共查询到20条相似文献,搜索用时 31 毫秒
1.
Ying Liu Yongpeng Jin Qi Guo Xiong Wang Sunlin Luo Wenjun Yang Juntao Li Yiqiang Chen 《Toxins》2022,14(9)
In this study, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for simultaneous determination of deoxynivalenol, aflatoxin B1, zearalenone, ochratoxin A, T-2 toxin and fumonisin B1 in feed and feedstuff was established. The sample was extracted with an acetonitrile–water mixture (60:40, v/v), purified by an immunoaffinity column, eluted with a methanol–acetic acid mixture (98:2, v/v), and reconstituted with a methanol–water mixture (50:50, v/v) after drying with nitrogen. Finally, the reconstituted solution was detected by LC-MS/MS and quantified by isotope internal standard method. The six mycotoxins had a good linear relationship in a certain concentration range, the correlation coefficients were all greater than 0.99, the limits of detection were between 0.075 and 1.5 µg·kg−1, and the limits of quantification were between 0.5 and 5 µg·kg−1. The average spike recoveries in the four feed matrices ranged from 84.2% to 117.1% with relative standard deviations less than 11.6%. Thirty-six actual feed samples were analyzed for mycotoxins, and at least one mycotoxin was detected in each sample. The proposed method is reliable and suitable for detecting common mycotoxins in feed samples. 相似文献
2.
Claudia Musilli Gaetano De Siena Maria Elena Manni Andrea Logli Elisa Landucci Riccardo Zucchi Alessandro Saba Riccardo Donzelli Maria Beatrice Passani Gustavo Provensi Laura Raimondi 《British journal of pharmacology》2014,171(14):3476-3484
BACKGROUND AND PURPOSE
3-Iodothyroacetic acid (TA1) is an end product of thyroid hormone metabolism. So far, it is not known if TA1 is present in mouse brain and if it has any pharmacological effects.EXPERIMENTAL APPROACH
TA1 levels in mouse brain were measured by HPLC coupled to mass spectrometry. After i.c.v. administration of exogenous TA1 (0.4, 1.32 and 4 μg·kg−1) to mice, memory acquisition-retention (passive avoidance paradigm with a light-dark box), pain threshold to thermal stimulus (51.5°C; hot plate test) and plasma glucose (glucorefractometer) were evaluated. Similar assays were performed in mice pretreated with s.c. injections of the histamine H1 receptor antagonist pyrilamine (10 mg·kg−1) or the H2 receptor antagonist zolantidine (5 mg·kg−1). TA1 (1.32 and 4 μg·kg−1) was also given i.c.v. to mice lacking histidine decarboxylase (HDC−/−) and the corresponding WT strain.KEY RESULTS
TA1 was found in the brain of CD1 but not of HDC mice. Exogenous TA1 induced amnesia (at 0.4 μg·kg−1), stimulation of learning (1.32 and 4 μg·kg−1), hyperalgesia (0.4, 1.32 and 4 μg·kg−1) and hyperglycaemia (1.32 and 4 μg·kg−1). All these effects were modulated by pyrilamine and zolantidine. In HDC−/− mice, TA1 (1.32 and 4 μg·kg−1) did not increase plasma glucose or induce hyperalgesia.CONCLUSIONS AND IMPLICATIONS
Behavioural and metabolic effects of TA1 disclosed interactions between the thyroid and histaminergic systems. 相似文献3.
Bo-Bin Jing Ying-Xue Li Hui Zhang Shu-Ting Ren Mei Wang Yi-Ping Li Xin-Liang Shen Yi-Li Wang Wei-Jin Zang Bing Wang 《British journal of pharmacology》2013,169(4):848-859
Background and Purpose
The glycoprotein IIb/IIIa receptor is the final common pathway of platelet aggregation, regardless of the agonist, and thus represents an ideal therapeutic target for blocking coronary thrombosis. In this study, the anti-platelet and antithrombotic actions of Z4A5, a new glycoprotein IIb/IIIa receptor inhibitor, were evaluated in a canine model of acute unstable angina.Experimental Approach
Z4A5 was given i.v. as a bolus followed by 60 min of continuous infusion at doses of 30 μg·kg−1 + 1 μg·kg−1·min−1, 30 μg·kg−1 + 5 μg·kg−1·min−1 or 300 μg·kg−1 + 5 μg·kg−1·min−1. Its antithrombotic effect was evaluated in a model of coronary thrombosis, the injured, stenosed left circumflex coronary artery, in which platelet-dependent cyclic flow reductions (CFRs) were induced by vascular compression and constriction to simulate clinical acute unstable angina. Platelet aggregation and coagulation parameters were determined in platelet-rich plasma and platelet poor plasma respectively.Key Results
The Z4A5 infusion induced a dose-dependent reduction in CFR frequency, which returned to baseline levels after the termination of the infusion at low doses. At medium dose that inhibited most part of platelet aggregation, it increased tongue bleeding time marginally with no dramatic changes in haemodynamic and coagulation parameters. Furthermore, the inhibition of ADP-induced platelet aggregation and prolonged bleeding time observed during Z4A5 infusion reverted to baseline levels after the termination of the infusion.Conclusions and Implications
Z4A5 is an effective antithrombotic agent for coronary artery thrombosis with a rapid-on and rapid-off pharmacological profile, and could be used as an alternative treatment of coronary artery ischaemic syndromes. 相似文献4.
