1
The ability of a range of substituted imidazole compounds to inhibit mouse cerebellar neuronal nitric oxide synthase (nNOS), bovine aortic endothelial NOS (eNOS) and inducible NOS (iNOS) from lungs ...of endotoxin‐pretreated rats was investigated. In each case the substrate (L‐arginine) concentration employed was 120 nM.
2
1‐(2‐Trifluoromethylphenyl) imidazole (TRIM) was a relatively potent inhibitor of nNOS and iNOS (IC50s of 28.2 μm and 27.0 μm respectively) but was a relatively weak inhibitor of eNOS (IC50, 1057.5 μm). The parent compound, imidazole, was a weak inhibitor of all three NOS isoforms (IC50s: nNOS, 290.6 μm; eNOS, 101.3 μm; iNOS, 616.0 μm). Substitution of imidazole with a phenyl group to yield 1‐phenylimidazole (PI) resulted in an isoform non‐selective increase in inhibitory potency (IC50s: nNOS, 72.1 μm; eNOS, 86.9 μm; iNOS, 53.9 μm). Further substitution of the attached phenyl group resulted in an increase in nNOS and a decrease in eNOS inhibitory potency as in TRIM, 1‐chlorophenylimidazole (CPI; IC50s: nNOS, 43.4 μm; eNOS, 392.3 μm; iNOS, 786.5 μm) and 1‐(2,3,5,6‐tetrafluorophenyl) imidazole (TETRA‐FPI; IC50s: nNOS, 56.3 μm; eNOS, 559.6 μm; iNOS, 202.4 μm).
3
The ability of TRIM to inhibit mouse cerebellar nNOS activity in vitro was influenced by the concentration of L‐arginine (0.12‐10.0 μm) in the incubation medium. When mouse cerebellar nNOS was used as enzyme source a double reciprocal (Lineweaver‐Burk) plot in the presence/absence of TRIM (50 μm) revealed a competitive inhibitory profile. The Km for L‐arginine and the Ki for TRIM calculated from these data were 2.4 μm and 21.7 μm, respectively. The ability of TRIM to inhibit mouse cerebellar nNOS activity in vitro was unaffected by varying the time of exposure of the enzyme to TRIM from 0–60 min at 0°C.
4
TRIM exhibits potent antinociceptive activity in the mouse as evidenced by inhibition of acetic acid induced abdominal constrictions. The ED50 for TRIM following i.p. administration was 20 mg kg−1 (94.5 μmol kg−1). The antinociceptive effect of TRIM was reversed by pretreatment of animals with L‐arginine (50 mg kg−1, i.p.) and was not accompanied by sedation, motor ataxia or behavioural changes (rearing, crossing, circling, dipping) as assessed by use of a box maze procedure.
5
L‐NG nitro arginine methyl ester (L‐NAME, 20 mg kg−1, i.v.) but not TRIM (0.5–20 mg kg−1, i.v.) increased mean arterial blood pressure (MAP) in the urethane‐anaesthetized rat.
6
L‐NAME (100 μm) potentiated the contractile response of the rabbit isolated aorta to phenylephrine (ED50; 0.084 ± 0.01 μm in the presence and 0.25 ± 0.05 μm in the absence of L‐NAME; maximum response, 7.7 ± 0.4 g in the presence and 5.6 ± 0.5 g in the absence of L‐NAME, n = 6, (P < 0.05) whilst TRIM (1–100 μm) was without effect. L‐NAME (100 μm) but not TRIM (1–100 μm) also reduced carbachol‐induced relaxation of the phenylephrine‐precontracted rabbit aorta preparation.
7
L‐NAME (50 μm) potentiated the vasoconstrictor effect of bolus‐injected noradrenaline (10–1000 nmol) and reduced the vasodilator effect of carbachol (10 μm) added to the Krebs reservoir in the rat perfused mesentery preparation. L‐NAME (50 μm) also reduced nitric oxide (NO) release (measured by chemiluminescence of nitrite in the Krebs perfusate) in response to noradrenaline (100 nmol; 53.8 ± 4.0 pmol ml−1 in the presence and 84.8 ± 8.0 pmol ml−1 in the absence of L‐NAME, n = 15, P < 0.05) and carbachol (10 μm; 63.9 ± 5.0 pmol ml−1 in the presence and 154.0 ± 9.0 pmol ml−1 in the absence of L‐NAME, n = 15, P < 0.05). TRIM (50 μm) did not affect either the vasoconstrictor response to noradrenaline or the vasodilator response to carbachol or the accompanying release of NO from the perfused rat mesentery.
