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Biomedical subjects

D Duval

Publications and source records attributed to D Duval.

At least 37 records · Page 2Linked to original sources
PubMed1995

Contributions of NO synthase and heme oxygenase to cGMP formation by cytokine and hemin treated brain capillary endothelial cells.

Two mechanisms contribute to cGMP formation by soluble guanylyl cyclase (i) NO production by NO synthase and (ii) CO production by heme oxygenase. We analyze here the contributions of these two pathways to IL1, TNF, lipopolysaccharide and hemin treated brain capillary endothelial cells. Cytokines and LPS induced cGMP formation in manners that were completely prevented by LY 83,583, methylene blue and by cyclosporin A. They were partially inhibited by inhibitor of NO synthase. Cyclosporin A acts by a posttranscriptional mechanism. Cells constitutively expressed mRNAs for heme oxygenase-1. Expression was enhanced by hemin but not by IL1 or lipopolysaccharide. Induction of heme oxygenase-1 and its inhibition by Sn protoporphyrin IX had no effect on cGMP levels.

Amino Acid Oxidoreductases↗
PubMed1995

Effect of glibenclamide on the metabolism of fatty acids in cultures of newborn rat heart cells under normoxic and hypoxic conditions.

Several deleterious biochemical alterations have been observed in myocardial cells during ischemia, including perturbations of transmembrane ion equilibria, production of noxious oxygen-derived radicals and loss of membrane phospholipids. Although the precise relationship between these alterations and the reduction of oxygen and glucose supplies is not fully understood, the decrease of intracellular ATP content appears to be a key event in the cascade. Recent evidence suggests that opening of ATP-sensitive K+ channels may constitute an endogenous protective mechanism during ischemia. We have thus tested the effects of glibenclamide, a channel blocker, and aprikalim, a channel opener, on the metabolism of membrane fatty acids in cultures of newborn rat heart cells under normoxic and hypoxic conditions. We showed that glibenclamide partially blocks the loss of membrane phospholipids induced by oxygen deprivation in contractile myocytes, whereas aprikalim fails to alter this metabolism under either normoxic or ischemic conditions. In cultures of fibroblast-like heart cells neither drug was able to modify fatty acid metabolism.

Adenosine Triphosphate↗
PubMed1995

Anti-anaphylactic activity of the novel selective histamine H1 receptor antagonist mizolastine in the rodent.

The anti-anaphylactic/anti-histamine activity of mizolastine (CAS 108612-45-9, SL 85.0324), a novel histamine H1 receptor antagonist devoid of sedative properties, has been evaluated in the rat, mouse and guinea pig. Mizolastine inhibited the passive cutaneous anaphylactic reduction caused by ovalbumin challenge in the rat (ED50 = 0.7 mg/kg i.v., 1.6 mg/kg p.o.) and effectively protected rats from the lethal shock induced by compound 48/80 (ED50 = 0.07 mg/kg p.o.). Mizolastine protected actively sensitized guinea pigs from anaphylactic mortality, bronchospasm and respiratory difficulties (increase in pulmonary resistance) preceding this event and from morphological modifications at doses from 0.05 mg/kg i.v. The pharmacological activity of mizolastine is linked to a selective blockade of histamine H1 receptors as indicated by the ability of this compound to antagonize rat paw edema induced by the subplantar injection of histamine (ED50 = 0.5 mg/kg p.o.) but not that induced by the injection of serotonin or bradykinin. Mizolastine also antagonized the increase in cutaneous capillary permeability caused by the intradermal injection of histamine (-80% at 0.3 mg/kg p.o.) and compound 48/80 (ED50 = 1.1 mg/kg p.o.) but not that induced by serotonin in the rat. In the guinea pig, mizolastine antagonized i.v. histamine-induced bronchoconstriction (ED50 = 0.03 mg/kg p.o.) and histamine-induced vascular permeability and edema in trachea and bronchi (ED50 < or = 0.05 mg/kg i.v.). Moreover, at higher doses, mizolastine antagonized the bronchospasm caused by systemic injection of platelet-activating factor (PAF) and leukotriene D4 (LTD4) (ED50's = 0.30 and 3.0 mg/kg p.o., respectively). However, mizolastine only weakly antagonized bronchospasm induced by aerosolized PAF (-67% at 50 mg/kg p.o.), failed to antagonize (up to 3 mg/kg i.v.) PAF-induced microvascular permeability of the tracheal mucosa in the guinea pig and was a weak inhibitor of PAF-induced platelet aggregation in the rabbit (IC50 = 74 mumol/l). In addition to antagonizing histamine H1 receptors, mizolastine also inhibits the release of histamine during allergic reactions in tissues. Thus, mizolastine antagonizes the antigen-induced in vivo release of histamine from mast cells in bronchoalveolar lavages of actively sensitized guinea pigs (minimal effective dose 0.3 mg/kg p.o.) and the release of histamine from mast cells in the peritoneal fluid of passively sensitized rats (ED50 = 0.9 mg/kg i.v.). In these various models, mizolastine was more potent than loratadine and terfenadine but less potent than ketotifen. The apparent half-life for the pharmacological actions of mizolastine ranged from 6 to 8 h.(ABSTRACT TRUNCATED AT 400 WORDS)

Anaphylaxis↗
PubMed1994

Cycloheximide and actinomycin D block the toxic effect of glutamic acid on PC12 cells.