Annunziatina Laurino Gaetano De Siena Francesco Resta Alessio Masi Claudia Musilli Riccardo Zucchi Laura Raimondi 《British journal of pharmacology》2015,172(7):1859-1868
Background and purpose
Itch is associated with increased sensitization to nociceptive stimuli. We investigated whether 3-iodothyroacetic acid (TA1), by releasing histamine, induces itch and increases sensitization to noxious and painful heat stimuli.Experimental Approach
Itch was evaluated after s.c. administration of TA1 (0.4, 1.32 and 4 μg·kg−1). Mice threshold to noxious (NHT) and to painful heat stimuli were evaluated by the increasing-temperature hot plate (from 45.5 to 49.5°C) or by the hot plate (51.5°C) test, respectively, 15 min after i.p. injection of TA1 (0.4, 1.32 and 4 μg·kg−1). Itch, NHT and pain threshold evaluation were repeated in mice pretreated with pyrilamine. Itch and NHT were also measured in HDC+/+ and HDC−/− following injection of saline or TA1 (1.32, 4 and 11 μg·kg−1; s.c. and i.p.). pERK1/2 levels were determined by Western blot in dorsal root ganglia (DRG) isolated from CD1 mice 15 min after they received (i.p.): saline, saline and noxious heat stimulus (46.5°C), TA1 (0.1, 0.4, 1.32, 4 μg·kg−1) or TA1 1.32 μg·kg−1 and noxious heat stimulus.Key Results
TA1 0.4 and 1.32 μg·kg−1 induced itch and reduced NHT; pyrilamine pretreatment prevented both of these effects. TA1 4 μg·kg−1 (i.p.) reduced pain threshold without inducing itch or modifying NHT. In HDC−/− mice, TA1 failed to induce itch and to reduce NHT. In DRG, pERK1/2 levels were significantly increased by noxious heat stimuli and by TA1 0.1, 0.4 and 1.32 μg·kg−1; i.p.Conclusions and Implications
Increased TA1 levels induce itch and an enhanced sensitivity to noxious heat stimuli suggesting that TA1 might represent a potential cause of itch in thyroid diseases. 相似文献5.
S M Gardiner P A Kemp J E March J Woolley T Bennett 《British journal of pharmacology》1998,125(7):1543-1550
- Male, Long Evans rats (350–450 g) were anaesthetized and had pulsed Doppler probes and intravascular catheters implanted to allow monitoring of regional (renal, mesenteric and hindquarters) haemodynamics in the conscious state. Our main objectives were to:- assess the effects of administering human recombinant tumour necrosis factor (TNF)-α and human recombinant interleukin-1 (IL-1)β, alone and together; determine the influence of pretreatment with a mixture of antibodies to TNF-α and IL-1β on responses to co-administration of the cytokines; ascertain if pretreatment with a mixture of the antibodies to TNF-α and IL-1β had any influence on the responses to lipopolysaccharide (LPS).
- TNF-α (10, 100 and 250 μg kg−1, in separate groups, n=3, 9 and 8, respectively) caused tachycardia (maximum Δ, +101±9 beats min−1) and modest hypotension (maximum Δ, −10±2 mmHg), accompanied by variable changes in renal and mesenteric vascular conductance, but clear increases in hindquarters vascular conductance; only the latter were dose-related (maximum Δ, +6±6, +27±9, and +61±12% at 10, 100 and 250 μg kg−1, respectively).
- IL-1β (1, 10, and 100 μg kg−1 in separate groups, n=8, 8 and 9, respectively) evoked changes similar to those of TNF-α (maximum Δ heart rate, +69±15 beats min−1; maximum Δ mean blood pressure, −14±2 mmHg; maximum Δ hindquarters vascular conductance, +49±17%), but with no clear dose-dependency.
