Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitric oxide (NO), a free radical gas implicated in a wide variety of biological reactions, is a novel signaling molecule that may regulate vasodilation, cerebral blood flow, and vascular permeability. This study was performed to determine whether NO mediates the selective increase in brain tumor microvessel permeability after intracarotid infusion of bradykinin in the RG2 rat glioma model. Intracarotid infusion of bradykinin selectively increased the transport of radiolabeled alpha-aminoisobutyric acid and dextran into brain tumors. Transport into normal brain was not increased. The administration of an NO synthase inhibitor, NG-nitro-L-arginine methyl ester, significantly inhibited the increased transport into tumors for both tracers. The inhibitory effect of NG-nitro-L-arginine methyl ester on the response to bradykinin was reversed by L-arginine. The expression of two NO synthase (NOS) isoforms in cultured RG2 glioma cell lines and intracerebral RG2 glioma was examined by immunohistochemistry and Western blot analysis. High levels of expression of neuronal NOS were detected in cultured and intracerebral RG2 cells but not in normal brain tissue, except in rare neuronal cells. The endothelial form of NOS was also expressed in cultured RG2 cells, but not as strongly as neuronal NOS expression. In intracerebral RG2 gliomas, expression of endothelial NOS in the tumor was detected at higher levels than in normal brain. These findings indicate that RG2 rat gliomas express high levels of NOS, which regulate the production of NO, compared with normal brain. We suggest that the selective permeability increase in brain tumor microvessels after bradykinin infusion is mediated by NO. Furthermore, the absence of high levels of NOS in normal brain may account for the attenuated permeability response to bradykinin in normal brain microvessels.
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PMID:Increased brain tumor microvessel permeability after intracarotid bradykinin infusion is mediated by nitric oxide. 875 74

We have investigated the modulation of the intracellular calcium concentration ([Ca2+]i) in rat C6 glioma cells following their activation by the agonists 5-hydroxytryptamine.HCl (5-HT) and bradykinin, using single cell imaging of [Ca2+]i with the calcium-sensitive dye Fura-2. The majority of the signals observed involved release of calcium from intracellular stores, and after prolonged application of 5-HT, but not bradykinin, the cells exhibited oscillations in [Ca2+]i levels. These calcium oscillations were dependent on the presence of extracellular calcium, and were unaffected by the calcium channel antagonists nifedipine and verapamil. Caffeine, which in other cell types is able to release calcium from inositol trisphosphate-insensitive stores, had very little effect on [Ca2+]i levels in C6 cells. On the other hand, bradykinin, although able to elevate [Ca2+]i probably by acting via the B2-receptor subtype, was unable to induce any calcium oscillations in these cells.
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PMID:5-Hydroxytryptamine-evoked [Ca2+]i oscillations in rat C6 glioma cells. 879 39

The effect and mechanism of the blood-brain barrier-permeabilizing agent, RMP-7, was investigated in a series of studies employing a rat RG2 glioma model. Changes in uptake of carboplatin into brain tumor and various nontumor brain tissue regions was determined using a sophisticated image analysis system. This system permitted quantitative autoradiography to be analyzed simultaneously with overlayed histological images from the same coronal brain section. A wide range of intracarotid doses of RMP-7 (0.01 to 9.0 micrograms/kg) was shown to significantly increase the permeability of carboplatin into tumor tissue and surrounding brain tissue (up to twofold) in a dose-dependent manner. Additionally, substantially greater permeability effects were seen in the tumor compared to healthy brain. Moreover, a clear topographic profile was observed in nontumor brain tissue, with progressively less uptake observed with increasing distance from the tumor. The fact that RMP-7 increased the uptake of carboplatin into ipsilateral brain tissue outside the tumor mass has potential implications for treating human glioma patients, for it is commonly recognized that tumor cells typically migrate from the tumor mass into surrounding brain tissue thereby escaping conventional attempts to destroy the malignant cells. To help elucidate the mechanism of RMP-7's permeability effects, the uptake of carboplatin was also determined under conditions where either the bradykinin B2 receptor antagonist, HOE140, or the B1 antagonist, [desArg10]HOE140, was coadministered with RMP-7. Results indicate that RMP-7's effects are mediated specifically through bradykinin B2 receptors. Furthermore, neither bradykinin antagonist alone affected the uptake of carboplatin into the leaky tumor region, suggesting that abnormal elevations in endogenous bradykinin activity are not likely responsible for the characteristic leaky nature of the tumor vascular barrier. The combined results from these studies therefore offer new insight into the characteristics of the vascular barriers in normal and tumor brain tissue and further elucidate the novel permeability effects of RMP-7. Together, they support its potential use as an adjunctive therapy for the selective delivery of chemotherapeutic drugs to brain tumors and possibly other neurodegenerative conditions.
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PMID:Unlocking the blood-brain barrier: a role for RMP-7 in brain tumor therapy. 881 55

