ARF), which seems to be mediated partly by adenosine. ARF significantly influences erythropoietin (EPO) secretion and plasma renin activity (PRA). The present study assessed the influence of theophylline, a nonspecific adenosine receptor antagonist, on renal function, EPO secretion and PRA after the use of RCA. Fifty-eight patients underwent X-ray examinations with administration of RCA. Patients were randomized to receive either 165 mg of theophylline or placebo (saline) before the injection of 40 ml of high-osmolar contrast medium Plasma concentrations of EPO and PRA were assayed in blood samples drawn 2 hours before and 3, 6, 12 and 24 hours after RCA. Glomerular filtration rate, evaluated from endogenous creatinine clearance, urinary excretion of beta 2-microglobulin (beta 2-M), Tamm-Horsfall protein (THP) and albumin were assessed one day before RCA, on the day of RCA injection and one day later. In patients not treated with theophylline, RCA injection was followed by a significant reduction of GFR and increased urinary excretion of both beta 2-M and THP, which declined or were normal one day later. Simultaneously there was a significant decrease of plasma EPO and PRA. Theophylline prevented the decline of GFR, the increase of urinary beta 2-M and THP and the reduction of plasma EPO and PRA. The drug did not influence urinary albumin excretion. We conclude that RCA-induced impairment of renal excretory, endocrine and tubular function can be prevented by giving theophylline before RCA. These results suggest that adenosine may play a role in the pathogenesis of RCA-induced nephropathy.
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PMID:The nonselective adenosine antagonist theophylline does prevent renal dysfunction induced by radiographic contrast agents. 965 Jan 24

Previously, we demonstrated that a single intravenous injection of theophylline can induce recovery in a hemidiaphragm paralyzed by cervical (C2) spinal cord hemisection for up to 3 h. The present study contrasts the actions of enprofylline and theophylline on inducing hemidiaphragmatic recovery after cervical spinal cord hemisection. Both drugs are methylxanthines; however, theophylline is an adenosine receptor antagonist while enprofylline is not. To further test the involvement of adenosine receptors, N6 (L-2-phenylisopropyl) adenosine (L-PIA), an analogue of adenosine was used in conjunction with theophylline. Following a left C2 spinal cord hemisection, animals were injected with either enprofylline (2.5-20 mg/kg) or theophylline (15 mg/kg) alone or in combination. Theophylline-injected animals demonstrated robust respiratory-related activity in the previously quiescent left phrenic nerve and hemidiaphragm. No recovery was observed in any of the enprofylline-injected rats. When enprofylline injection was followed later with theophylline, recovery occurred. Prior L-PIA administration blocked theophylline-induced recovery. When given after theophylline, L-PIA attenuated and then blocked the induced activity in both the nerve and hemidiaphragm ipsilateral to spinal cord hemisection. We conclude that adenosine receptor antagonism is implicated in hemidiaphragmatic recovery after hemisection and theophylline may be useful in the treatment of spinal cord injured patients with respiratory deficits.
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PMID:Theophylline-induced recovery in a hemidiaphragm paralyzed by hemisection in rats: contribution of adenosine receptors. 968 Feb 64

1. We investigated by intravital microscopy in rats, the in vivo direct effects of theophylline on the diameters of second and third order diaphragm arterioles. 2. Theophylline (1-100 microM) dilated second and third order diaphragm arterioles significantly, and with an amplitude which was not statistically different from the one obtained with adenosine (1-100 microM). Enprofylline (1-100 microM), a theophylline analogue with poor adenosine-receptor antagonism but with similar or higher phosphodiesterases inhibition properties than theophylline, also dilated diaphragm arterioles, causing however, a significantly smaller dilatation than theophylline. 3. Neither the A1 adenosine receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (CPX, 50 nM), nor the A2 adenosine receptor antagonist 3,7-dimethyl-1-proparglyxanthine (DMPX, 10 microM) reduced significantly theophylline-induced arteriolar dilatation. 4. Theophylline (100 nM) abolished adenosine-induced arteriolar dilatation. 5. The dilatation induced by theophylline was unchanged by the nitric oxide (NO) synthase inhibitor N(omega)-nitro-L-arginine (NNA, 300 microM). 6. Theophylline-induced arteriolar dilatation was abolished by the prostaglandin synthesis inhibitors mefenamic acid or indomethacin (20 microM). 7. These findings show that theophylline induced a significant dilatation of diaphragm arterioles via the release of prostaglandins.
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PMID:Theophylline dilates rat diaphragm arterioles via the prostaglandins pathway. 972 45

The effect and mechanism of action of adenosine on the pulmonary circulation of rabbits were studied. Adenosine (10(-5)-10(-3) M) produced a concentration-dependent decrease in pulmonary arterial tension of precontracted pulmonary arterial rings. Removal of endothelium (denuded) augmented the adenosine-induced vasodilation in the pulmonary arterial rings. Theophylline (5 x 10(-5) M), an adenosine receptor antagonist, reduces the vasodilation induced by adenosine in intact and denuded rings. Pretreatment of the pulmonary rings with the cyclooxygenase inhibitor indomethacin (5 x 10(-6) M) significantly attenuated the adenosine-induced relaxation in denuded but not in the intact pulmonary arterial rings. Methylene blue (5 x 10(-5) M), a guanylate cyclase inhibitor, significantly reduced the relaxation induced by adenosine in both the intact and the denuded arterial rings. Adenosine significantly attenuated the pressor responses of serotonin and acetylcholine in the intact and denuded rabbit's pulmonary arterial rings. The results of this study indicate that adenosine induces pulmonary vasodilation and that functional endothelium is not required to evoke this dilation. In addition, guanylate cyclase activity and the generation of cGMP is essential for adenosine to induce vasodilation in the rabbit lung. Furthermore, the results of this study may suggest that adenosine could be used to reduce the severity of pulmonary hypertension and possibly pulmonary edema.
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PMID:Effect of adenosine on pulmonary circulation of rabbits. 1021 84


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