- TNF-α (250 μg kg−1) and IL-1β (10 μg kg−1) together caused tachycardia (maximum Δ, +76±15 beats min−1) and hypotension (maximum Δ, −24±2 mmHg) accompanied by increases in renal, mesenteric and hindquarters vascular conductances (+52±6%, +23±8%, and +52±11%, respectively). Thereafter, blood pressure recovered, in association with marked reductions in mesenteric and hindquarters vascular conductances (maximum Δ, −50±3% and −58±3%, respectively). Although bolus injection of LPS (3.5 mg kg−1) caused an initial hypotension (maximum Δ, −27±11 mmHg) similar to that seen with co-administration of the cytokines, it did not cause mesenteric or hindquarters vasodilatation, and there was only a slow onset renal vasodilatation. The recovery in blood pressure following LPS was less than after the cytokines, and in the former condition there was no mesenteric vasoconstriction. By 24 h after co-administration of TNF-α and IL-1β or after bolus injection of LPS, the secondary reduction in blood pressure was similar (−16±2 and −13±3 mmHg, respectively), but in the former group the tachycardia (+117±14 beats min−1) and increase in hindquarters vascular conductance (+99±21%) were greater than after bolus injection of LPS (+54±16 beats min−1 and +43±9%, respectively).
- Pretreatment with antibodies to TNF-α and IL-1β (300 mg kg−1) blocked the initial hypotensive and mesenteric and hindquarters vasodilator responses to co-administration of the cytokines subsequently. However, tachycardia and renal vasodilatation were still apparent. Premixing antibodies and cytokines before administration prevented most of the effects of the latter, but tachycardia was still present at 24 h.
- Pretreatment with antibodies to TNF-α and IL-1β before infusion of LPS (150 μg kg−1 h−1 for 24 h) did not affect the initial fall in blood pressure, but suppressed the hindquarters vasodilatation and caused a slight improvement in the recovery of blood pressure. However, pretreatment with the antibodies had no effect on the subsequent cardiovascular sequelae of LPS infusion.
- The results indicate that although co-administration of TNF-α and IL-1β can evoke cardiovascular responses which, in some respects, mimic those of LPS, and although antibodies to the cytokines can suppress most of the cardiovascular effects of the cytokines, the antibodies have little influence on the haemodynamic responses to LPS, possibly because, during infusion of LPS, the sites of production and local action of endogenous cytokines, are not accessible to exogenous antibodies.
6.
In this study, a total of 299 grain samples of wheat were collected from four production regions: the maize, sugar beet, potato and feed sectors of Slovakia. The samples were analyzed for deoxynivalenol (DON) content by using an enzyme-linked immunosorbent assay Ridascreen® Fast DON. Analysis of variance revealed a significant difference between years in DON contents (p < 0.027). The occurrence of samples with DON was 82.2% in 2010, with maximum DON content of 7.88 mg kg−1, and 70.7% in 2011, with maximum DON content of 2.12 mg·kg−1. The total mean DON content was 0.62 mg·kg−1; in the feed region 0.22 mg·kg−1; 0.63 mg·kg−1 in the maize region; 0.78 mg·kg−1 in the sugar beet region; 0.45 mg·kg−1 the potato region. The limit of 1.25 mg·kg−1 imposed by the European Union (EU) for DON content was exceeded in 13.7% of the studied samples. The average monthly rainfall for May to June played a critical role in DON content of wheat grains for maize and sugar beet producing regions. The present results indicate that DON content was at a high level in grains from wheat grown during 2010. 相似文献
7.
- Age-matched (3–4 months old) male, heterozygous, hypertensive, transgenic ((mRen-2)27) rats (abbreviated to TG rats) and the normotensive control animals (homozygous, Hannover Sprague-Dawley rats (abbreviated to SD rats), were chronically instrumented for the assessment of regional haemodynamic responses to continuous lipopolysaccharide (LPS) infusion (150 μg kg−1 h−1, i.v.)
- The early (1–2 h) hypotension in SD rats (−11±3 mmHg; n=7) was significantly less than that in TG rats (−35±3 mmHg; n=8), but by 24 h mean arterial blood pressure (MAP) in both strains of rat was not different from the pre-LPS value (SD rats: baseline, 108±3 mmHg; 24 h LPS, 112±4 mmHg; TG rats: baseline, 171±2 mmHg; 24 h LPS, 169±3 mmHg). At this stage in the SD rats there was a renal vasodilatation (Δ vascular conductance, 29±10 [kHz mmHg−1]103) but not in TG rats (Δ vascular conductance 2±3[kHz mmHg−1]103).
- Co-infusion of LPS and the non-selective endothelin receptor antagonist, SB 209670 (600 μg kg−1 bolus, 600 μg kg−1 h−1) between 24 and 31 h in SD rats caused a fall in MAP of 16±2 mmHg accompanied by hindquarters vasodilatation (Δ vascular conductance 11±3 (kHz mmHg−1)103). In TG rats, under the same conditions, the fall in MAP was −60±6 mmHg, and there were renal, mesenteric and hindquarters vasodilatations (Δ vascular conductance, 23±5, 32±7, and 14±4 (kHz mmHg−1)103, respectively). All effects, except the hindquarters vasodilatation, were greater in TG than in SD rats.
