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1.
This study investigated the effects of cortisol and insulin, hormones that affect both glycaemic status and vascular function, on the in vitro contractility of isolated healthy equine small laminar veins. Small veins (150–500 μm) draining the digital laminae from healthy horses or ponies were investigated by wire myography. Concentration response curves were constructed for noradrenaline (NA), phenylephrine (PE), endothelin‐1 (ET‐1) and 5‐hydroxytryptamine (5‐HT) in the presence of either cortisol (10?6 m ) or insulin (1000 μIU/mL). Cortisol significantly increased the maximum contractility of laminar veins to the vasoconstrictors NA and 5‐HT but decreased the maximal contraction to ET‐1. Insulin decreased the contractility of vessels to PE and ET‐1. It is possible that short‐term cortisol excess could enhance venoconstrictor responses to 5‐HT and NA in laminar veins in vivo, thereby predisposing to laminitis. Additionally, a reduction in the ability of insulin to counteract alpha‐adrenoreceptor and ET‐1‐mediated contraction, likely to occur in subjects with insulin resistance, may further exacerbate venoconstriction in animals prone to laminitis. These mechanisms may also predispose horses with disorders such as equine Cushing's disease and equine metabolic syndrome to laminitis.  相似文献   

2.
The role of the transporter P‐glycoprotein (P‐gp) in the disposition kinetics of different drugs therapeutically used in veterinary medicine has been demonstrated. Considering the anatomo‐physiological features of the ruminant species, the constitutive expression of P‐gp (ABCB1) along the sheep gastrointestinal tract was studied. Additionally, the effect of repeated dexamethasone (DEX) administrations on the ABCB1 gene expression in the liver and small intestine was also assessed. The ABCB1 mRNA expression was determined by real‐time quantitative PCR. P‐gp activity was evaluated in diffusion chambers to determine the efflux of rhodamine 123 (Rho 123) in the ileum from experimental sheep. The constitutive ABCB1 expression was 65‐fold higher in the liver than in the intestine (ileum). The highest ABCB1 mRNA expression along the small intestine was observed in the ileum (between 6‐ and 120‐fold higher). The treatment with DEX did not elicit a significant effect on the P‐gp gene expression levels in any of the investigated gastrointestinal tissues. Consistently, no significant differences were observed in the intestinal secretion of Rho 123, between untreated control (Peff S‐M = 3.99 × 10?6 ± 2.07 × 10?6) and DEX‐treated animals (Peff S‐M = 6.00 × 10?6 ± 2.5 × 10?6). The understanding of the efflux transporters expression and activity along the digestive tract may help to elucidate clinical implications emerging from drug interactions in livestock.  相似文献   

3.
OBJECTIVE: To compare the responses of equine digital arteries (EDAs) and equine digital veins (EDVs) to endothelin-1 (ET-1) and determine the role of the endothelium and type of receptors involved in the modulation and mediation of those responses, respectively. SAMPLE POPULATION: 5 to 9 palmar digital vessels/experiment from 28 healthy horses. PROCEDURE: Rings of dissected vessels were mounted under tension between force transducer wires in organ baths containing Krebs-Henseleit solution at 30 degrees C. Responses of EDAs and EDVs (with intact [+e] or denuded [-e] endothelium) to cumulative concentrations of ET-1 (10(-10) to 3 X 10(-7) M) were compared. For (+e)EDAs and (+e)EDVs precontracted with a thromboxane-mimetic (U44069; 10(-8) M) and (-e)EDAs and (-e)EDVs, responses to an ETB receptor agonist (S6c; 10(-10) to 3 X 10(-7) M) were evaluated. Responses to ET-1 (10(-7) M) in (-e)EDAs and (-e)EDVs were evaluated after incubation with an ETA receptor antagonist (BQ-123; 3 X 10(-7) M), an ETB receptor antagonist (BQ-788; 3 X 10(-7) M), or vehicle solution. RESULTS: Endothelin-1 induced a concentration-dependent contraction of endothelium-intact and -denuded EDAs and EDVs; EDVs were more sensitive. Neither vessel type relaxed in response to S6c, although 2 of the (-e)EDAs contracted mildly. Whereas BQ-123 inhibited the (-e)EDA and (-e)EDV responses to ET-1, BQ-788 had no effect. CONCLUSIONS AND CLINICAL RELEVANCE: Endothelin-1 induced digital vasoconstriction (marked constriction in veins). This action was unaffected by endothelium and mediated predominantly by ETA receptors. These findings suggest ET-1 can induce selective digital venoconstriction.  相似文献   

