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At least 505 records · Page 28Linked to original sources
PubMed1997

Effect of phospholipase A2 activation on the receptor function in the rat left atrium: unmasking of a positive inotropic effect of methacholine.

1. To elucidate the functional consequence of endogenous phospholipase A2 activation, the effect of pretreatment with melittin on (-)-isoprenaline, forskolin and methacholine inotropic responses in isolated rat left atria was studied. 2. Melittin pretreatment resulted in a significant decrease of the positive inotropic response of (-)-isoprenaline, whereas no significant change in the forskolin response was seen. 3. A more prominent negative inotropic effect of methacholine could be perceived after melittin pretreatment. These effects of melittin were not simply reversed by mepacrine, a phospholipase A2 inhibitor. 4. After combined mepacrine/melittin pretreatment, a positive inotropic response was elicited by methacholine, which could be blocked by atropine but not by (+/-)-propranolol. 5. It is suggested that the combination of mepacrine/melittin abolishes the activity of an inhibitory G protein.

Adrenergic beta-Agonists↗
PubMed2000

Microinfusion of the non-competitive N-methyl-D-aspartate receptor antagonist MK-801 (dizocilpine) into the dorsal hippocampus of wistar rats does not affect latent inhibition and prepulse inhibition, but increases startle reaction and locomotor activity.

Latent inhibition (the retarded conditioning to a stimulus following its repeated non-reinforced pre-exposure) and prepulse inhibition (the reduction in the startle response to an intense acoustic stimulus when this stimulus is immediately preceded by a prepulse) reflect cognitive and sensorimotor gating processes, respectively, and are deficient in schizophrenic patients. The disruption of latent inhibition and prepulse inhibition in the rat is used as an animal model for the attentional deficits associated with schizophrenia. The present study tested the extent to which latent inhibition and prepulse inhibition, startle reaction and locomotor activity in the open field were affected by infusing the non-competitive N-methyl-D-aspartate receptor antagonist MK-801 (dizocilpine) into the dorsal hippocampus of Wistar rats. We used the same dose of MK-801 (6.25microg/0.5microl per side) previously found to be effective in the disruption of prepulse inhibition when infused into the dorsal hippocampus of Sprague-Dawley rats [Bakshi V. P. and Geyer M. A. (1998) J. Neurosci. 18, 8394-8401; Bakshi V. P. and Geyer M. A. (1999) Neuroscience 92, 113-121]. Bilateral infusion of MK-801 into the dorsal hippocampus did not disrupt latent inhibition. Furthermore, in contrast to previous studies, we failed to find a significant disruption of prepulse inhibition after MK-801 infusion into the dorsal hippocampus, although MK-801 infusion was effective in increasing the startle amplitude as well as locomotor activity in an open field. From our results, we suggest that N-methyl-D-aspartate receptor-mediated processes within the dorsal hippocampus are not necessary for the normal maintenance of the attentional processes reflected by latent inhibition and prepulse inhibition.

Animals↗
PubMed2001

Hyperactivity and disruption of prepulse inhibition induced by N-methyl-D-aspartate stimulation of the ventral hippocampus and the effects of pretreatment with haloperidol and clozapine.

This study re-examined the hyperactivity and disruption of prepulse inhibition induced by N-methyl-D-aspartate stimulation of the rat ventral hippocampus and compared how both effects were affected by pretreatment with either haloperidol or clozapine. While the hyperactivity is thought to depend on dopamine receptor activation in the nucleus accumbens, the dopamine D2-class receptor blocker haloperidol failed to antagonize the disruption of prepulse inhibition in previous studies. However, an ameliorative effect of the atypical neuroleptic clozapine on disruption of prepulse inhibition was suggested by our previous experiments [Zhang et al. (1999) NeuroReport 10, 1-6]. In the present study, bilateral infusion of N-methyl-D-aspartate (0.5microg/side) into the ventral hippocampus of Wistar rats increased open field locomotor activity and disrupted prepulse inhibition. Both effects were observed immediately after infusion but disappeared 24h later. Injection of haloperidol (0.2mg/kg) or clozapine (5mg/kg), 45min prior to N-methyl-D-aspartate infusion, totally antagonized the hyperactivity but did not affect the disruption of prepulse inhibition. We conclude that dopaminergic mechanisms are differentially involved in the hyperactivity and disruption of prepulse inhibition induced by N-methyl-D-aspartate stimulation of the ventral hippocampus. Activation of accumbal dopamine receptors, which is blocked by clozapine and haloperidol to a comparable extent, seems to be crucial for the hyperactivity but not the disruption of prepulse inhibition. The present finding that both clozapine and haloperidol failed to antagonize the disruption of prepulse inhibition induced by N-methyl-D-aspartate stimulation of the ventral hippocampus is discussed with respect to our previous contrary finding concerning the ameliorative effect of clozapine and with respect to the disruption of prepulse inhibition in rats being considered as a model of sensorimotor gating deficits in schizophrenia.

