Plasma drug concentrations and clinical effects of a peripheral alpha‐2‐adrenoceptor antagonist,MK‐467, in horses sedated with detomidine

ObjectiveTo investigate plasma drug concentrations and the effect of MK-467 (L-659′066) on sedation, heart rate and gut motility in horses sedated with intravenous (IV) detomidine.Study designExperimental randomized blinded crossover study.AnimalsSix healthy horses.MethodsDetomidine (10 μg kg^?1 IV) was administered alone (DET) and in combination with MK-467 (250 μg kg^?1 IV; DET + MK). The level of sedation and intestinal sounds were scored. Heart rate (HR) and central venous pressure (CVP) were measured. Blood was collected to determine plasma drug concentrations. Repeated measures anova was used for HR, CVP and intestinal sounds, and the Student's t-test for pairwise comparisons between treatments for the area under the time-sedation curve (AUC_sed) and pharmacokinetic parameters. Significance was set at p < 0.05.ResultsA significant reduction in HR was detected after DET, and HR was significantly higher after DET + MK than DET alone. No heart blocks were detected in any DET + MK treated horses. DET + MK attenuated the early increase in CVP detected after DET, but later the CVP decreased with both treatments. Detomidine-induced intestinal hypomotility was prevented by MK-467. AUC_sed was significantly higher with DET than DET + MK, but maximal sedations scores did not differ significantly between treatments. MK-467 lowered the AUC of the plasma concentration of detomidine, and increased its volume of distribution and clearance.Conclusions and clinical relevanceMK-467 prevented detomidine induced bradycardia and intestinal hypomotility. MK-467 did not affect the clinical quality of detomidine-induced sedation, but the duration of the effect was reduced, which may have been caused by the effects of MK-467 on the plasma concentration of detomidine. MK-467 may be useful clinically in the prevention of certain peripheral side effects of detomidine in horses.     

Detomidine and the combination of detomidine and MK‐467, a peripheral alpha‐2 adrenoceptor antagonist,as premedication in horses anaesthetized with isoflurane

ObjectiveTo investigate MK-467 as part of premedication in horses anaesthetized with isoflurane.Study designExperimental, crossover study with a 14 day wash-out period.AnimalsSeven healthy horses.MethodsThe horses received either detomidine (20 μg kg⁻¹ IV) and butorphanol (20 μg kg⁻¹ IV) alone (DET) or with MK-467 (200 μg kg⁻¹ IV; DET + MK) as premedication. Anaesthesia was induced with ketamine (2.2 mg kg⁻¹) and midazolam (0.06 mg kg⁻¹) IV and maintained with isoflurane. Heart rate (HR), mean arterial pressure (MAP), end-tidal isoflurane concentration, end-tidal carbon dioxide tension, central venous pressure, fraction of inspired oxygen (FiO₂) and cardiac output were recorded. Blood samples were taken for blood gas analysis and to determine plasma drug concentrations. The cardiac index (CI), systemic vascular resistance (SVR), ratio of arterial oxygen tension to inspired oxygen (P_aO₂/FiO₂) and tissue oxygen delivery (DO₂) were calculated. Repeated measures anova was applied for HR, CI, MAP, SVR, lactate and blood gas variables. The Student's t-test was used for pairwise comparisons of drug concentrations, induction times and the amount of dobutamine administered. Significance was set at p < 0.05.ResultsThe induction time was shorter, reduction in MAP was detected, more dobutamine was given and HR and CI were higher after DET+MK, while SVR was higher with DET. Arterial oxygen tension and P_aO₂/FiO₂ (40 minutes after induction), DO₂ and venous partial pressure of oxygen (40 and 60 minutes after induction) were higher with DET+MK. Plasma detomidine concentrations were reduced in the group receiving MK-467. After DET+MK, the area under the plasma concentration time curve of butorphanol was smaller.Conclusions and clinical relevanceMK-467 enhances cardiac function and tissue oxygen delivery in horses sedated with detomidine before isoflurane anaesthesia. This finding could improve patient safety in the perioperative period. The dosage of MK-467 needs to be investigated to minimise the effect of MK-467 on MAP.     