4.
LaBranche, T. P., Ehrich, M. F., Eyre, P. Characterization of bovine neutrophil β2‐adrenergic receptor function. J. vet. Pharmacol. Therap. doi: 10.1111/j.1365‐2885.2009.01143.x. This study compares bovine leukocyte β‐adrenergic receptor densities to that of the rat, demonstrates for the first time a functional β2‐adrenergic receptor signaling pathway in steer neutrophils, and investigates the effect of an inflammatory stimulus on that signaling pathway. The β1‐/β2‐adrenergic antagonist [3H]CGP‐12177 demonstrated that rat lymphocyte specific binding‐site density was highest, followed by steer and dairy cow lymphocytes, and lastly steer and dairy cow neutrophils. The β2‐adrenergic agonist terbutaline stimulated steer neutrophil adenosine 3,5‐cyclic monophosphate (cAMP) production, an effect increased by inclusion of ≥1 × 10?8 m phorbol 12‐myristate 13‐acetate (PMA), an activator of protein kinase C. Both terbutaline and the nonselective phosphodiesterase inhibitor 3‐isobutyl‐1‐methylxanthine (IBMX) independently decreased steer neutrophil superoxide anion production in a concentration‐dependent manner, with 1 × 10?4 m IBMX enhancing both the potency and efficacy of the terbutaline effect (up to 74% reduction in superoxide anion production). Superoxide anion production was also reduced by the synthetic cAMP analog 8‐bromo‐cAMP, which increased the potency of the IBMX effect on superoxide anion production. Taken together, these data demonstrate the presence of a β2‐adrenergic receptor signaling pathway in bovine neutrophils much like that described in other animal species, as well as the potential for an inflammatory stimulus to alter its function.  相似文献   

5.
The aim of this study was to evaluate if hypoxia in feline fibrosarcomas can be detected. This was done using positron emission tomography (PET), two hypoxia tracers and polarographic pO2 measurements. Of the seven cats included, five received [18F]‐fluoromisonidazole and two 2‐(2‐nitro‐1H‐imidazol‐1‐yl)‐N‐(2,2,3,3,3‐pentafluoropropyl) acetamide. Perfusion was evaluated with [15O]‐H2O (n = 4) and with contrast‐enhanced power Doppler ultrasonography (n = 5). Hypoxia was detected in three cats. Polarographic pO2 measurements did not confirm PET results. In the ultrasonographic evaluation, low vascularity and low perfusion were seen with a peripheral vascular pattern and no perfusion in the centre of the tumour. This was in contrast to the [15O]‐H2O scans, where central perfusion of the tumour was also found. In conclusion, it appears that hypoxia exists in this tumour type. The presence of tumour necrosis and heterogeneous hypoxia patterns in these tumours may explain the found discrepancies between the applied techniques.  相似文献   

6.
Growing porcine oocytes from early antral follicles can acquire meiotic and developmental competence under suitable culture conditions, but at lower rates compared to full‐grown oocytes. We postulated that estradiol‐17β (E2) supported the acquisition of meiotic and developmental competence as well as cumulus‐expansion ability during growth culture. Growing oocytes from early antral follicles (1.2 to 1.5 mm in diameter) were grown in vitro for 5 days in a medium containing 0, 10?7, 10?6, 10?5 or 10?4 mol/L E2; after in vitro maturation, 35, 58, 47, 74 and 49% of oocytes matured to metaphase II, 25, 79, 77, 90 and 97% acquired cumulus‐expansion ability, and 23, 54, 63, 89 and 64% were fully surrounded by cumulus cells, respectively. Following maturation, electro‐stimulation was applied to the oocytes grown with 10?5 mol/L E2. After 6 days of culture, in vitro‐grown oocytes developed to the blastocyst stage at a rate similar to that for full‐grown oocytes (31% and 40%, respectively). Therefore, we suggest that the use of E2 during growth culture improves the meiotic and developmental competence of oocytes, cumulus‐expansion ability, and cumulus cell attachment to the oocytes.  相似文献   