The intracarotid infusion of bradykinin has been shown to selectively increase capillary permeability in a brain tumor without affecting either normal brain capillary permeability or the systemic blood pressure. We examined whether the intracarotid infusion of bradykinin could selectively increase the delivery of a new watersoluble antitumor agent, cis-diammine glycolato-platinum (254-S, 303.2 mol. wt.), to transplanted RG2 glioma in rats. The platinum contents in the brain, tumor tissues and plasma were measured using an atomic absorption spectrophotometer. The transfer ratio of 254-S from plasma to the tissues was calculated and expressed as the volume of plasma containing platinum per g tissue (Dp, microliter g-1). Intracarotid bradykinin infusion at a rate of 20 micrograms kg-1 min-1 increased the delivery of 254-S in the tumor tissue by 1.3-fold when compared with intracarotid infusion of 0.9% saline (48.78 +/- 18.11 vs. 37.12 +/- 12.53; p < 0.05). In normal brain tissue including the ipsilateral cortex, the contralateral basal ganglia and the contralateral cortex, bradykinin did not significantly increase the delivery of 254-S in comparison with 0.9% saline (12.28 +/- 9.53 vs. 10.70 +/- 5.05, 4.96 +/- 3.54 vs 4.96 +/- 4.80, 7.64 +/- 4.10 vs. 13.07 +/- 11.38, respectively). These results indicate that the intracarotid infusion of bradykinin selectively increases the delivery of 254-S to the brain tumor without affecting the normal brain. This method may, therefore, enhance the antitumor effect of 254-S for the treatment of brain tumors and also reduce neurotoxicity in the normal brain.
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PMID:Increased delivery of a new cisplatin analogue (254-S) in a rat brain tumor by an intracarotid infusion of bradykinin. 883 61

The novel bradykinin (BK) analog, RMP-7, was characterized in a series of in vitro tests to establish its selectivity as a B2 agonist. It was then used to study bradykinin's role in permeabilizing the blood brain barrier (BBB) and blood brain-tumor barrier (BTB), using an RG2 rat glioma model. These studies demonstrated that: (1) B2 receptor stimulation permeabilizes both the BBB and BTB in a dose-related fashion with greater effects observed in brain tumor-associated tissue, (2) the increased permeability is sensitive, rapid and transient, and (3) tachyphylaxis occurs with continuous agonist administration, suggesting autoregulation of the system's effects. These data therefore support the existence of a sophisticated, responsive and tightly regulated BK system whose activity modulates the permeability of the BBB.
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PMID:Permeability of the blood brain barrier by the bradykinin agonist, RMP-7: evidence for a sensitive, auto-regulated, receptor-mediated system. 885 61

1. The Ca(2+)-antagonism of tetrandrine (TET) on the Ca2+ mobilization in various types of cells were reviewed. Inositol trisphosphate (IP3)-generating drugs were used as Ca(2+)-mobilizing agonists and the effects were compared with those produced by using the microsomal Ca(2+)-ATPase inhibitor thapsigargin (TG), which is a tool for analysing Ca2+ store-regulated Ca2+ entry (capacitative Ca2+ entry). 2. In rat phaeochromocytoma PC12 cells, 100 mumol/L TET abolished high K+ (30 mmol/L)-induced sustained increases in cytoplasmic Ca2+ concentrations ([Ca2+]i) and partially inhibited bradykinin (1 mumol/L)- or TG (100 nmol/L)-induced Ca2+ entry. 3. In NIH/3T3 fibroblasts and rat parotid acinar cells, 100 mumol/L TET abolished Ca2+ entry induced by bombesin (1 mumol/L) and carbachol (100 mumol/L), respectively, or TG (100 nmol/L). However, in the human leukaemia T cell line Jurkat, 100 mumol/L TET did not inhibit Ca2+ entry evoked by either the anti-CD3 antibody OKT3 (10 mg/L) or TG (100 nmol/L). 4. In rat glioma C6 cells, the effects of TET on Ca2+ mobilization were further examined. At a high concentration, TET (300 mumol/L) alone did not affect [Ca2+]i in C6 cells. Tetrandrine inhibited the peak and sustained increases in [Ca2+]i induced by bombesin and TG in a dose-dependent manner. Although TET or TG did not produce increases in IP3, TET did inhibit increases in IP3 produced by bombesin. 5. Our results suggest that the action of TET on Ca2+ entry is dependent on cell types and that TET inhibits both Ca2+ entry from the extracellular medium and Ca2+ release from intracellular stores in rat glioma C6 cells.
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PMID:Tetrandrine as a calcium antagonist. 888 3