The cardiopulmonary effects of a peripheral alpha‐2‐adrenoceptor antagonist,MK‐467, in dogs sedated with a combination of medetomidine and butorphanol

ObjectiveTo compare the cardiopulmonary effects of intravenous (IV) and intramuscular (IM) medetomidine and butorphanol with or without MK-467.Study designProspective, randomized experimental cross-over.AnimalsEight purpose–bred beagles (two females, six males), 3–4 years old and weighing 14.5 ±1.6 kg (mean ± SD).MethodsAll dogs received four different treatments as follows: medetomidine 20 μg kg^?1 and butorphanol tartrate 0.1 mg kg^?1 IV and IM (MB), and MB combined with MK-467,500 μg kg^?1 (MBMK) IV and IM. Heart rate (HR), arterial blood pressures (SAP, MAP, DAP), central venous pressure (CVP), cardiac output, respiratory rate (f_R), rectal temperature (RT) were measured and arterial blood samples were obtained for gas analysis at baseline and at 3, 10, 20, 30, 45 and 60 minutes after drug administration. The cardiac index (CI), systemic vascular resistance index (SVRI) and oxygen delivery index (DO₂I) were calculated. After the follow-up period atipamezole 50 μg kg^?1 IM was given to reverse sedation.ResultsHR, CI and DO₂I were significantly higher with MBMK after both IV and IM administration. Similarly, SAP, MAP, DAP, CVP, SVRI and RT were significantly lower after MBMK than with MB. There were no differences in f_R between treatments, but arterial partial pressure of oxygen decreased transiently after all treatments. Recoveries were uneventful following atipamezole administration after all treatments.Conclusions and clinical relevanceMK-467 attenuated the cardiovascular effects of a medetomidine-butorphanol combination after IV and IM administration.     

Effect of MK‐467 on organ blood flow parameters detected by contrast‐enhanced ultrasound in dogs treated with dexmedetomidine

ObjectiveTo evaluate the dexmedetomidine‐induced reduction in organ blood flow with quantitative contrast‐enhanced ultrasound (CEUS) method and to observe the influence of MK‐467 on such reduction.Study designRandomized cross‐over study.AnimalsSix adult purpose‐bred laboratory beagle dogs (mean body weight 15.3 ± 1.9 kg).MethodsContrast‐enhanced ultrasound was performed on six conscious healthy laboratory beagles. The animals on separate occasions underwent three treatments: awake without any medication (CTRL), dexmedetomidine 10 μg kg^?1 (DEX) and DEX + MK‐467 500 μg kg^?1 (DMK) intravenously (IV). The kidney (10–15 minutes post‐treatment), spleen (25–30 minutes post‐treatment), small intestine (40–45 minutes post‐treatment) and liver (50–55 minutes post‐treatment) were examined with CEUS. A time curve was generated and the following perfusion parameters were analysed: arrival time (AT), time to peak from injection (TTPinj), peak intensity (PI) and wash‐in rate (Wi). In addition to CEUS, renal glomerular filtration rate was indirectly estimated by the rate of iohexol elimination.ResultsAT and TTPinj were significantly higher for DEX than for CTRL in all studied organs. The same parameters were significantly higher for DEX than for DMK in the kidney, spleen and small intestine. PI was significantly lower for DEX than for CTRL or DMK in the kidney. Wi was significantly lower for DEX than for CTRL or DMK in the kidney and significantly lower than for CTRL only in the small intestine. Plasma concentration of iohexol was significantly higher after DEX than CTRL administration.ConclusionsContrast‐enhanced ultrasound was effective in detecting DEX‐induced changes in blood flow. MK‐467 attenuated these changes.Clinical relevanceClinicians should consider the effects of the sedation protocol when performing CEUS. Addition of MK‐467 might beneficially impact the haemodynamic function of sedation with alpha‐2 adrenoceptor agonists.     

Thermographic imaging of superficial temperature in dogs sedated with medetomidine and butorphanol with and without MK‐467 (L‐659’066)