7.
Abstract

Leucaena leucocephala is a fast‐growing tree that can provide both high quality forage and firewood. The objective of this trial was to determine the optimum height and frequency of cutting for both wood and forage production. Cutting heights at 0.3 m, 0.6 m and 1.0 m were superimposed on 3‐month and 6‐month cutting frequencies on mature rows of L. leucocephala for three years. Effects of year or its interaction with the other factors were not significant (P≥0.10). There was an increase (P=0.07) in wood production but not forage production (P≥0.10) with the longer interval. Cutting height had an effect on forage (P<0.001) production, with 5.47 t ha?1 a?1 for the 0.3‐m height, 7.62 t ha?1 a?1 for the 0.7‐m height, and 8.71 t ha?1 a?1 for the 1.0‐m height. Cutting height also had an effect on wood production (P<0.001), with 7.22 t hd?1 a?1 for the 0.3‐m height, 9.33 t ha?1 a?1 for the 0.7‐mheight, and 11.55 t hd?1 a?1 for the 1.0‐m height. In this experiment, the six‐month interval produced more wood than the three‐month interval, but there were no differences in quantity of forage dry matter in L. leucocephala; there were advantages in both wood and forage production with the taller trunk base.  相似文献   

8.
The aims of the present study were to clarify the effect of kisspeptin10 (Kp10) on the secretion of growth hormone (GH) from bovine anterior pituitary (AP) cells, and evaluate the ability of sex steroid hormones to enhance the sensitivity of somatotrophic cells to Kp10. AP cells prepared from 8–11‐month‐old castrated calves were incubated for 12 h with estradiol (E2, 10?8 mol/L),progesterone (P4, 10?8 mol/L), testosterone (T, 10?8 mol/L), or vehicle only (control), and then for 2 h with Kp10. The amount of GH released in the medium was measured by a time‐resolved fluoroimmunoassay. Kp10 (10?6 or 10?5 mol/L) significantly stimulated the secretion of GH from the AP cells regardless of steroid treatments (P < 0.05), and E2, P4, and T had no effect on this response. The GH‐releasing response to growth hormone‐releasing hormone (GHRH, 10?8 mol/L) was significantly greater than that to Kp10 (P < 0.05). The present results suggest that Kp10 directly stimulates the release of GH from somatotrophic cells and sex steroid hormones do not enhance the sensitivity of these cells to Kp10. Furthermore, they suggest that the GH‐releasing effect of Kp10 is less potent than that of GHRH.  相似文献   

9.
Donalisio, C., Barbero, R., Cuniberti, B., Vercelli, C., Casalone, M., Re, G. Effects of flunixin meglumine and ketoprofen on mediator production in ex vivo and in vitro models of inflammation in healthy dairy cows. J. vet. Pharmacol. Therap.  36 , 130–139. In this study, ex vivo assays were carried out in dairy cows to evaluate the anti‐inflammatory effects of two nonsteroidal anti‐inflammatory drugs: ketoprofen (KETO) and flunixin meglumine (FM). Twelve healthy Holstein dairy cattle were randomly allocated to two groups (n=6): group 1 received FM and group 2 received KETO at recommended therapeutic dosages. The anti‐inflammatory effects of both drugs were determined by measuring the production of coagulation‐induced thromboxane B2 (TXB2), lipopolysaccharides (LPS) (10 μg/mL)‐induced prostaglandin E2 (PGE2), and calcium ionophore (60 μm )‐induced leukotrien B4 (LTB4). Cytokine production was assessed by measuring tumor necrosis factor‐α (TNF‐α), interferon‐γ (IFN‐γ) and interleukin‐8 (CXCL8) concentrations after incubation in the presence of 10 μg/mL LPS. The IC50 of FM and KETO was determined in vitro by determining the concentration of TXB2 and PGE2 in the presence of scalar drug concentrations (10?9–10?3 m ). Both FM and KETO inhibited the two COX isoforms in vitro, but showed a preference for COX‐1. FM and KETO showed similar anti‐inflammatory effects in the cow.  相似文献   