Neuroblastoma x glioma hybrid NG 108-15 and neuroblastoma x fibroblast hybrid NL308 cells possess endogenous bradykinin B2 receptors and m4 muscarinic acetylcholine receptors (mAChRs), which couple to phospholipase C and adenylate cyclase, respectively. Four genetic subtypes of mAChRs differed in their effects when stimulated in NG108-15 and NL308 cells overexpressing mAChRs. Broadly speaking, the principal effects fell into two categories: the odd-numbered receptors (m1 and m3) activated phospholipase C and increased inositol trisphosphate/Ca2+, as bradykinin did, whereas the even-numbered receptors (m2 and m4) inhibited adenylate cyclase via a pertussis toxin (PTx)-sensitive G-protein in NG108-15 cells. But all four types of NL308 cells overexpressing each m1, m2, m3 and m4 receptor activated phospholipase C, while keeping the PTx-sensitivity in m2/m4, but not in m1/m3 receptors. Coupling to ion channel effectors showed a comparable dichotomy in NG108-15 cells, while cross-activation occurred in NL308 cells.
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PMID:Inositol trisphosphate/Ca2+ as messengers of bradykinin B2 and muscarinic acetylcholine m1-m4 receptors in neuroblastoma-derived hybrid cells. 890 60

In single rat glioma cells, the signal transduction process activated by the UTP sensitive purinergic nucleotide receptor was studied by determining [Ca2+]i by Fura-2 fluorescence and measuring pH by BCECF fluorescence to elucidate the control of [Ca2+]i oscillations by intracellular pH. Addition of UTP for long time periods (some min) causes a [Ca2+]i response composed of i) an initial large peak and a following sustained increase (160 s duration), and ii) subsequent regular [Ca2+]i oscillations (amplitude 107 nM, frequency 1.5 oscillations per min). The maintenance of the [Ca2+]i oscillations depends on the continued presence of agonist. The oscillations are abolished by reducing extracellular Ca2+ concentration. The interaction of UTP receptors and bradykinin receptors during the [Ca2+]i oscillations was investigated because previous studies have already shown that the peptide causes comparable [Ca2+]i oscillations. During [Ca2+]i oscillations induced by UTP or bradykinin, long-term admission of both hormones (400-500 s) causes a large initial response superimposed on regular [Ca2+]i oscillations. Short pulses (12 s) of the second agonist given in any phase of the oscillations induce large [Ca2+]i peaks. In both cases, the following oscillations are not disturbed. The influence of cytosolic pH was studied by alkalinizing pHi by application of NH4Cl. [Ca2+]i oscillations stop after addition of NH4Cl. Recovery of NH4Cl-induced alkalinization is reduced by furosemide. To the same degree, the interruption of [Ca2+]i oscillations is significantly prolonged in the presence of furosemide. Thus cytosolic alkalinization suppresses hormone-induced [Ca2+]i oscillations in rat glioma cells. The understanding of the molecular mechanism of this interference of pH should provide an important contribution for unravelling the function of cytosolic pH in cellular signal transduction.
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PMID:P2U nucleotide receptor activation in rat glial cell line induces [Ca2+]i oscillations which depend on cytosolic pH. 892 98