Summary
This guideline updates and replaces the 4th edition of the AAGBI Standards of Monitoring published in 2007. The aim of this document is to provide guidance on the minimum standards for ...physiological monitoring of any patient undergoing anaesthesia or sedation under the care of an anaesthetist. The recommendations are primarily aimed at anaesthetists practising in the United Kingdom and Ireland. Minimum standards for monitoring patients during anaesthesia and in the recovery phase are included. There is also guidance on monitoring patients undergoing sedation and also during transfer of anaesthetised or sedated patients. There are new sections discussing the role of monitoring depth of anaesthesia, neuromuscular blockade and cardiac output. The indications for end‐tidal carbon dioxide monitoring have been updated.
The proliferation of vascular smooth muscle cells (VSMCs) in blood vessels after endothelial injury contributes to the onset of atherosclerosis. Heparin is a potent antiproliferative agent for VSMCs ...in vivo and in vitro. Although heparin has shown promise in suppressing VSMC proliferation after invasive procedures in laboratory animals, the mechanism of its antiproliferative actions is largely unknown. Here, we present evidence for the first time that the antiproliferative action of heparin is in part mediated by its ability to activate double-stranded RNA-activated protein kinase (PKR), an interferon-induced protein kinase.
We have analyzed the VSMC proliferation by cell-cycle analysis and correlated it to the kinase activity of PKR in the presence of heparin. Heparin treatment of VSMCs results in activation of PKR by direct binding and results in a block in G1- to S-phase transition. PKR-null cells are largely insensitive to the antiproliferative actions of heparin, and inhibition of PKR in VSMCs results in a partial abrogation of the antiproliferative effects of heparin.
These results invoke the involvement of novel PKR-dependent regulatory pathways in mediating the antiproliferative actions of heparin.
A review and reinterpretation of previous experimental data on the deformation of partially melted crustal rocks reveals that the relationship of aggregate strength to melt fraction is non‐linear, ...even if plotted on a linear ordinate and abscissa. At melt fractions, Φ < 0.07, the dependence of aggregate strength on Φ is significantly greater than at Φ > 0.07. This melt fraction (Φ = 0.07) marks the transition from a significant increase in the proportion of melt‐bearing grain boundaries up to this point to a minor increase thereafter. Therefore, we suggest that it is the increase of melt‐interconnectivity that causes the dramatic strength drop between the solidus and a melt fraction of 0.07. We term this drop the ‘melt connectivity transition’ (MCT). A second, less‐pronounced strength drop occurs at higher melt fractions and corresponds to the breakdown of the solid (crystal) framework. This is the ‘solid‐to‐liquid transition’ (SLT), corresponding to the well known ‘rheologically critical melt percentage’. Although the strength drop at the SLT is about four orders of magnitude, the absolute value of this drop is small compared with the absolute strength of the unmelted aggregate, rendering the SLT invisible in a linear aggregate strength v. melt‐fraction diagram. On the other hand, the more important MCT has been overlooked in previous work because experimental data usually are plotted in logarithmic strength v. melt‐fraction diagrams, obscuring large strength drops at high absolute strength values. We propose that crustal‐scale localization of deformation effectively coincides with the onset of melting, pre‐empting attainment of the SLT in most geological settings. The SLT may be restricted to controlling flow localization within magmatic bodies, especially where melt accumulates.
Energy-transport effects can alter the structure that develops as a supernova evolves into a supernova remnant. The Rayleigh-Taylor instability is thought to produce structure at the interface ...between the stellar ejecta and the circumstellar matter, based on simple models and hydrodynamic simulations. Here we report experimental results from the National Ignition Facility to explore how large energy fluxes, which are present in supernovae, affect this structure. We observed a reduction in Rayleigh-Taylor growth. In analyzing the comparison with supernova SN1993J, a Type II supernova, we found that the energy fluxes produced by heat conduction appear to be larger than the radiative energy fluxes, and large enough to have dramatic consequences. No reported astrophysical simulations have included radiation and heat conduction self-consistently in modeling supernova remnants and these dynamics should be noted in the understanding of young supernova remnants.
