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)

We have recently reported that coronary microembolization sustains myocardial ischemia with hyperemic response of coronary blood flow (CBF) induced by massive release of adenosine from the ischemic myocardium. In this study, we tested the hypothesis that this hyperemic flow caused by released adenosine improves myocardial ischemia. In eight dogs (control), microspheres (5.0 X 10(4)/ml of base-line CBF) were repetitively injected until CBF decreased toward zero, and the changes in CBF, fractional shortening, lactate extraction ratio (LER), and adenosine release were studied. In 15 other dogs, an identical procedure was done with an intracoronary infusion of prazosin (4 micrograms.kg-1.min-1, n = 8) or theophylline (0.1 mg.kg-1.min, n = 7) to elucidate the effect of adenosine, since prazosin inhibits release of adenosine from ischemic myocardium and theophylline blocks adenosine receptors. In 16 other dogs, hemodynamic and metabolic parameters were examined with and without these drugs after a single injection of microspheres (1.0 X 10(5)/ml of base-line CBF). In the control group, CBF increased to 170 +/- (SE) 14% of the base-line CBF at 16-30% of maximal embolization. In contrast, intracoronary infusion of prazosin markedly attenuated adenosine release and hyperemic response and significantly deteriorated both fractional shortening and LER. Theophylline also significantly attenuated the hyperemic response and tended to decrease both fractional shortening and LER. A salutary effect of adenosine release was further confirmed by the improvement of ischemic changes in the same dog after withdrawal of prazosin and theophylline associated with an increase in CBF. Thus we conclude that adenosine released from ischemic myocardium improves ischemia in microembolization through the hyperemic response.
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PMID:Adenosine-induced hyperemia attenuates myocardial ischemia in coronary microembolization in dogs. 275 Sep 40

The effect of the xanthine derivatives theophylline and propentofylline (HWA 285) on postischemic selective nerve cell damage was studied in the hippocampus of the Mongolian gerbil and assessed by measuring the decrease of Nissl staining in the CA1 area. Theophylline administered 15 min prior to a 2-min period of bilateral carotid occlusion led within 4 days to a marked damage of CA1 neurons which was not seen in untreated animals. Prolongation of the ischemic period to 5 min led to the same degree of damage in theophylline-treated and untreated animals revealing that the protective power of endogenous adenosine is limited. In contrast to theophylline, treatment with propentofylline (10 mg/kg, i.p.) antagonized cell death; such a protection by propentofylline was also achieved after 5 min ischemia in animals treated with theophylline. This indicates that propentofylline does not exert its protective effect via adenosine-mediated mechanisms.
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PMID:Propentofylline (HWA 285) protects hippocampal neurons of Mongolian gerbils against ischemic damage in the presence of an adenosine antagonist. 335 57

Isometric exercise increases sympathetic nerve activity and blood pressure. This exercise pressor reflex is partly mediated by metabolic products activating muscle afferents (metaboreceptors). Whereas adenosine is a known inhibitory neuromodulator, there is increasing evidence that it activates afferent nerves. We, therefore, examined the hypothesis that adenosine stimulates muscle afferents and participates in the exercise pressor reflex in healthy volunteers. Intraarterial administration of adenosine into the forearm, during venous occlusion to prevent systemic effects, mimicked the response to exercise, increasing muscle sympathetic nerve activity (MSNA, lower limb microneurography) and mean arterial blood pressure (MABP) at all doses studied (2, 3, and 4 mg). Heart rate increased only with the highest dose. Intrabrachial adenosine (4 mg) increased MSNA by 96 +/- 25% (n = 6, P < 0.01) and MABP by 12 +/- 3 mmHg (P < 0.01). Adenosine produced forearm discomfort, but equivalent painful stimuli (forearm ischemia and cold exposure) increased MSNA significantly less than adenosine. Furthermore, adenosine receptor antagonism with intrabrachial theophylline (1 microgram/ml forearm per min) blocked the increase in MSNA (92 +/- 15% vs. 28 +/- 6%, n = 7, P < 0.01) and MABP (38 +/- 6 vs. 27 +/- 4 mmHg, P = 0.01) produced by isometric handgrip (30% of maximal voluntary contraction) in the infused arm, but not the contralateral arm. Theophylline did not prevent the increase in heart rate produced by handgrip, a response mediated more by central command than muscle afferent activation. We propose that endogenous adenosine contributes to the activation of muscle afferents involved in the exercise pressor reflex in humans.
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PMID:Role of adenosine in the sympathetic activation produced by isometric exercise in humans. 816 67