10.
Devil's claw is used for the treatment of inflammatory symptoms and degenerative disorders in horses since many years, but without the substantive pharmacokinetic data. The pharmacokinetic parameters of harpagoside, the main active constituent of Harpagophytum procumbens DC ex Meisn., were evaluated in equine plasma after administration of Harpagophytum extract FB 8858 in an open, single‐dose, two‐treatment, two‐period, randomized cross‐over design. Six horses received a single dose of Harpagophytum extract, corresponding to 5 mg/kg BM harpagoside, and after 7 days washout period, 10 mg/kg BM harpagoside via nasogastric tube. Plasma samples at certain time points (before and 0–24 hr after administration) were collected, cleaned up by solid‐phase extraction, and harpagoside concentrations were determined by LC‐MS/MS using apigenin‐7‐glucoside as internal standard. Plasma concentration‐time data and relevant parameters were described by noncompartmental model through PKSolver software. Harpagoside could be detected up to 9 hr after administration. Cmax was found at 25.59 and 55.46 ng/ml, t1/2 at 2.53 and 2.32 hr, respectively, and tmax at 1 hr in both trials. AUC0–inf was 70.46 and 117.85 ng hr ml?1, respectively. A proportional relationship between dose, Cmax and AUC was observed. Distribution (Vz/F) was 259.04 and 283.83 L/kg and clearance (CL/F) 70.96 and 84.86 L hr?1 kg?1, respectively. Treatment of horses with Harpagophytum extract did not cause any clinically detectable side effects.  相似文献   

11.
Melatonin may play an important role in protecting gametes and embryos from the potential harmful effects of oxidative stress. In this study, we first examined two different heat stress (HS) treatments for in vitro oocyte maturation (Experiment 1: 38.5 vs 41.0°C, during the first 20 h; Experiment 2: 38.5 vs 41.5°C, during the entire period) on bovine oocyte maturation and embryo development. Second, we tested different melatonin concentrations added to the maturation and culture medium (Experiment 3: 0, 10?12, 10?9, 10?4 m ; Experiment 4: 0, 10?3 m ), both with and without HS (38.5 or 41.5°C, respectively). In Experiment 1, the HS treatment resulted in a lower maturation rate and number of cells/blastocyst (C/B) and a higher blastocyst rate than that in the control group. In Experiment 2, oocytes/embryos from heat‐stressed oocytes (HSO) had a lower maturation, cleavage and blastocyst rates, as well as a lower C/B compared with the control. In Experiment 3, in HSO groups, 10?4 m melatonin resulted in an increased blastocyst rate compared with 0 m melatonin, with a similar blastocyst rate to the non‐HSO without melatonin. Melatonin did not have any effect in embryos from non‐HSO groups compared with the control. In Experiment 4, 10?3 m melatonin produced lower cleavage and blastocyst rates in HSO and lower blastocyst rate in non‐HSO when compared to melatonin‐untreated oocytes/embryos. In conclusion, 10?4 m melatonin was found to alleviate bovine oocytes from the harmful effects of HS.  相似文献   