- In TG rats infused with LPS alone for 31 h, between 24 and 31 h the fall in MAP was −17±4 mmHg, and the changes in renal, mesenteric and hindquarters vascular conductances were 5±3, −4±5, and 12±4 (kHz mmHg−1)103, respectively.
- Administration of the angiotensin (AT1)-receptor antagonist, losartan (10 mg kg−1, i.v.) following co-infusion of LPS and SB 209670 between 24 and 31 h caused similar falls in MAP in SD and TG rats (−12±3 and −14±4 mmHg, respectively).
- These results, together with previous findings, are consistent with a relative enhancement of the contribution of endothelin to the maintenance of cardiovascular status in endotoxaemic TG rats, particularly through a mesenteric vasoconstrictor action.
8.
Min Xu Dan Liu Li-hong Ding Kun-ling Ma Min Wu Lin-li Lv Yi Wen Hong Liu Ri-ning Tang Bi-cheng Liu 《Acta pharmacologica Sinica》2014,35(12):1537-1545
Aim:
FTY720, a new immunomodulatory drug with low cytotoxicity, is currently used to treat multiple sclerosis. In this study, we investigated the effects of FTY720 on inflammatory cell infiltration in albumin overload-induced nephropathy of rats.Methods:
Male Wistar rats were subjected to right-side nephrectomy and divided into 3 groups. One week after the surgery, albumin overload (AO) group was treated with BSA (5 g·kg−1·d−1, ip) for 9 weeks; AO+FTY720 group was given BSA (5 g·kg−1·d−1, ip) plus FTY720 (0.5 g·kg−1·d−1, ip) for 9 weeks; and control group received daily ip injection of equivalent volume of saline. All rats were killed 9 weeks after nephrectomy.Results:
AO rats exhibited gradually increased urinary protein excretion accompanied by elevated urinary N-acetyl-β-O-glucosaminidase activity, and both reached their peak values at week 7. Furthermore, AO significantly increased lymphocytes and monocytes in circulation and the inflammatory cells recruited to tubulointerstitium, and the expression of inflammatory cytokines MCP-1, TNF-α and IL-6, as well as sphingosine 1-phosphate (S1P) receptors S1pr1 and S1pr3, and S1P-synthesizing enzyme sphingosine kinase 1 (Sphk1) in the kidney. Concomitant administration of FTY720 significantly attenuated all the AO-induced pathological changes.Conclusion:
FTY720 alleviates tubulointerstitium inflammation in an AO rat model of nephropathy via down-regulation of the Sphk1 pathway. 相似文献9.
Background and Purpose
To determine the minimally effective dose of cannabidiolic acid (CBDA) that effectively reduces lithium chloride (LiCl)-induced conditioned gaping reactions (nausea-induced behaviour) in rats and to determine if these low systemic doses of CBDA (5–0.1 μg·kg−1) relative to those of CBD could potentiate the anti-nausea effects of the classic 5-hydroxytryptamine 3 (5-HT3) receptor antagonist, ondansetron (OND).Experimental Approach
We investigated the efficacy of low doses of CBDA to suppress acute nausea, assessed by the establishment of conditioned gaping to a LiCl-paired flavour in rats. The potential of threshold and subthreshold doses of CBDA to enhance the reduction of nausea-induced conditioned gaping by OND were then determined.Key Results
CBDA (at doses as low as 0.5 μg·kg−1) suppressed nausea-induced conditioned gaping to a flavour. A low dose of OND (1.0 μg·kg−1) alone reduced nausea-induced conditioned gaping, but when it was combined with a subthreshold dose of CBDA (0.1 μg·kg−1) there was an enhancement in the suppression of LiCl-induced conditioned gaping.Conclusions and Implications
CBDA potently reduced conditioned gaping in rats, even at low doses and enhanced the anti-nausea effect of a low dose of OND. These findings suggest that combining low doses of CBDA and OND will more effectively treat acute nausea in chemotherapy patients. 相似文献10.
Carlos M Villalón David Centurión Miguel Luján-Estrada José A Terrón Araceli Sánchez-López 《British journal of pharmacology》1997,120(7):1319-1327
- The vasodilator effects of 5-hydroxytryptamine (5-HT) in the external carotid bed of anaesthetized dogs with intact sympathetic tone are mediated by prejunctional sympatho-inhibitory 5-HT1B/1D receptors and postjunctional 5-HT receptors. The prejunctional vasodilator mechanism is abolished after vagosympathectomy which results in the reversal of the vasodilator effect to vasoconstriction. The blockade of this vasoconstrictor effect of 5-HT with the 5-HT1B/1D receptor antagonist, GR 127935, unmasks a dose-dependent vasodilator effect of 5-HT, but not of sumatriptan. Therefore, the present study set out to analyse the pharmacological profile of this postjunctional vasodilator 5-HT receptor in the external carotid bed of vagosympathectomized dogs pretreated with GR 127935 (20 μg kg−1, i.v.).