Animals↗
PubMed1997

Acute exposure to ozone does not influence neuroreceptor density and sensitivity in guinea pig lung.

The effects of acute exposure of guinea pigs to 3 ppm of ozone for 2 h on the receptor density and sensitivity of the muscarinergic-, the histaminergic- and the beta-adrenergic receptor systems were studied, in order to provide more insight in the complex mechanisms underlying the well known ozone-induced changes in receptor functionality. The exposure to ozone did not change either the total amount of receptors present in lung tissue, nor the receptor sensitivity of the systems studied. Although no effects were observed, this does not yet fully exclude the receptor system for being a target of ozone exposure. The receptor function can be changed after exposure to ozone, e.g., the coupling with the G-protein can be influenced. Furthermore, the G-protein itself may have been altered or changes can occur at lower levels in the receptor signal transmission route leading to functional changes after stimulation of the receptor with an agonist.

Animals↗
PubMed2001

High-performance liquid chromatography with electrochemical detection for the determination of 7-monohydroxyethylrutoside in plasma.

MonoHER (7-monohydroxyethyl rutoside) is a semisynthetic flavonoid, which can be used as a modulator for doxorubicin-induced cardiotoxicity. To study the pharmacokinetics of monoHER in mice and human an HPLC procedure was developed to measure the level of monoHER in plasma. After extraction of monoHER with methanol, the supernatant was equally diluted (v/v) with 25 mM phosphate buffer (pH 3.33). This solution was analysed by HPLC, using a reversed-phase ODS column, with a mobile phase consisting of 49% methanol and 51% of an aqueous solution containing 10 mM sodium dihydrogen phosphate (pH 3.4), 10 mM acetic acid and 36 microM EDTA. The retention time of monoHER was about 5.2 min. The lower limit of quantification of monoHER was set at 0.3 microM and the calibration line was linear up to 75 microM. The within-day accuracy and precision of the quality control samples (0.45, 1.0, 10 and 40 microM) were better than 15 and 13%, respectively. The between-day accuracy and precision were less than 3, 20%, respectively. The recovery of monoHER (using quality control concentrations) was concentration independent and ranged from 90.5 to 95.3% except for the lowest quality control, 0.45 microM, of which the recovery was 85%. The concentration of monoHER in plasma decreased with 10% when stored at -80 degrees C for one month and with 20% when stored at -20 degrees C for 3 weeks. The repeated injection of monoHER in aliquots of 10 microM, stored in the autosampler tray (4 degrees C), showed a consistent decrease during a run: 15% over 24 h. To compensate for this decrease, sample duplicates were analysed in a mirror image sequence.

Animals↗
PubMed2001

Determination of monohydroxyethylrutoside in heart tissue by high-performance liquid chromatography with electrochemical detection.