12.
To elucidate the dependence of aerobic energy metabolism and utilization of glucose in contraction of urinary bladder smooth muscle, we investigated the changes in the reduced pyridine nucleotide (PNred) fluorescence, representing glycolysis activity, and determined the phosphocreatine (PCr) and ATP contents of the porcine urinary bladder during contractions induced by high K+ or carbachol (CCh) and with and without hypoxia (achieved by bubbling N2 instead of O2) or in a glucose-free condition. Hyperosmotic addition of 65 mM KCl (H-65K+) and 1 µM CCh induced a phasic contraction followed by a tonic contraction. A glucose-free physiological salt solution (PSS) did not change the subsequent contractile responses to H-65K+ and CCh. However, hypoxia significantly attenuated H-65K+- and CCh-induced contraction. H-65K+ and CCh induced a sustained increase in PNred fluorescence, representing glycolysis activity. Hypoxia enhanced H-65K+- and CCh-induced increases in PNred fluorescence, whereas glucose-free PSS decreased these increases, significantly. In the presence of H-65K+, hypoxia decreased the PCr and ATP contents; however, the glucose-free PSS did not change the PCr contents. In conclusion, we demonstrated that high K+- and CCh-induced contractions depend on aerobic metabolism and that an endogenous substrate may be utilized to maintain muscle contraction in a glucose-free PSS in the porcine urinary bladder.  相似文献   

13.
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14.
Reasons for performing study: Research into kinematics of the healthy equine back, has been performed in the walk and trot. This study focuses on back kinematics during canter, over a range of velocities. Flexion extension (FE) movements in canter are greatest in the lumbosacral (LS) region. Previous research has focused on canter velocity of 7 m/s; therefore quantification of LS kinematics at varying velocities is required to understand LS functions in equine locomotion. Hypothesis: Range of flexion‐extension movement through the lumbosacral joint increases with increasing velocity. Methods: Six Thoroughbred horses (mean age 9.6 years) cantered on treadmill at 4 velocities (6.0, 6.5, 7.0 and 8.0 m/s, respectively). Reflective markers were placed over the 5th lumbar vertebra (L5), the lumbosacral junction (LS) and the 3rd sacral vertebra (S3). Lumbosacral angle (LS) was defined as the angle formed between L5, LS and S3. Flexion‐extension (FE) range of motion (ROM) was analysed using a 2 camera, 3D motion capture system ProReflex1. Linear regression was used to determine strengths of relationships between speed of canter and lumbosacral FE movements. Results: Range of FE ROM seen at the lumbosacral joint increased linearly with speed. FE ROM ranged 6.1°± 1.9 at 6 m/s, 6.3°± 1.9 at 6.5 m/s, 6.6°± 1.9 at 7 m/s and 7.2°± 1.9 at 8 m/s. Linear regression showed positive associations between speed and LS FE range of motion (r2= 0.993; P = 0.003). Conclusions and potential relevance: Results show linear relationships between LS FE movements and submaximal canter velocities. These results provide information on the LS joint at canter. Understanding the effects of velocity on the back of healthy horses may aid our understanding of the demands placed on this joint in sport horses at this gait.  相似文献   

15.
Acepromazine (ACP), a member of the phenothiazine family, has antioxidant properties and interacts with reactive oxygen species produced by stimulated neutrophils ( Serteyn et al. 1999 ). We found that ACP reduced the differentiation of monocytes induced by an overnight incubation with a crude Chlamydia pneumoniae extract ( Serteyn et al. 2001 ). The same model was used to test the effects of phenothiazines on the TNF‐α release by activated monocytes. A crude Chlamydia pneumoniae extract was obtained by mechanical disruption and centrifugation (1 minute, 1500 r.p.m.) of 78 hours infected McCoy cells. Monocytes (THP1 cell line; 2 × 106 cells by assay) were incubated overnight with 30 µL of Chlamydia pneumoniae crude extract (equivalent to an endotoxin charge of 3.5 pg) in the presence or absence of phenothiazines (from 10?6 to 10?4 M) ( Mouithys‐Mickalad et al. 2001 ). For estimation of TNF‐α release, the supernatants were collected, centrifuged (to eliminate the undifferentiated monocytes) and used for TNF‐α measurements (n = 6) (Quantikine HS human TNF‐α, R&D Systems, UK). Acepromazine was compared to other phenothiazines (chlorpromazine, trifluoperazine) or to structural analogues of phenothiazines (phenoxazine, thioxanthen‐9‐one and methylene blue). For each assay, cytotoxicity was evaluated by microscopic examination and blue trypan exclusion method. Mean values of TNF‐α were compared by a Student t‐test (p < 0.05). TNF‐α release by Chlamydia‐treated THP1 was significantly decreased by ACP in a dose‐dependent manner, 378 ± 30, 209 ± 38 and 189 ± 35 ng mL?1 for 10?6, 10?5 and 10?4 M compared to the control values 385 ± 9 ng mL?1. Similar inhibitions of TNF‐α release were obtained with trifluoperazine (313 ± 25 and 265 ± 14 ng mL?1 at 10?6 and 10?5 M) and chlorpromazine (323 ± 29 and 227 ± 13 ng mL?1 at 10?6 and 10?5 M), but at 10?4 M, these two drugs were cytotoxic. The other structurally parent compounds increased significantly the TNF‐α production: 630 ± 46 and 468 ± 60 ng mL?1 for thioxanthen‐9‐one and 547 ± 17 and 331 ± 111 ng mL?1 for methylene blue at 10?5 and 10?6 (M). At 10?4 M, the two compounds were cytotoxic. Phenoxazine increased the TNF‐α production, slightly at 10?6 and 10?5 M (444 ± 39 and 424 ± 16 ng mL?1, respectively) and significantly at 10?4 M (959 ± 30 ng mL?1). Further studies are needed to verify if the inhibition of TNF‐α release by some phenothiazines could be linked to a reduction of the signal transduction, especially the NF‐κB pathway. These results could be interesting for the anaesthesia or treatment of animals suffering from a systemic inflammatory reaction.  相似文献   