Programmed cell death is considered to play a key role during development and also during physiopathological events such as neurodegenerative diseases and ischaemia. We have recently shown in PC12 cells that glutamate induces a progressive cytotoxicity which is only visible 8-10 h after incubation with glutamate for at least 4-6 h. We now present evidence that the toxic action of glutamate may correspond to programmed cell death because it is blocked by either actinomycin D or cycloheximide. This effect, however, may not be due to apoptosis since it is not blocked by aurintricarboxylic acid, a non-specific inhibitor of endonucleases, and neither chromatin condensation nor DNA fragmentation or liberation is seen after glutamate treatment.

Animals↗
PubMed1994

Neuroprotective efficacy of N omega-nitro-L-arginine after focal cerebral ischemia in the mouse and inhibition of cortical nitric oxide synthase.

The neuroprotective effects of various doses of N omega-nitro-L-arginine have been correlated with the degree of N omega-nitro-L-arginine-induced inhibition of cortical nitric oxide synthase activity measured ex vivo. Following focal cerebral ischemia induced by permanent occlusion of middle cerebral artery in the mouse, repeated administration of 1 mg/kg i.p. of N omega-nitro-L-arginine (beginning 5 min after surgery) reproducibly decreased by 66-76% the infarct volume measured at 6 days post-occlusion. This dose of N omega-nitro-L-arginine decreased cortical nitric oxide (NO) synthase activity by 70-73%. The neuroprotective efficacy of N omega-nitro-L-arginine increased dose-dependently over the range of doses of 0.1-1 mg/kg. Within this dose range of N omega-nitro-L-arginine, there was a good parallelism between the extent of inhibition of cortical NO synthase activity measured ex vivo and the degree of neuroprotection. However, higher doses of N omega-nitro-L-arginine (3 and 10 mg/kg i.p.), which inhibited NO synthase activity more effectively (up to 94%) failed to significantly reduce the infarct size. Repeated administrations of increasing doses of L-arginine (up to 30 mg/kg i.p.) with a low dose of N omega-nitro-L-arginine (1 mg/kg i.p.) caused a dose-dependent reduction in the neuroprotective efficacy of N omega-nitro-L-arginine while the extent of NO synthase inhibition measured ex vivo did not decrease significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Oxidoreductases↗
PubMed1994

Cytotoxic effects of glutamic acid on PC12 cells.

In order to investigate the biochemical mechanisms responsible for glutamate-induced cell death, we have tested the effect of this excitatory amino acid on the growth and survival of several cell lines of neural origin. Most of the cell lines studied were insensitive to glutamate, but we observed in PC12 cells that addition of glutamate (1-10 mmol/l) led to a dose-dependent cell damage (70% of cell lysis at 10 mmol/l as estimated by lactate dehydrogenase release). This effect which was not due to an inhibition of cell proliferation was only obvious after 8-10 h of incubation and required the continuous presence of glutamate for at least 4-6 h, to become apparent. Studies of the cytotoxic effect of several glutamate analogues showed that neither N-methyl-D-aspartate nor kainate, ibotenate, trans(+/-) 1-amino 1,3-cyclopentane dicarboxylic acid or alpha-amino-3-hydroxy-5-methyl isoxazole-4-propionic acid exerted any significant action and that quisqualate only was more potent than glutamate itself. A known antagonist of non-NMDA receptors, the 6,7-dinitroquinoxaline-2,3-dione, was able to significantly decrease the glutamate and quisqualate-induced cell lysis. In addition, we observed that glutamate effect was associated with a significant increase in arachidonate liberation from prelabelled cells.

Animals↗
PubMed1994

A pilot, early angiographic patency study using a direct thrombin inhibitor as adjunctive therapy to streptokinase in acute myocardial infarction.