7-Monohydroxyethylrutoside (monoHER) is one of the components of the registered drug Venoruton. It showed a good protection against the cardiotoxic effects of doxorubicin. The analysis of monoHER was developed to study the pharmacokinetic profile of the drug in heart tissue. MonoHER was extracted from heart tissue homogenate with methanol. The supernatant was diluted 1:1 (v/v) with 25 mM phosphate buffer and injected onto a reversed-phase ODS column. The mobile phase consisted of 49% methanol and 51% of an aqueous solution containing 10 mM sodium dihydrogenphosphate (pH 3.4), 10 mM acetic acid and 36 microM EDTA. The retention time of monoHER was about 5.2 min and no endogenous peaks were interfering. The lower limit of quantification was 0.072 nmol g(-1) wet heart tissue. The calibration line was linear up to 24 nmol g(-1). The within-day accuracy and precision of the quality controls (0.12, 1.2 and 12.0 nmol g(-1)) were smaller than 17 and 19%, respectively. The between-day accuracy and precision were better than 6 and 11%, respectively. The recovery of monoHER from heart tissue ranged from 104.1 to 114.3% and was concentration independent. MonoHER was stable in heart tissue when stored at -80 degrees C for 6 months. Repeated injection of monoHER from aliquots of 7.2 nmol g(-1) placed on the sample tray at 4 degrees C for 24 h showed a decrease in the concentration of 30.3%. Analyzing sample duplicates in a mirror image sequence could compensate for the influence of this gradual decrease. The small sample volume allowed one to measure monoHER in the hearts of mice.

Animals↗
PubMed2000

Stability of monoHER in an aqueous formulation for i.v. administration.

MonoHER is a semisynthetic flavonoid used successfully in modulating the cardiotoxic effect of doxorubicin but not its antitumor activity. The oral bioavailability of monoHER is <1%. Therefore, it should be prepared as an i.v. formulation for use in clinical trials. The solubility of monoHER in water is highly pH dependent. At pH</=8.3 the drug precipitates 4 h after preparation. DMSO was tested for enhancing the solubility of monoHER in aqueous solutions. In all DMSO-based aqueous solutions monoHER recrystalized again at pH<8.3 and room temperature within 4 h after preparation. Moreover, the stability of monoHER was lower in a DMSO stock solution than after dilution with an aqueous solution. The stability of monoHER was tested in alkaline solutions (pH 8.3 and 9.5) using an HPLC-DAD procedure to detect all possible degradation products within 10 min after injection. Minor degradation occurred to monoHER in alkaline solutions when exposed to daylight or 1% H(2)O(2). MonoHER intensively degraded when exposed to a high temperature (80 degrees C). The stability of monoHER was almost the same in saline or 5% glucose when kept at room temperature and an alkaline pH of 8.3 and 9.5. Under shelf-life conditions the stability of monoHER in 5% glucose (pH 8.4), decreased with about 10% during 48 h after preparation.

Antioxidants↗
PubMed2001

Flavonoids as peroxynitrite scavengers: the role of the hydroxyl groups.

It has been reported that flavonoids efficiently protect against peroxynitrite toxicity. Two pharmacophores have been identified in flavonoids, namely the catechol group in ring B and the hydroxyl (OH) group at the 3-position. In this study, this structure-activity relationship was further examined. It was found that catechol (1,2-dihydroxybenzene) is a potent peroxynitrite scavenger, whereas phenol (hydroxybenzene) is not. Of the flavonols tested without a catechol group in ring B, kaempferol (OH groups at positions 3,5,7,4') and galangin (OH groups at positions 3,5,7) are also potent scavengers, whereas apigenin (OH groups at positions 5,7,4') and chrysin (OH groups at positions 5,7) are not. This confirms the importance of the OH group at the 3-position. However, the synthetic flavonol TUM 9761 and 3-hydroxyflavone (OH group only at position 3) are poor scavengers. Based on these results, the structure-activity relationship on the peroxynitrite scavenging activity of flavonols was refined. The catechol in ring B remains important. Also the 3-OH group remains important, but the activity of this pharmacophore is influenced by the substituents at position 5 and at position 7.

Catechols↗
PubMed2003

Lack of inhibition of endothelial nitric oxide synthase in the isolated rat aorta by doxorubicin.

Besides inducing cardiotoxicity, doxorubicin also affects the vasculature. Recent observations in cultured endothelial cells indicated that the endothelial form of nitric oxide synthase might be inhibited by doxorubicin thereby seriously interfering with vascular function. We have investigated the effect of doxorubicin on the relaxation induced by the muscarinic agonist carbachol in the isolated rat aorta. It was found that doxorubicin at concentrations up to 50 microM does not alter the relaxant response to carbachol. Direct measurement of nitrite, the metabolite of NO*, by the Griess assay confirmed our observation that NO*)production is not inhibited by doxorubicin.