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 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

The purpose of this study was to investigate platelet effects on postischemic heart function in conjunction with adenosine effects on intracoronary platelet adhesion. Homologous platelets were infused into the coronaries of isolated guinea pig hearts, either during low-flow ischemia or during reperfusion, and external heart work (EHW) and intracoronary platelet adhesion were determined. In most experiments, thrombin was added to the perfusate. The influence of endogenous adenosine was studied by use of the uptake blocker dipyridamole and the unspecific adenosine-receptor blocker theophylline, the A1-receptor blocker 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), and the A2-receptor blocker 3,7-dimethyl-1-propargylxanthine (DMPX). The importance of nitric oxide and prostaglandin I2 (PGI2) was tested by using nitro-L-arginine (NOLAG) and indomethacin, respectively. When platelets were applied with thrombin during low-flow ischemia, EHW recovered to only 63 +/- 4% of the preischemic value, as compared with 89 +/- 3% without platelets (p < 0.05). Despite thrombin, platelets incurred no significant functional loss when applied in the first minute of reperfusion (but again in the fifth minute); however, when theophylline was also present, recovery of EHW amounted to only 42 +/- 12%. Intracoronary adhesion of platelets was negligible without thrombin, and highest during low-flow ischemia with thrombin (35 +/- 3% of the applied number). No adhesion occurred during the first minute of reperfusion, whereas in the fifth minute, adhesion was again 20.8 +/- 4%. Dipyridamole increased adenosine release and attenuated adhesion at this time. Theophylline increased adhesion in the first minute of reperfusion (33 +/- 6.4%), whereas NOLAG and indomethacin proved to be ineffective. DPCPX and DMPX each increased platelet retention during the first minute of reperfusion, their effects being additive. Intracoronary adhesion of platelets induced by thrombin in isolated hearts can reduce postischemic recovery of heart function. During reperfusion, but not during low-flow, endogenous adenosine can prevent platelet adhesion and loss of myocardial function, an action mediated both by A1- and A2-receptor-dependent mechanisms.
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PMID:Adenosine endogenously released during early reperfusion mitigates postischemic myocardial dysfunction by inhibiting platelet adhesion. 967 36

Raising intracellular cAMP or cGMP concentrations protects lungs from ischemia-reperfusion injury. These nucleotides are catabolized by a number of distinct phosphodiesterase (PDE) isoenzyme subfamilies. We examined the ability of PDE inhibitors of differing selectivities to protect lungs from the effects of prolonged hypothermic storage. Rat lungs were perfused with bicarbonate buffer mixed with rat blood (4:1 vol/vol, 37 degrees C), ventilated, and vascular resistance, airway compliance, and resistance, and gas exchange measured. Lungs were then flushed with, and immersed in, St. Thomas' Hospital Solution (STH) (4 degrees C) or STH containing rolipram, milrinone, zaprinast, or theophylline. After 8 h storage, function was reassessed during 40 min reperfusion. Lungs stored in STH containing rolipram or theophylline had improved function on reperfusion. After 40 min reperfusion, pulmonary compliance (Cstat) was 0.07 +/- 0.01 ml/cm H(2)O in lungs stored in STH alone. Adding rolipram (100 microM) or theophylline (3,000 microM) to the STH used for flushing and storage improved Cstat after reperfusion to 0.17 +/- 0.02 ml/cm H(2)O (p < 0.05) and 0.17 +/- 0.02 ml/cm H(2)O (p < 0. 05), respectively. Theophylline also improved the increase in perfusate PO(2) on transit through the lung after storage to 25.16 +/- 2.33 compared with 4.72 +/- 2.18 mm Hg in lungs stored in STH alone (p < 0.05). Of the selective PDE inhibitors tested, rolipram (type IV inhibitor) was most effective. However, the nonselective agent, theophylline, provided the best protection of function after storage and reperfusion of rat lungs.
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PMID:Comparison of phosphodiesterase inhibitors of differing isoenzyme selectivity added to St. Thomas' hospital cardioplegic solution used for hypothermic preservation of rat lungs. 1098 94