- One-minute intracarotid (i.c.) infusions of 5-HT (0.330 μg min−1), 5-carboxamidotryptamine (5-CT; 0.010.3 μg min−1), 5-methoxytryptamine (1100 μg min−1) and lisuride (31000 μg min−1) resulted in dose-dependent increases in external carotid blood flow (without changes in blood pressure or heart rate) with a rank order of agonist potency of 5-CT>>5-HT⩾5-methoxytryptamine>lisuride, whereas cisapride (1001000 μg min−1, i.c.) was practically inactive. Interestingly, lisuride (mean dose of 85±7 μg kg−1, i.c.), but not cisapride (mean dose of 67±7 μg kg−1, i.c.), specifically abolished the responses induced by 5-HT, 5-CT and 5-methoxytryptamine, suggesting that a common site of action may be involved. In contrast, 1 min i.c. infusions of 8-OH-DPAT (33000 μg min−1) produced dose-dependent decreases, not increases, in external carotid blood flow and failed to antagonize (mean dose of 200±33 μg kg−1, i.c.) the agonist-induced vasodilator responses.
- The external carotid vasodilator responses to 5-HT, 5-CT and 5-methoxytryptamine were not modified by intravenous (i.v.) pretreatment with either saline, (±)-pindolol (4 mg kg−1) or ritanserin (100 μg kg−1) plus granisetron (300 μg kg−1), but were dose-dependently blocked by i.v. administration of methiothepin (10 and 30 μg kg−1, given after ritanserin plus granisetron), mesulergine (10 and 30 μg kg−1), metergoline (1 and 3 mg kg−1), methysergide (1 and 3 mg kg−1) or clozapine (0.3 and 1 mg kg−1). Nevertheless, the blockade of the above responses, not significant after treatment with the lower of the two doses of metergoline and mesulergine, was nonspecific after administration of the higher of the two doses of methysergide and clozapine.
- Based upon the above rank order of agonist potencies and the antagonism produced by a series of drugs showing high affinity for the cloned 5-ht7 receptor, our results indicate that the 5-HT receptor mediating external carotid vasodilatation in GR 127935-pretreated vagosympathectomized dogs is operationally similar to the putative 5-HT7 receptor mediating relaxation of vascular and non-vascular smooth muscles (e.g. rabbit femoral vein, canine coronary artery, rat systemic vasculature and guinea-pig ileum) as well as tachycardia in the cat.
11.
M Nesher U Shpolansky N Viola M Dvela N Buzaglo H Cohen Ben-Ami H Rosen D Lichtstein 《British journal of pharmacology》2010,160(2):346-354
Background and purpose:
All cardiac steroids have a similar structure, bind to and inhibit the ubiquitous transmembrane protein Na+, K+-ATPase and increase the force of contraction of heart muscle. However, there are diverse biological responses to different cardiac steroids both at the cellular and at the molecular level. Moreover, we have recently shown that ouabain inhibits digoxin- and bufalin-induced changes in membrane traffic. The present study was designed to test the hypothesis that ouabain also has an inhibitory effect on cardiotoxicity induced by other cardiac steroids.Experimental approach:
The hypothesis was tested in isolated heart muscle preparations and in an in vivo model of cardiotoxicity in guinea pigs.Key results:
Ouabain at a low dose attenuated the toxicity induced by bufalin and digoxin in heart muscle preparations. In addition, ouabain at the low dose (91 ng·kg−1·h−1), but not at a higher dose (182 ng·kg−1·h−1), delayed the development of digoxin-induced (500 µg·kg−1·h−1) cardiotoxicity in anaesthetized guinea pigs, as manifested by delayed arrhythmia and terminal ventricular fibrillation, as well as a reduced heart rate. In addition, as observed with ouabain, the phosphoinositide 3-kinase inhibitor wortmannin (100 µg·kg−1·h−1) delayed the digoxin-induced arrhythmia in anaesthetized guinea pigs.Conclusions and implications:
The present study demonstrates the inhibitory effect, probably through signal transduction pathways, of ouabain on digoxin- and bufalin-induced cardiotoxicity in guinea pigs. Further understanding of this phenomenon could be beneficial for increasing the therapeutic window for cardiac steroids in the treatment of chronic heart failure. 相似文献12.