In the present study, we investigated the effects of chronic in vitro administration of amitriptyline, a tricyclic antidepressant, on cyclic GMP formation stimulated by 5-hydroxytryptamine (5-HT) in the neuroblastoma x glioma hybrid cell line, NG 108-15, 5-HT (0.01-100 microM)-stimulated cyclic GMP formation was concentration-dependent and was sensitive to ICS 205-930, a 5-HT3 receptor antagonist. Exposure of NG 108-15 cells to 5 microM amitriptyline for 3 days significantly reduced 5-HT-stimulated cyclic GMP formation. Acute treatment with amitriptyline had no effect on 5-HT-stimulated cyclic GMP formation. The reduction by chronic amitriptyline exposure of 10 microM 5-HT-stimulated cyclic GMP formation was concentration-dependent over the concentration range examined (0.5 to 10 microM). The IC50 of amitriptyline was 1.9 microM. In contrast, amitriptyline exposure, even at a concentration of 8 microM, failed to modify cyclic GMP formation stimulated by bradykinin, sodium nitroprusside, or atrial natriuretic peptide. Increases in intracellular Ca2+ concentration ([Ca2+]i) evoked by 10 microM 5-HT were attenuated in amitriptyline-exposed cells, while 100 nM bradykinin-induced [Ca2+]i increases were not affected. In addition, chronic exposure to 5 microM amitriptyline caused a decrease in affinity (Kd) of [3H]zacopride specific binding to 5-HT3 recognition sites. The Bmax for the labelled ligand remained unchanged. These results suggest that chronic amitriptyline exposure reduces 5-HT-stimulated cyclic GMP formation and [Ca2+]i increases, and this may reflect the functional changes of 5-HT3 receptors.
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PMID:Chronic amitriptyline exposure reduces 5-HT3 receptor-mediated cyclic GMP formation in NG 108-15 cells. 900 9

1. Bradykinin has multiple effects on differentiated NG108-15 neuroblastoma x glioma cells: it increases Ins(1,4,5)P3 production and intracellular Ca2+ concentration [Ca2+]i evokes a Ca2+ activated K+ current (IK(Ca)) and inhibits M current (IM). We studied the effect of the aminosteroid U73122 and the antibiotic neomycin, both putative blockers of phospholipase C (PLC), on these four bradykinin effects. 2. Preincubation with 1 or 5 microM U73122 for 15 min partly suppressed Ins(1,4,5)P3 generation and the increase in [Ca2+]i induced by 1 microM bradykinin. U73122 10 microM caused total and irreversible inhibition. The inactive analogue U73343 was without effect. 3. Resting levels of Ins(1,4,5)P3 were not affected. However, resting [Ca2+]i was increased by 10 microM U73122, but not by U73343. Individual cells responded to 10 microM U73122 with a small increase in [Ca2+]i, followed in some cells by a large further rise. 4. Pretreatment of whole-cell clamped cells with 1 microM U73122 for 30 min reduced the bradykinin-induced IK(Ca) to a fifth of its normal size. To suppress it totally, a 7-12 min pretreatment with 5 microM U73122 was required. Again, U73343 was without effect. 5. U73122 and U73343 at concentrations of 5-10 microM irreversibly decreased the holding current (Ih) which at a holding potential of -30 or -20 mV mainly flows through open M channels. The decrease was often preceded by a transient increase. 6. M current (IM) measured with 1 s pulses, was also decreased by 5-10 microM U73122 and U73343, but short applications of U73122 could cause a small increase. The bradykinin-induced inhibition of IM was not affected by U73122. 7. Preincubation with 1 or 3 mM neomycin for 15 min did not affect Ins(1,4,5)P3 generation and the increase in [Ca2+]i induced by bradykinin. Pretreatment with 3 mM neomycin for about 20 min diminished the bradykinin-induced IK(Ca) to a fifth of its normal size. 8. The four main conclusions drawn from the results are: (a) U73122 suppresses bradykinin-induced PLC activation and IK(Ca), but not IM inhibition. (b) This indicates that the transient outward current IK(Ca), but not the decrease of IM in response to bradykinin, is mediated by PLC. (c) U73122 itself inhibits IM and mobilizes Ca2+ from intracellular stores. (d) Externally applied neomycin is not an effective inhibitor of PLC-mediated signalling pathways in NG108-15 cells.
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PMID:The effects of bradykinin on K+ currents in NG108-15 cells treated with U73122, a phospholipase C inhibitor, or neomycin. 913 90


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