Adenosine (ADO) has an important role in the ischemic brain as an endogenous neuroprotective factor. On the other hand, intraischemic hypothermia ameliorates ischemic neuronal injury. To investigate the effect of ADO during intraischemic mild hypothermia, the extracellular concentration of ADO, its metabolites, dopamine (DA), and local cerebral blood flow were measured in rat striatum during and after 20 min of global ischemia. Additionally, the histopathological outcome was estimated after 48 h of recirculation. Three experimental groups were used: (1) a normothermic group (NT) maintained at 37 degrees C during and after ischemia; (2) a hypothermic group (HT), exposed to intraischemic hypothermia (32.0 degrees C) and postischemic normothermia; and (3) a hypothermia plus theophylline group (HT+T), with the same temperature conditions as in the HT group, combined with intravenously administration of theophylline (10 mg/kg), an antagonist of adenosine receptor, which was given 10 min before ischemia. The level of ADO in HT was significantly higher than ADO levels in NT. In contrast, ischemic DA release was significantly inhibited in HT compared with NT. Theophylline administration had no effect on intraischemic hypothermia induced modulation of extracellular ADO and DA concentration. The postischemic delayed hypoperfusion was ameliorated in HT, and theophylline eliminated this effect in HT+T. A protective effect on histopathological outcome was observed in HT and HT+T. These results suggest that ADO plays an essential role in the inhibition of postischemic delayed hypoperfusion, but this effect is not crucial role in the protective effect induced by intraischemic hypothermia.
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PMID:Neuroprotection role of adenosine under hypothermia in the rat global ischemia involves inhibition of not dopamine release but delayed postischemic hypoperfusion. 1237 83

Several previous studies have demonstrated a beneficial effect of the adenosine receptor (AdoR) antagonist theophylline in different forms of acute renal failure in laboratory animals and in humans. Therefore, we wanted to test whether theophylline can also improve impaired allograft function following ischemia reperfusion injury in experimental kidney transplantation (KT). Orthotopic transplantation of the left kidney was performed from Fisher 344 into Lewis rats. All transplanted rats received daily cyclosporine (5 mg/kg). The effect of theophylline treatment (10 mg/kg) on graft function was compared with appropriate controls on day 5 after KT by assessment of glomerular filtration rate (GFR) (inulin clearance). On day 5, GFR of allografts in control rats was 0.23 +/- 0.05 ml/min/g kidney weight (n = 10) compared with 0.50 +/- 0.09 ml/min/g in rats receiving theophylline (n = 9, p < 0.01), representing a 2-fold increase in GFR. Renal AdoR A(1) mRNA content was significantly increased in both KT groups compared with their respective control groups, whereas mRNA of AdoR A(2a), A(2b), and A(3) were found to be unchanged. Theophylline did not affect significantly interstitial infiltration of the graft by monocytes/macrophages and T-cells. Likewise, serum cytokines [interleukin (IL)-2, IL-6, IL-10, tumor necrosis factor-alpha] and erythropoietin plasma levels were not different among the allograft groups. The present study demonstrates that theophylline remarkably improved early renal allograft function in rats undergoing KT without influencing cytokine serum patterns or tissue inflammation. Since theophylline is a commonly used medication in humans, clinical studies in patients undergoing KT are warranted.
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PMID:Theophylline improves early allograft function in rat kidney transplantation. 1641 Apr 6

This chapter describes the effects of the natural methylxanthines caffeine and theophylline on kidney function. Theophylline in particular was used traditionally to increase urine out put until more potent diuretics became available in the middle of the last century. The mildly diuretic actions of both methylxanthines are mainly the result of inhibition of tubular fluid reabsorption along the renal proximal tubule. Based upon the use of specific adenosine receptor antagonists and the observation of a complete loss of diuresis in mice with targeted deletion of the A1AR gene, transport inhibition by methylxanthines is mediated mainly by antagonism of adenosine A1 receptors (A1AR) in the proximal tubule. Methylxanthines are weak renal vasodilators, and they act as competitive antagonists against adenosine-induced preglomerular vasoconstriction. Caffeine and theophylline stimulate the secretion of renin by inhibition of adenosine receptors and removal of the general inhibitory brake function of endogenous adenosine. Since enhanced intrarenal adenosine levels lead to reduced glomerular filtration rate in several pathological conditions theophylline has been tested for its therapeutic potential in the renal impairment following administration of nephrotoxic substances such as radiocontrast media, cisplatin, calcineurin inhibitors or following ischemia-reperfusion injury. In experimental animals functional improvements have been observed in all of these conditions, but available clinical data in humans are insufficient to affirm a definite therapeutic efficacy of methylxanthines in the prevention of nephrotoxic or postischemic renal injury.
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PMID:Methylxanthines and the kidney. 2085 5


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