Mahmoud M El-Mas Hanan M El-Gowelli Abdel-Rheem M Ghazal Osama F Harraz Mahmoud M Mohy El-Din 《British journal of pharmacology》2009,158(6):1629-1640
Background and purpose:
This study investigated the role of central sympathetic activity and related mitogen-activated protein kinase (MAPK) signalling in the cardiovascular effects of ethanol in a model of acute renal failure (ARF).Experimental approach:
The effects of pharmacological interventions that inhibit peripheral or central sympathetic activity or MAPK on the cardiovascular actions of ethanol in rats with ARF induced by glycerol were evaluated.Key results:
Glycerol (50%, 10 mL·kg−1, i.m.) caused progressive increases and decreases in blood pressure (BP) and heart rate (HR) respectively. Subsequent i.v. ethanol (0.25 or 1 g·kg−1) elicited dose-related changes in BP (decreases) and HR (increases). These effects were replicated after intracisternal (i.c.) administration of ethanol. Blockade of nicotinic cholinoceptors (nAChR, hexamethonium, 20 mg·kg−1) or α1-adrenoceptors (prazosin, 1 mg·kg−1) attenuated cardiovascular effects of ethanol. Ethanol hypotension was also attenuated after the centrally acting sympatholytic drug moxonidine (selective I1-site agonist, 100 µg·kg−1 i.v.), but not guanabenz (selective α2-receptor agonist, 30 µg·kg−1, i.v.), suggesting involvement of central circuits of I1 sites in ethanol-evoked hypotension. Selective blockade I1 sites (efaroxan) but not α2 (yohimbine) adrenoceptors abolished the hypotensive response to ethanol. Intracisternal administration of PD98059 or SB203580, inhibitors of extracellular signal-regulated kinase (ERK 1/2) and p38 MAPK, respectively, reduced the hypotensive action of moxonidine or ethanol. When used simultaneously, the two MAPK inhibitors produced additive attenuation of ethanol hypotension.Conclusions and implications:
Sympathoinhibitory pathways of central I1-sites and downstream ERK/p38 MAPK signalling were involved in the hypotensive action of ethanol in ARF. 相似文献13.
Solid bar microextraction (SBME), followed by liquid chromatography with fluorescence detection (HPLC-FLD), for the quantification of ochratoxin A in wheat and maize was developed. Ground wheat and maize grains were extracted with acetonitrile-water-acetic acid (79:20:1, v/v/v), followed by defatting with cyclohexane, and subjected to SBME-LC-FLD analysis. SBME devices were constructed by packing 2 mg sorbent (C18) into porous polypropylene micro-tubes (2.5 cm length, 600 μm i.d., and 0.2 μm pore size). SBME devices were conditioned with methanol and placed into 5 mL stirred sample solutions for 70 min. After extraction, OTA was desorbed into 200 μL of methanol for 15 min, the solution was removed in vacuum, the residue was dissolved in 50 μL of methanol-water (1:1, v/v) and ochratoxin A content was determined by HPLC-FLD. Under optimized extraction conditions, the limit of detection of 0.9 μg·kg−1 and 2.5 μg·kg−1 and the precision of 3.4% and 5.0% over a concentration range of 1 to 100 μg·kg−1 in wheat and maize flour, respectively, were obtained. 相似文献
14.
Tamara Rodríguez-Cabo ngeles Moroo Fabiola Arvalo Jorge Correa Juan Pablo Lamas Araceli E. Rossignoli Juan Blanco 《Toxins》2021,13(11)
In the late autumn of 2018 and 2019, some samples taken by the official monitoring systems of Cantabria and the Basque Country were found to be paralytic shellfish poisoning (PSP)-positive using a mouse bioassay. To confirm the presence of PSP toxins and to obtain their profile, these samples were analyzed using an optimized version of the Official Method AOAC 2005.06 and using LC–MS/MS (HILIC). The presence of some PSP toxins (PSTs) in that geographical area (~600 km of coast) was confirmed for the first time. The estimated toxicities ranged from 170 to 983 µg STXdiHCl eq.·kg−1 for the AOAC 2005.06 method and from 150 to 1094 µg STXdiHCl eq.·kg−1 for the LC–MS/MS method, with a good correlation between both methods (r2 = 0.94). Most samples contained STX, GTX2,3, and GTX1,4, and some also had NEO and dcGTX2. All of the PSP-positive samples also contained gymnodimine A, with the concentrations of the two groups of toxins being significantly correlated. The PSP toxin profiles suggest that a species of the genus Alexandrium was likely the causative agent. The presence of gymnodimine A suggests that A. ostenfeldii could be involved, but the contribution of a mixture of Alexandrium species cannot be ruled out. 相似文献
15.
E A van Schaick H J M M de Greef M W E Langemeijer M J Sheehan A P IJzerman M Danhof 《British journal of pharmacology》1997,122(3):525-533
- The purpose of this study was to develop and validate an integrated pharmacokinetic-pharmacodynamic model for the anti-lipolytic effects of the adenosine A1-receptor agonist N6-(p-sulphophenyl)adenosine (SPA). Tissue selectivity of SPA was investigated by quantification of haemodynamic and anti-lipolytic effects in individual animals.
- After intravenous infusion of SPA to conscious normotensive Wistar rats, arterial blood samples were drawn for determination of blood SPA concentrations, plasma non-esterified fatty acid (NEFA) and β-hydroxybutyrate levels. Blood pressure and heart rate were monitored continuously.