Flexible, large area electronics - macroelectronics - using amorphous silicon, low-temperature polysilicon, or various organic and inorganic nanocrystalline semiconductor materials is beginning to ...show great promise. While much of the activity in macroelectronics has been display-centric, a number of applications where macroelectronics is needed to enable solutions that are otherwise not feasible are beginning to attract technical and/or commercial interest. In this paper, we discuss the application drivers and the technology needs and device performance requirements to enable high performance applications to include RF systems.
► Effects of TiO2 NP, 0.1 or 1.0mgl−1; TiO2 bulk, 1.0mgl−1 exposure on zebrafish. ► 21-d post exposure recovery period tested TiO2 effects on reproductive success. ► GSH levels higher in fish exposed ...to TiO2 NP compared to bulk and control fish. ► Fecundity lower in 1.0mgl−1 TiO2 (NP & bulk) compared to 0.1mgl−1 and controls. ► Limited toxicity of bulk or NP TiO2 during exposure but reproductive effects.
There are limited data on the sub-lethal physiological effects of titanium dioxide nanoparticles (TiO2 NPs) in adult fishes, and the consequences of TiO2 NP exposure on reproductive success are also unclear. This study aimed to examine the sub-lethal effects of a 14-d aqueous TiO2 (TiO2 NP, 0.1 or 1.0mgl−1; TiO2 bulk, 1.0mgl−1) exposure on the physiology and reproductive health of zebrafish. After the 14-d exposure, fish were examined for haematology, whole body electrolyte and trace metal profiles, biochemistry, and histopathology. Then, during a 21-d post exposure recovery period, effects of the TiO2 exposure on reproductive success were evaluated. Whole body Ti concentrations increased significantly in fish exposed to both the 1.0mgl−1 TiO2 NP and bulk TiO2 compared to controls, but concentrations returned to control levels by the end of the recovery period. No change in erythrocyte counts were observed, but there was a two-fold decline in leukocyte counts in all TiO2 treatment groups relative to time-matched controls. Whole body electrolyte and trace metal profiles were not affected by exposure to TiO2, and there were no changes in Na+K+-ATPase activity in brain, gill or liver tissues. Total glutathione (GSH) levels in brain, gill and liver tissues were higher in fish exposed to TiO2 NP (both 0.1 and 1.0mgl−1) compared to bulk TiO2 and control fish. Histological examination of gill, liver, brain and gonad tissues showed little evidence of treatment-related morphological change. At the end of the 14-d exposure adult zebrafish were able to reproduce; however, the cumulative number of viable embryos produced was lower in fish exposed to 1.0mgl−1 TiO2 (both NP and bulk) by the end of the 21-d recovery period. Overall, this study showed limited toxicity of bulk or nano scale TiO2 during the exposure; however reproduction was affected in both bulk and NP 1.0mgl−1 groups.
The effect of inhibition of nitric oxide synthase (NOS) on hindpaw hyperalgesia (assessed using mechanical and thermal noxious stimuli) and oedema formation following intraplantar injection of ...carrageenan (150 μl, 2% w v
−1) in the rat was determined. For this purpose, NOS inhibitors including
l-N
G nitro-arginine methyl ester (
l-NAME; isoform non-selective NOS inhibitor), 7-nitroindazole (7-NI) and 1-(2-trifluoromethylphenyl) imidazole (TRIM; both relatively selective inhibitors of neuronal NOS) were used. Mechanical/thermal nociceptive threshold values and hindpaw weight were recorded prior to and 3 h after administration of carrageenan. NOS inhibitors (5–25 mg kg
−1, i.p.) were administered 2.5 h after carrageenan.
l-NAME, 7-NI and TRIM inhibited carrageenan-induced mechanical and thermal hyperalgesia. Calculated ED
50 values (μmol kg
−1, i.p.) were 63.4, 96.2 and 92.7 (mechanical) and 42.2, 53.9 and 62.1 (thermal), respectively. None of the drugs affected pain perception in the non-injected hindpaw or carrageenan-induced hindpaw weight gain. Thus, 7-NI and TRIM, at doses previously reported not to influence cardiovascular haemodynamics, inhibit hyperalgesia in the rat regardless of the type of noxious stimulus employed. Accordingly, selective inhibitors of neuronal NOS may prove useful for the treatment of prolonged pain in man.
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