16.
ObjectiveTo investigate the effect of acepromazine (ACP) on reactive oxygen species (ROS) production by stimulated equine neutrophils.Study designEx vivo biochemical experiments.AnimalsIsolated neutrophils from healthy untreated horses.MethodsNeutrophils were incubated with ACP at concentrations of 10?4, 10?5 or 10?6 m and then stimulated with phorbol-myristate-acetate (PMA) before measurement of lucigenin-enhanced chemiluminescence (CL). In a second experiment neutrophils were incubated in the presence of α-keto-γ methylthiobutyric acid (KMB) and treated with ACP at concentrations of 10?4, 10?5 or 10?6 m. Subsequent PMA stimulation lead to neutrophilic ROS production and decomposition of KMB to ethylene, which is measured by gas chromatography. Electron paramagnetic resonance-spin trapping (EPR) analysis was performed with PMA-stimulated neutrophils in the presence of ACP (10?4, 10?5 or 10?6 m) directly added to the cell suspension. In the second experiment, the same concentrations of ACP were pre-incubated with neutrophils, then centrifuged to eliminate the excess of ACP and re-suspended in phosphate buffer before stimulation with PMA. In all experiments, the results of ACP-treated and ACP-untreated stimulated neutrophils were compared.ResultsOverall, results obtained with lucigenin-enhanced CL and KMB oxidation were in agreement with those seen in electron paramagnetic resonance spectroscopy. Acepromazine induced a dose-dependent inhibitory effect on neutrophilic ROS production. Electron paramagnetic resonance also showed, at high ACP concentration, the appearance of a cation radical derived from ACP. In contrast, electron paramagnetic resonance study performed with pre-incubated neutrophils showed an important dose-dependent inhibitory effect of ACP.ConclusionThe results indicate that ACP can neutralize O˙?2 or its by-products during the stimulation of neutrophils.Clinical relevanceThese findings may have a therapeutic relevance when phenothiazines are used in horses suffering from inflammatory diseases in which neutrophil activation and ROS production are implicated.  相似文献   