- The relationship between the SPA concentrations and the NEFA lowering effect was described by the indirect suppression model. Administration of SPA at different rates and doses (60 μg kg−1 in 5 min and 15 min, and 120 μg kg−1 in 60 min) led to uniform pharmacodynamic parameter estimates. The averaged parameters (mean±s.e., n=19) were Emax: −80±2% (% change from baseline), EC50: 22±2 ng ml−1, and Hill factor: 2.2±0.2.
- In another group, given 400 μg kg−1 SPA in 15 min, pharmacodynamic parameters for both heart rate and anti-lipolytic effect were derived within the same animal. The reduction in heart rate was directly related to blood concentration on the basis of the sigmoidal Emax model. SPA inhibited lipolysis at concentrations lower than those required for an effect on heart rate. The EC50 values (mean±s.e., n=6) were 131±31 ng ml−1 and 20±3 ng ml−1 for heart rate and NEFA lowering effect, respectively.
- In conclusion, the relationship between blood SPA concentrations and anti-lipolytic effect was adequately described by the indirect suppression model. For SPA a 6 fold difference in potency was observed between the effects on heart rate and NEFAs, indicating some degree of tissue selectivity in vivo.
16.
D J Baker A M Atkinson G P Wilkinson G J Coope A D Charles B Leighton 《British journal of pharmacology》2014,171(7):1629-1641
Background and Purpose
The global heterozygous glucokinase (GK) knockout (gkwt/del) male mouse, fed on a high-fat (60% by energy) diet, has provided a robust and reproducible model of hyperglycaemia. This model could be highly relevant to some facets of human type 2 diabetes (T2D). We aimed to investigate the ability of standard therapeutic agents to lower blood glucose at translational doses, and to explore the glucose-lowering potential of novel glucokinase activators (GKAs) in this model.Experimental Approach
We measured the ability of insulin, metformin, glipizide, exendin-4 and sitagliptin, after acute or repeat dose administration, to lower free-feeding glucose levels in gkwt/del mice. Further, we measured the ability of novel GKAs, GKA23, GKA71 and AZD6370 to control glucose either alone or in combination with some standard agents.Key Results
A single dose of insulin (1 unit·kg−1), metformin (150, 300 mg·kg−1), glipizide (0.1, 0.3 mg·kg−1), exendin-4 (2, 20 μg·kg−1) and GKAs reduced free-feeding glucose levels. Sitagliptin (10 mg·kg−1), metformin (300 mg·kg−1) and AZD6370 (30, 400 mg·kg−1) reduced glucose excursions on repeat dosing. At a supra-therapeutic dose (400 mg·kg−1), AZD6370 also lowered basal levels of glucose without inducing hypoglycaemia.Conclusion and Implications
Standard glucose-lowering therapeutic agents demonstrated significant acute glucose lowering in male gkwt/del mice at doses corresponding to therapeutic free drug levels in man, suggesting the potential of these mice as a translatable model of human T2D. Novel GKAs also lowered glucose in this mouse model. 相似文献17.
Shunsuke Kageyama Hiroshi Yamamoto Mitsuyo Nagano Harumi Arisaka Takashi Kayahara Ryota Yoshimoto 《British journal of pharmacology》1997,122(1):165-171
- A murine anti-human vWF monoclonal antibody, AJvW-2, was developed that inhibited the interaction between platelet glycoprotein Ib (GPIb) and von Willebrand factor (vWF) during the ristocetin- (IC50=0.7±0.1 μg ml−1) and botrocetin- (IC50=1.8±0.3 μg ml−1) induced aggregation of human platelets.
- AJvW-2 inhibited the high shear stress (10.8 N m−2) induced aggregation of human platelets dose-dependently with an IC50=2.4±0.3 μg ml−1, but had no effect on low shear stress induced platelet aggregation (1.2 N m−2) up to 100 μg ml−1.
- AJvW-2 also inhibited the high shear stress (5.0 N m−2) induced adhesion of human platelets to collagen I with the same efficacy (IC50=2.4±0.3 μg ml−1), but had no effect at low shear conditions (1.5 N m−2).
- AJvW-2 inhibited the botrocetin-induced aggregation of platelets from guinea-pig, rat, rabbit, dog and pig at the same concentration range as human platelets; it likewise also inhibited the high shear stress induced aggregation and adhesion to collagen I of guinea-pig platelets.
- AJvW-2 prevented arterial thrombus formation in guinea-pigs at a dose of 100 μg kg−1 without prolonging the template bleeding time, whereas the GPIIb/IIIa antagonist lamifiban mediated inhibition of thrombosis at 1000 μg kg−1 was accompanied by a significant prolongation of the bleeding time.
