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  • 1
    ISSN: 1440-1681
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: 1. A significant renal vasodilation was observed previously after an acute cyclo-oxygenase (COX) inhibition induced with indomethacin. Because this effect could be due to COX-dependent intrarenal metabolization of arachidonic acid through cytochrome P450 (CYP450) pathways, the aim of the present study was to investigate, in vivo, possible interactions between COX and CYP450 mono-oxygenases.2. Mean arterial pressure (MAP) and renal blood flow (RBF), using an electromagnetic flow transducer for RBF evaluation, were measured continuously in 71 anaesthetized euvolaemic rats. Appropriate solvents (vehicle), 3 mg/kg indomethacin, 17-octadecynoic acid (17-ODYA; 2 mmol/L), either miconazole (MI; 1.5 mmol/L) or N-methylsulphonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH; 5 mg/kg) and N′-hydroxyphenylformamidine (HET0016; 5 or 10 mg/kg) were administered to inhibit either COX, CYP450 mono-oxygenases, epoxygenases or hydroxylase, respectively. The CYP450 and COX inhibitors were also combined as follows: 17-ODYA/indomethacin, MI (or MS-PPOH)/indomethacin, HET0016/indomethacin and indomethacin/HET0016.3. Mean arterial pressure and RBF were not modified by vehicle, 17-ODYA or MI (or MS-PPOH). However, MAP decreased slightly (P 〈 0.05; paired t-test, 5 d.f.) and RBF increased transiently (P 〈 0.05; anova, 5 d.f.) after HET0016. In contrast, MAP decreased by 10 mmHg (P 〈 0.05) and RBF increased by 10% (P 〈 0.05) after indomethacin. This enhancement was prevented by 17-ODYA or MI (or MS-PPOH), but not by HET0016. Moreover, RBF increased step-wise to 21% in the indomethacin/HET0016 experiment (P 〈 0.05). Consequently, changes from baseline in renal vascular resistance differed among treatments, averaging −2 ± 3 (vehicle), −13 ± 3 (indomethacin; P 〈 0.05 vs vehicle), −4 ± 3 (17-ODYA/indomethacin), −3 ± 4 (MI or MS-PPOH/indomethacin), −15 ± 3 (HET0016/indomethacin; P 〈 0.05) and −22 ± 4% (indomethacin/HET0016; P 〈 0.05).4. In conclusion, these results demonstrate that the renal vasodilation induced by indomethacin can be prevented by prior inhibition of CYP450 mono-oxygenases and further suggest that the CYP450 epoxygenases pathway may prevail.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1440-1681
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: 1. The purpose of the present study was to test the effects of synthetic atrial natriuretic peptide (ANP) on renal haemodynamics and excretory capacities of salt and water in the rat during an ‘acute volumic stress’, which was induced by brisk disturbances of the circulatory volume.2. To this end, 29 anaesthetized male Wistar rats were rapidly injected with 1 mL of 0.85% NaCl, repeated twice at 60 s intervals. The injectates contained no ANP (n = 5) or 1 × 0.25 (n = 6), 3 × 0.25 (n = 6), 1 × 2.5 (n = 6) or 3 × 2.5 μg (n = 6) ANP, added to the first injectate only (1 ×) or to each injectate (3 ×). Renal blood flow (RBF) was continuously measured with an electromagnetic flow transducer.3. Renal blood flow increased transiently (approximately 30 s) by approximately 13% (P 〈 0.05) during each injection of saline without ANP. Addition of 0.25 or 2.5 μg ANP to the first injectate enhanced RBF by 21 and 35%, respectively (both P 〈 0.05), but did not modify the time sequence. Furthermore, addition of 0.25 μg ANP to the second and third injectate produced an almost similar change in RBF at the end of each injection (ΔRBF = 20 and 17%, respectively). In contrast, the addition of 2.5 μg ANP to the second and third injectate did not produce the same changes in RBF observed at the end of the first injection. The amplitude of the change in RBF was then similar to the increase in RBF induced by 1 mL saline without ANP. Mean arterial pressure (MAP) did not change significantly during repeated injections of saline alone or with addition of 0.25 μg ANP to the first injectate. However, MAP decreased significantly (by 5, 9 and 9 mmHg) after the injection of 3 × 0.25, 1 × 2.5 or 3 × 2.5 μg ANP, respectively.4. Sodium excretion was rapidly increased from 2.600±0.654 to 9.330±1.322 μmol/min after injection of 3 × 1 mL of 0.85% NaCl (P 〈 0.05). Thereafter, sodium excretion remained enhanced throughout the experiment, so that 70% of the sodium load injected was recovered at the end of the experiment. Atrial natriuretic peptide added to the injectates further elevated the maximal responses in diuresis and natriuresis induced by saline injections