Animals↗
PubMed2003

Inhibition of various glutathione S-transferase isoenzymes by RRR-alpha-tocopherol.

The activity of human cytosolic glutathione S-transferases (GSTs) can positively or negatively be changed by various compounds. It is for instance known that RRR-alpha-tocopherol inhibits GST P1-1 [Haaften van R.I.M. et al. (2001) Alpha-tocopherol inhibits human glutathione S-transferase pi. BBRC 280, 631-633]. The effect of RRR-alpha-tocopherol on the other isoenzymes of GST in purified forms of the isoenzymes and in human liver cytosol (GST M and GST A) and lysate of human erythrocytes (GST P) is studied. It is found that all isoenzymes (purified enzymes and enzymes present in homogenates) are inhibited, in a concentration-dependent way, by RRR-alpha-tocopherol. GST P is in both cases inhibited with the highest potency compared to the other isoenzymes. It also appeared that the purified GST P1-1 isoenzyme is non-competitively inhibited by RRR-alpha-tocopherol. The IC(50) values of RRR-alpha-tocopherol for the purified isoenzymes of GST are much lower compared to the IC(50) values for human lysate and human liver cytosol. This is probably due to binding of RRR-alpha-tocopherol to proteins, e.g. albumin and hemoglobin, with higher affinity than to GST; so more RRR-alpha-tocopherol is needed to inhibit the enzyme. However, the inhibition of GSTs by RRR-alpha-tocopherol can still be of physiological relevance, because due to dermal application of cosmetic products very high concentrations vitamin E can be reached in the skin, where GST P1-1 is present. RRR-alpha-tocopherol might also be a good lead compound for the development of a new class of inhibitors of GST that can be used as adjuvant in cancer therapy.

Adult↗
PubMed2001

New synthetic flavonoids as potent protectors against doxorubicin-induced cardiotoxicity.

A series of 3,7-disubstituted-2(3',4'-dihydroxyphenyl) flavones has been studied as potential cardioprotective agents in doxorubicin antitumor therapy. The influence of substituents on the 3 and 7 position of the flavone nucleus on antioxidant activity cytotoxicity and cardioprotective properties was explored to improve the activity of our lead compound 7-monohydroxyethylrutoside. In the protection against Fe(2+)/vitamin C-induced microsomal lipid peroxidation (LPO assay), IC(50) values ranged from 0.2 to 37 microM. In general, the 3-substituted flavones were the most potent compounds in this assay. The cytotoxicity of the new compounds was tested (up to 250 microM) in hepatocytes. LDH leakage ranged from 2.6-29.2%, whereas the GSH concentrations decreased to 87.3-41.3%. Only four compounds out of this series protected the isolated mouse left atrium against doxorubicin-induced toxicity. Because of the positive inotropic effect of 8d (N-(3-(3',4'-dihydroxyflavon-7-yl)oxypropyl)-N,N,N-trimethylammonium chloride) and 10c (3-hydroxyethoxy-7,3',4'-trihydroxyflavone) on the atrium, compounds 9i (3',4'-dihydroxy-3-glucosylflavone) and 10d (N-(3-(7,3',4'-trihydroxyflavon-3-yl)oxypropyl)-N,N,N-trimethylammonium chloride) were selected to be evaluated as cardioprotective agents in vivo.

Animals↗
PubMed2003

Systemic poly(ADP-ribose) polymerase-1 activation, chronic inflammation, and oxidative stress in COPD patients.

Oxidative stress and systemic inflammation in chronic obstructive pulmonary disease (COPD) strongly suggest a role for the nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1, E.C.2.4.2.30) in the disease pathophysiology. PARP-1 is highly activated by reactive oxygen species-induced DNA strand breaks, upon which it forms extensive poly(ADP-ribose) (PAR) polymers from its substrate NAD(+). We hypothesized that in COPD, chronic inflammation and oxidative stress would lead to systemic PARP-1 activation and to a reduced NAD(+) status. In a patient-control study, systemic PARP-1 activation was assessed by immunofluorescent detection of PAR polymers in peripheral blood lymphocytes. The percentage of PAR polymer-positive lymphocytes appeared to be higher in COPD patients (27 +/- 3%) than in healthy age-matched controls (17 +/- 2%, p <.05). Trolox equivalent antioxidant capacity (TEAC) of deproteinized plasma (p <.001), plasma uric acid (p <.05), as well as blood NAD(+) (p <.01) of stable COPD patients were significantly reduced when compared to controls. In addition, levels of proinflammatory cytokines IL-6, IL-8, and sICAM-1 were increased (p <.005) in COPD patients. In this study, evidence was found for the presence of systemic inflammation, chronic oxidative stress, and systemic PARP-1 activation in stable COPD patients. These data support a contribution of oxidative stress-induced PARP-1 activation to the pathophysiology of COPD.