BACKGROUND: The success of streptokinase in acute myocardial infarction is hampered by the high failure rate to achieve early reperfusion. This study evaluates the possible benefit of Hirulog (Biogen, Cambridge, Mass), a direct thrombin inhibitor, as adjunct therapy to streptokinase to enhance early patency and prevent rethrombosis. Heparin has been shown to be of very limited benefits in this setting. METHODS AND RESULTS: Forty-five patients were randomized to Hirulog or heparin (2:1 ratio). Coronary angiography documented a TIMI 2 or 3 flow after 90 minutes in 77% of the patients treated with Hirulog and streptokinase and in 47% of patients treated with heparin and streptokinase (P < .05) and after 120 minutes in 87% and 47% of patients, respectively (P < .01). TIMI 3 flow was established in 77% of patients with Hirulog compared with 40% with heparin (P < .02). The clinical outcome and the bleeding rate was also favorable to Hirulog; no reocclusion was observed at late angiography performed 4.7 days later. CONCLUSIONS: Hirulog in this pilot study significantly improved the early patency rate of the infarct-related artery with a favorable clinical profile. This new direct thrombin inhibitor exhibits promise as adjunctive therapy to thrombolysis.

Coronary Angiography↗
PubMed1993

Biochemical and histological alterations induced by fluid percussion brain injury in the rat.

In the present study we have characterized the time-course of the histopathological and biochemical alterations resulting from mechanical brain injury caused by lateral fluid percussion centered over the parietal cortex in the rat. The injury device used was an HPLC pump coupled to a solenoid valve which delivered a constant and short lasting (10 ms) impact pressure (1.6 atm). This traumatic procedure resulted in an accumulation of blood in the subarachnoid space and cortical edema at 4-24 h post-trauma. From 4 h after injury, cortical neurons exhibited a pathologic appearance and phagocytic cells invaded the brain parenchyma. At 3 and 7 days post-injury, complete neuronal loss was observed in the parietal cortex around the impact site. In the ipsilateral cortex, the time-course of histologically assessed neuronal loss and phagocytic/glial activation paralleled the time-course of the loss of omega 1-2 (benzodiazepine) sites (a neuronal marker) and of the increase in p sites (peripheral-type benzodiazepine binding sites; a glial/macrophage marker). Neuronal loss and increase in the density of the glial/macrophage biochemical marker were also observed in the hippocampus but not in the contralateral cortex or in other subcortical structures, suggesting a selective vulnerability of the hippocampus to this traumatic procedure. There was a very good spatial correlation between the histological alterations and the changes in the density of the neuronal and glial/macrophage biochemical markers (as assessed by autoradiography). The volume of the lesion, integrated from the surface of the lesion measured at 10 coronal levels cut at a 1 mm interval and stained with haemalum and eosin, represented 32.9 +/- 1.7 mm3.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Tumour angiogenesis.

The progressive emergence of a close relationship between the formation of blood vessels in the vicinity of tumour cells and the development and spreading of tumours, strongly suggests that angiogenesis might be a prerequisite for tumour development. Angiogenesis starts and develops in response to two sets of extracellular signals: soluble angiogenic factors and extracellular matrix. Different experimental models have been used to study angiogenesis in vivo, but they have numerous limitations. Three-dimensional culture systems reconstitute normal interactions between endothelial cells and the surrounding extracellular matrix. Numerous parameters including angiogenic growth factors and cytokines, cell-to-cell interactions and cell-to-extracellular matrix adhesion influence the growth and differentiation of endothelial cells in vitro as well as in vivo. Angiogenesis plays a major role not only in tumour growth but also in metastasis development. Mechanisms of switching to angiogenic phenotype have been recently described and onset of angiogenic activity is now recognized as another discrete step in tumorigenesis. Tumour cells can induce b-FGF expression and exportation, VEGF and VEGF receptor expression and inactivation of the cancer suppressor gene encoding for a fragment of thrombospondin. A controlled net proteolytic balance produced by tumour cells or endothelial cells is required to favour migration and invasion of endothelial cells and angiogenesis. The hypothesis that assessment of tumour angiogenesis might predict tumour aggressiveness in human cancer has recently gained support from several clinical studies. This has been shown for cutaneous melanoma, breast carcinoma, and non-small-cell lung cancer by quantitation of microvessels in human biopsies using von Willebrand factor or CD3 antigen labelling with specific antibodies. However, more specific and sensitive markers are needed to improve this approach for predicting tumour aggressiveness. Folkman proposed twenty years ago that inhibition of angiogenesis might represent a suitable complementary strategy for the treatment of various forms of cancer. Since then numerous angiostatic compounds have been identified but very few of them fit the required criteria of a potential drug. Fumagillin and particularly its synthetic analogue AGM 1470 might be developed for use in humans in the near future.

Amino Acid Sequence↗
PubMed1993

Carbocisteine improves the mucociliary transport rate in rats with SO2-induced bronchitis.