without ANP (P 〈 0.001). A maximal effect was observed after the addition of 2.5 μg ANP to the first saline solution. When the amount of sodium excreted was calculated by integrating the areas under the curve of the natriuretic responses, a relationship was established as a function of the amount of ANP added to the saline solutions. It was characterized by a threshold in the presence of 2.5 μg ANP added to the first injectate when the integration period was limited to 4 min 30 s and 14 min 30 s after starting the first injection of the varying test solutions. When the integration period was extended until the end of the experiment (2 h), the amount of sodium excreted in each group was further enhanced, especially after injection of 3 × 1 mL of 0.85% NaCl without ANP or with 1 × 0.25 and 3 × 0.25 μg ANP. Differences in sodium excretion between groups were attenuated (P 〈 0.054, ANOVA).5. In conclusion, our results demonstrate differential effects of synthetic ANP on renal vascular reactivity and excretory capacity. These effects were superimposed on changes induced by acute volumic stress. In particular, effects of saline injections on renal vascular compliance were amplified in the presence of ANP added in varying amounts to the injectates. This amplification was limited to 2.5 μg ANP.
    Type of Medium: Electronic Resource
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  • 3
    Publication Date: 2018-09-05
    Description: Background: Biomarkers of tobacco exposure have a central role in studies of tobacco use and nicotine intake. The most significant exposure markers are nicotine itself and its metabolites in urine. Therefore, it is important to evaluate the performance of laboratories conducting these biomarker measurements. Methods: This report presents the results from a method performance study involving 11 laboratories from 6 countries that are currently active in this area. Each laboratory assayed blind replicates of seven human urine pools at various concentrations on three separate days. The samples included five pools blended from smoker and nonsmoker urine sources, and two additional blank urine samples fortified with pure nicotine, cotinine, and hydroxycotinine standards. All laboratories used their own methods, and all were based on some form of liquid chromatography/tandem mass spectrometry. Results: Overall, good agreement was found among the laboratories in this study. Intralaboratory precision was good, and in the fortified pools, the mean bias observed was 〈 + 3.5% for nicotine, approximately 1.2% for hydroxycotinine, and less than 1% for cotinine (1 outlier excluded in each case). Both indirect and direct methods for analyzing the glucuronides gave comparable results. Conclusions: This evaluation indicates that the experienced laboratories participating in this study can produce reliable and comparable human urinary nicotine metabolic profiles in samples from people with significant recent exposure to nicotine. Impact: This work supports the reliability and agreement of an international group of established laboratories measuring nicotine and its metabolites in urine in support of nicotine exposure studies. Cancer Epidemiol Biomarkers Prev; 27(9); 1083–90. ©2018 AACR .
    Print ISSN: 1055-9965
    Electronic ISSN: 1538-7755
    Topics: Medicine
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  • 4
    Publication Date: 2018-10-04
    Description: Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by a mutation in the huntingtin (HTT) protein, resulting in acquisition of toxic functions. Previous studies have shown that lowering mutant HTT has the potential to be broadly beneficial. We previously identified HTT single-nucleotide polymorphisms (SNPs) tightly linked to the HD mutation and developed antisense oligonucleotides (ASOs) targeting HD-SNPs that selectively suppress mutant HTT. We tested allele-specific ASOs in a mouse model of HD. Both early and late treatment reduced cognitive and behavioral impairments in mice. To determine the translational potential of the treatment, we examined the effect of ASO administration on HTT brain expression in nonhuman primates. The treatment induced robust HTT suppression throughout the cortex and limbic system, areas implicated in cognition and psychiatric function. The results suggest that ASOs specifically targeting mutated HTT might have therapeutic effects on HD-mediated cognitive impairments.
    Print ISSN: 1946-6234
    Electronic ISSN: 1946-6242
    Topics: Medicine
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