17.
Selective muscarinic receptor antagonists were used to identify muscarinic receptor subtypes in equine trachealis strips. The M1 receptor antagonist pirenzepine (10–7 mol/L to 3 × 10–5 mol/L) and the M3 receptor antagonist 4-diphenylacetoxy-N-methylpiperidine (4-DAMP, 10–9 mol/L to 3 × 10–7 mol/L3) dose dependently inhibited the contractile responses to electrical field stimulation (EFS) and exogenous acetylcholine (ACh). Schild plots yielded a pA2 value for pirenzepine vs ACh of 6.75 ± 0.09, which is consistent with the affinity for M2 or M3 receptors, and a pA2 value for 4-DAMP vs ACh of 8.47 ± 0.09, which is in agreement with the affinity for M3 receptors. The M2 receptor antagonist gallamine (10–5 mol/L and 10–4 mol/L) did not affect the response of trachealis to exogenous ACh and low-frequency EFS (0.1–2 Hz) but decreased the responses to high-frequency EFS (4–16 Hz). These results suggest that the muscarinic receptors mediating contractions induced by ACh in equine tracheal smooth muscle are of the M3 subtype. The lack of an increase in the response to EFS following gallamine suggests that functional prejunctional inhibitory M2 receptors are not present on the cholinergic nerves innervating equine tracheal smooth muscle.  相似文献   

18.
Despite the severity and common occurrence of equine endotoxaemia, the available anti‐endotoxic treatments do not effectively target key inflammatory mechanisms such as leucocyte activation and cytokine production. In this study, four compounds with potential anti‐endotoxic effects, namely rolipram, azithromycin, ethyl pyruvate and metformin, were investigated in vitro using equine whole blood stimulated with bacterial lipopolysaccharide. TNF‐α and IL‐1β production were measured in plasma. Rolipram was the most potent inhibitor of cytokine production (IC50 0.84 and 4.68 μm for TNF‐α and IL‐1β, respectively) with almost complete inhibition of TNF‐α, but inhibited IL‐1β by only 39.46%. Azithromycin produced almost complete inhibition of both cytokines, but tended to be less potent than rolipram (IC50 10.66 and 17.4 μm for TNF‐α and IL‐1β, respectively). Metformin inhibited TNF‐α production with similar potency to rolipram and azithromycin (IC50 3.35 μm ) but showed significantly lower efficacy (45.93%; P < 0.05), and had no inhibitory effect on IL‐1β. Ethyl pyruvate was the least potent (IC50 68.35 μm and >10 mm for TNF‐α and IL‐1β production, respectively). Further work is required to investigate whether these or related compounds may have potential use in the treatment of equine endotoxaemia in vivo.  相似文献   

19.
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20.
Calcium ionophore A23187 induced time and concentration dependent pro-duction of immunoreactive leukotriene (LT) B4 by equine heparinized whole blood in vitro. Time dependent production of immunoreactive LTB4 by equine neutrophils and immunoreactive LTC4 by equine eosinophils in vitro was also demonstrated. The 5-lipoxygenase activating protein (FLAP) inhibitors, BAY X 1005 and BAY Y 1015, produced concentration dependent inhibition of ionophore-induced LTB4 synthesis by equine whole blood (mean ± SEM IC50sn= 5; 6.14 ± 0.28 μm vs. 12.30 ± 0.75 μm for BAY Y 1015 and BAY X 1005, respectively) and neutrophils (mean ± SEM IC50sn= 5; 0.003 ± 0.001 μm vs. 0.045 ± 0.021 μm for BAY Y 1015 and BAY X 1005, respectively) and LTC4 synthesis by equine eosinophils (mean ± SEM IC50sn= 5; 0.0036 ± 0.0002 μm and 0.108 ± 0.023 μm for BAY Y 1015 and BAY X 1005, respectively) in vitro. In all three assays, BAY Y 1015 was more potent than BAY X 1005, and for both compounds much higher concentrations were required to inhibit LT synthesis by whole blood compared to isolated neutrophils and eosinophils. Plasma concentration–time relationships and pharmacokinetic parameters for BAY Y 1015 administered intravenously and orally to six horses at a dosage of 10 mg/kg in a two period cross-over study were established. The study also evaluated the anti-inflammatory properties of BAY Y 1015 and its ability to inhibit ex vivo whole blood LTB4 synthesis and in vivo LTB4 synthesis in a tissue cage model of acute inflammation. At this dosage, BAY Y 1015 failed to significantly inhibit immunoreactive LTB4 synthesis or the oedema produced by intradermal injection of the mild irritant, carrageenan.  相似文献   

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