In order to study the effect of carbocisteine on the mucociliary function of the respiratory tract, we performed a double-blind study on rats with SO2-induced (400 ppm) hypersecretion. During the experimental bronchitis, the treated group of rats received carbocisteine through a stomach tube at a dose level of 500 mg/kg for 15 days, whereas the untreated group of rats received distilled water. After killing the rats, and following lung excision, the respiratory mucus was scraped off and collected by using a glass capillary. The mucus degree of purulence was macroscopically estimated and the mucus transport rate was measured by using the frog palate technique. The mean mucus relative transport rate, measured on the frog palate, was 0.60 +/- 0.17 in the untreated group and was significantly higher (P < 0.01) in the treated group (0.73 +/- 0.14). Carbocisteine also significantly altered (P < 0.01) the mucus macroscopical aspect, leading to a decrease in the number of rats with purulent mucus. These results suggest that carbocisteine maintains an efficient mucus transport rate, leading to a less infected respiratory tract.

Animals↗
PubMed1992

SL 82.0715, an NMDA antagonist acting at the polyamine site, does not induce neurotoxic effects on rat cortical neurons.

In the present study, we have examined by light and electron microscopy whether SL 82.0715, a polyamine site-directed N-methyl-D-aspartate (NMDA) antagonist, causes pathological changes in cerebrocortical neurons similar to those observed with NMDA receptor channel blockers in the rat brain. Dizocilpine (1, 2 and 5 mg.kg-1, s.c.) induced a dose-dependent vacuolization of the neuronal cytoplasm in specific neurons of the retrosplenial and posterior cingulate cortices (layers III and IV) even at the lowest dose studied, at 6 h post-injection. In contrast, SL 82.0715 (10 and 30 mg.kg-1 i.p., 6 h post-injection) did not induce such morphological alterations. These results indicate that NMDA receptor blockade is not necessarily associated with alterations of cortical neuronal morphology.

Animals↗
PubMed1992

Lactate dehydrogenase (LDH) activity of the cultured eukaryotic cells as marker of the number of dead cells in the medium [corrected].

One significant problem in monitoring a culture's evolution is to assess change in cell viability. We have demonstrated that LDH release could be a good indicator of cellular damage of many cell lines, especially during shear stress or sonication. Moreover, we have found a significant correlation between the number of dead cells, determined by Trypan Blue staining, and LDH activity measurements in the supernatant of hybridoma strains, whatever the culture conditions. We have also shown that when viability is still near 100% no LDH is released even at high cell concentrations. Therefore, LDH should serve as a potential marker of cell injury and death.

Animals↗
PubMed1992

Role of metabolic waste products in the control of cell proliferation and antibody production by mouse hybridoma cells.

In order to determine the factors limiting the proliferation and productivity of mouse hybridoma cells in batch/fed-batch cultures, we tested the influence of various environmental parameters on the growth of a model cell line VO 208. We observed that, among the major metabolic waste products, ammonium ions at concentrations superior to that present in the medium at the end of a batch culture do not exert a significant toxic effect on cell growth, whereas in contrast, lactic acid is cytotoxic at concentrations reached in cultures. Feeding of fructose instead of glucose during the stationary phase of the culture markedly prolongs the life span of the culture and enhances the antibody secretion accordingly. However, we failed to observe a satisfactory proliferation pattern in cultures grown in a glucose-free fructose-supplemented medium. We also noted that vitamin supply may be limiting in fed-batch cultures. It thus appears that thorough examination of the cell metabolic needs allows the designing of a culture regimen which significantly improves cell growth and secretion.

Ammonia↗
PubMed1992

Study on the effect of oral administration of carbocysteine on ventilatory parameters in the SO2 inhalation model of bronchitis in the rat.

In order to study the physiological correlates of the beneficial action of carbocisteine (S-carboxy-methyl-cysteine), we have measured the changes occurring in ventilatory parameters in rats made bronchitic by prolonged exposure (2 weeks) to air containing sulfur dioxide (SO2). In animals treated with distilled water (1 ml/100 g/day), statistically significant (P < 0.05) changes in respiratory frequency (-20%) and tidal volume (+31%) were found. As a result of these opposing changes, the ventilation/min was stable. Moreover, the compliance was decreased (33%, P < 0.05) and the resistance was greatly enhanced (+ 99%, P < 0.05). The concomitant administration of carbocisteine (500 mg/kg po/day) with SO2 inhalation significantly (P < 0.05) prevented the development of resistance without effecting significant changes in the other parameters except for a slight improvement in ventilation/min. In conclusion, this improved respiratory resistance in the bronchitic carbocisteine-treated animals tallies with a decrease in mucus retention associated with the return to normal of rheological characteristics of the secreted mucus.

Administration, Inhalation↗