Antioxidants↗
PubMed1990

Ischaemic disease of the colon and rectum after surgery for abdominal aortic aneurysm: a prospective study of the incidence and risk factors.

In a prospective study of 100 patients operated on for an infrarenal localised aortic aneurysm, routine postoperative colonoscopy revealed ischaemic colonic disease, defined as ulceration or necrosis of different degrees in three of 66 patients (4.5%) operated on electively or semi-acute, and in six of 34 patients (17.6%) operated on for a rupture of their aneurysm. Colonoscopic findings were interpreted as transmural gangrene in three patients, extensive superficial necrosis in one, and ulceration in five. Exploratory laparotomy, however, led to a definite diagnosis of transmural gangrene in only one patient. This patient was the only one whose death was directly related to this complication, notwithstanding timely surgical intervention. Four patients had severe and protracted diarrhoea, while four others exhibited no clinical symptoms at all. Ischaemic colonic lesions were found more often in patients who had been exposed to a period of preoperative shock, than in those who were operated on in a stable circulatory state (20.7 vs. 4.2%; P less than 0.05). It was also more common in patients in whom the patency of at least one hypogastric artery could not be preserved (36 vs 5.6%; P less than 0.02). Ligation of a patent inferior mesenteric artery was not in this study related to the development of ischaemic colonic disease, nor was a period of prolonged (greater than 1 h) cross clamping of the aorta. Postoperative diarrhoea was an early warning sign of ischaemic colonic disease in five of nine patients. Other clinical symptoms or signs were of no value at all in this respect.(ABSTRACT TRUNCATED AT 250 WORDS)

Aorta, Abdominal↗
PubMed1998

Protein A immunoadsorption (i.a.) in renal transplantation patients with vascular rejection.

Vascular rejection after renal transplantation is connected with a higher frequency of allograft dysfunction or graft loss. Plasmapheresis as an adjunctive therapy in the treatment of humoral mediated acute graft rejection was compared with protein A immunoadsorption. Eleven patients with acute graft rejection and high titers of cytotoxic HLA-Ab and/or signs of vascular rejection at graft biopsy (performed in 9 patients) have been treated. Six of them have a stable graft function, the longest graft survival until now is 41 months, four are back on haemodialysis and one patient died from CMV-pneumonia with a stable graft function 9 months after transplantation. We conclude that IA is a useful adjunctive therapy in the treatment of vascular rejection after renal transplantation. Further investigations are necessary to optimize criteria for inclusion.

Endothelium, Vascular↗
PubMed2003

Current research and treatment for epithelial ovarian cancer. A Position Paper from the Helene Harris Memorial Trust.

In March 2003, an international mulltidisciplinary group of scientists and clinicians with a specific interest in ovarian cancer met for 4 days to discuss research into and treatment of this challenging disease. Under the headings of molecular genetics, molecular biology, the biology of ovarian cancer, old therapies, new targets and the early detection of the disease, this Position Paper summarises the presentations and discussion from the 9th Biennial Helene Harris Memorial Trust Forum on Ovarian Cancer. In particular, we highlight the potential of international collaborations in translating laboratory science into useful clinical interventions.

Antineoplastic Agents↗
PubMed1998

Inhibition of lipid peroxidation mediated by indolizines.

Esters, ethers, carbonates and carbamates of 1-indolizinols and azaindolizinols exhibit a profound inhibition of lipid peroxidation in vitro. The antioxidants were prepared by cyclization of pyridines and diazines with diphenylcyclopropenone followed by introduction of the O-substituent.

Antioxidants↗