- These results suggest that AJvW-2 is a potent inhibitor of the GPIb-vWF interaction and a potential novel antithrombotic agent with lower bleeding risk than GPIIb/IIIa antagonists.
18.
- The potential influences of nitric oxide (NO) and prostaglandins on the renal effects of angiotensin II (Ang II) have been investigated in the captopril-treated anaesthetized rat by examining the effect of indomethacin or the NO synthase inhibitor, Nω-nitro-L-arginine methyl ester (L-NAME), on the renal responses obtained during infusion of Ang II directly into the renal circulation.
- Intrarenal artery (i.r.a.) infusion of Ang II (1–30 ng kg−1 min−1) elicited a dose-dependent decrease in renal vascular conductance (RVC; −38±3% at 30 ng kg−1 min−1; P<0.01) and increase in filtration fraction (FF; +49±8%; P<0.05) in the absence of any change in carotid mean arterial blood pressure (MBP). Urine output (Uv), absolute (UNaV) and fractional sodium excretion (FENa), and glomerular filtration rate (GFR) were unchanged during infusion of Ang II 1–30 ng kg−1 min−1 (+6±17%, +11±17%, +22±23%, and −5±9%, respectively, at 30 ng kg−1 min−1). At higher doses, Ang II (100 and 300 ng kg−1 min−1) induced further decreases in RVC, but with associated increases in MBP, Uv and UNaV.
- Pretreatment with indomethacin (10 mg kg−1 i.v.) had no significant effect on basal renal function, or on the Ang II-induced reduction in RVC (−25±7% vs −38±3% at Ang II 30 ng kg−1 min−1). In the presence of indomethacin, Ang II tended to cause a dose-dependent decrease in GFR (−38±10% at 30 ng kg−1 min−1); however, this effect was not statistically significant (P=0.078) when evaluated over the dose range of 1–30 ng kg−1 min−1, and was not accompanied by any significant changes in Uv, UNaV or FENa (−21±12%, −18±16% and +36±38%, respectively).
- Pretreatment with L-NAME (10 μg kg−1 min−1 i.v.) tended to reduce basal RVC (control −11.8±1.4, +L-NAME −7.9±1.8 ml min−1 mmHg−1×10−2), and significantly increased basal FF (control +15.9±0.8, +L-NAME +31.0±3.7%). In the presence of L-NAME, renal vasoconstrictor responses to Ang II were not significantly modified (−38±3% vs −35±13% at 30 ng kg−1 min−1), but Ang II now induced dose-dependent decreases in GFR, Uv and UNaV (−51±11%, −41±14% and −31±17%, respectively, at an infusion rate of Ang II, 30 ng kg−1 min−1). When evaluated over the range of 1–30 ng kg−1 min−1, the effect of Ang II on GFR and Uv were statistically significant (P<0.05), but on UNaV did not quite achieve statistical significance (P=0.066). However, there was no associated change in FENa observed, suggesting a non-tubular site of interaction between Ang II and NO.
- In contrast to its effects after pretreatment with L-NAME alone, Ang II (1–30 ng kg−1 min−1) failed to reduce renal vascular conductance in rats pretreated with the combination of L-NAME and the selective angiotensin AT1 receptor antagonist, (1 mg kg−1 i.v.). This suggests that the renal vascular effects of Ang II are mediated through AT1 receptors. Over the same dose range, Ang II also failed to significantly reduce GFR or Uv. GR117289
- In conclusion, the renal haemodynamic effects of Ang II in the rat kidney appear to be modulated by cyclooxygenase-derived prostaglandins and NO. The precise site(s) of such an interaction cannot be determined from the present data, but the data suggest complex interactions at the level of the glomerulus.
19.
A survey on the occurrence of ochratoxin A (OTA) and sterigmatocystin (STC) in grated cheese products obtained from hard grana-type cheeses was carried out, where 107 grated products were collected in retail outlets and analysed. OTA and STC were found in 48.6% and 94.4% of the samples, in a range from <LOD to 25.05 µg kg−1 and from <LOD to 6.87 µg kg−1, respectively. STC was detected in all the OTA-contaminated samples. The OTA and STC occurrence in cheese is due to environmental contamination during ripening, leading to fungal growth and mycotoxin production on the cheese surface. This statement was confirmed by analysing the surface of 16 hard grana cheese rinds, which resulted contaminated by both OTA and STC, with concentration ranging from 3 to 370 µg kg−1. This finding demonstrates that rind inclusion increases the mycotoxin concentration in grated cheeses. The mycotoxin level significantly decreased from the surface (0–1.5 mm) to inner parts of cheese rinds (1.5–4.5 mm). Industrial wheel-cleaning techniques can represent a useful treatment to reduce both toxins in grated cheese products. 相似文献
20.
S Bosnyak IK Welungoda A Hallberg M Alterman RE Widdop ES Jones 《British journal of pharmacology》2010,159(3):709-716