ObjectiveTo record, with a thermal camera, peripheral temperature changes during different sedation protocols and to relate the results to changes in the rectal temperature.Study designRandomized crossover part-blinded experimental study.AnimalsEight healthy purpose-bred neutered Beagles (two females and six males) weight 14.5 ± 1.6 kg (mean ± SD) and aged 3–4 years.MethodsEach dog was sedated four times. Treatments were medetomidine 20 μg kg^?1 and butorphanol 0.1 mg kg^?1 (MB) with or without MK-467 500 μg kg^?1 (MK). Both drug combinations were administered IV and IM as separate treatments. A thermal camera (T425, FLIR) with a resolution of 320 by 240 was used for imaging.The dogs were placed in lateral recumbency on an insulated mattress. Digital (DFT) and metatarsal footpad temperatures (MFT) were measured with thermography. Thermograms and rectal temperature (RT) were taken before and at 3, 10, 20, 30, 45 and 60 minutes after treatment.ResultsAt 60 minutes after drug administration, MFT was higher (p < 0.001) after MB+MK (34.5 ± 1.1 IV, 34.8 ± 0.5 IM) than MB (31.1 ± 2.9 IV, 30.5 ± 3.6 IM), DFT was higher (p < 0.001) after MB+MK (33.6 ± 1.4 IV, 34.0 ± 0.6 IM) than MB (26.7 ± 1.4 IV, 26.7 ± 2.5 IM), and RT was lower (p < 0.001) after MB+MK (36.7 ± 0.8 IV, 36.9 ± 0.3 IM) than MB (37.5 ± 0.3 IV, 37.4 ± 0.4 IM), with both routes. The change from baseline was greater with MB+MK than MB in all variables.ConclusionsSuperficial temperature changes can be seen and detected with thermography. MK-467 used with MB resulted in increased superficial temperatures and a decline in rectal temperature compared to MB alone.Clinical relevanceThe sedation protocol may influence core temperature loss, and may also have an effect on thermographic images.     

The α2A‐adrenoceptor subtype plays a key role in the analgesic and sedative effects of xylazine

Xylazine, the classical α₂‐adrenoceptor (α₂‐AR) agonist, is still used as an analgesic and sedative in veterinary medicine, despite its low potency and affinity for α₂‐ARs. Previous pharmacological studies suggested that the α_2A‐AR subtype plays a role in mediating the clinical effects of xylazine; however, these studies were hampered by the poor subtype‐selectivity of the antagonists used and a lack of knowledge of their bioavailability in vivo. Here, we attempted to elucidate the role of the α_2A‐AR subtype in mediating the clinical effects of xylazine by comparing the analgesic and sedative effects of this drug in wild‐type mice with those in α_2A‐AR functional knockout mice using the hot‐plate and open field tests, respectively. Hippocampal noradrenaline turnover in both mice was also measured to evaluate the contribution of α_2A‐AR subtype to the inhibitory effect of xylazine on presynaptic noradrenaline release. In wild‐type mice, xylazine (10 or 30 mg/kg) increased the hot‐plate latency. Furthermore, xylazine (3 or 10 mg/kg) inhibited the open field locomotor activity and decreased hippocampal noradrenaline turnover. By contrast, all of these effects were abolished in α_2A‐AR functional knockout mice. These results indicate that the α_2A‐AR subtype is mainly responsible for the clinical effects of xylazine.     

Expression of VEGFR and PDGFR‐α/‐β in 187 canine nasal carcinomas

Radiotherapy represents the standard of care for intranasal carcinomas. Responses to tyrosine kinase inhibitors (TKIs) have been reported but data on expression of target receptor tyrosine kinases (rTKs) is limited. This study characterizes the expression of vascular endothelial growth factor receptor (VEGFR), platelet‐derived growth factor receptor (PDGFR)‐α and PDGFR‐β in canine intranasal carcinomas. Histological samples from 187 dogs were retrieved. Immunohistochemistry was performed using commercially available antibodies. Expression of rTKs was classified into weak, moderate or intense and additionally recorded as cytoplasmic, membranous, cytoplasmic‐membranous, nuclear or stromal. VEGFR was expressed in 158 dogs with predominantly moderate expression (36.9%) and a cytoplasmic‐membranous expression pattern (70.9%). PDGFR‐α was detected in 133 with predominantly weak expression (57.9%) and cytoplasmic pattern (87.9%). PDGFR‐β was identified in 74 patients with a predominantly moderate expression (17.6%) and cytoplasmic expression pattern (63.5%). Co‐expression of rTKs was common. These results confirm expression of VEGFR, PDGFR‐α and PDGFR‐β in canine intranasal carcinomas and support the utility of TKIs.     

β‐hydroxy‐β‐methyl butyrate promotes leucine metabolism and improves muscle fibre composition in growing pigs

The aim of this study was to investigate the effects of excess leucine (Leu) vs. its metabolites α‐ketoisocaproate (KIC) and β‐hydroxy‐β‐methyl butyrate (HMB) on Leu metabolism, muscle fibre composition and muscle growth in growing pigs. Thirty‐two pigs with a similar initial weight (9.55 ± 0.19 kg) were fed 1 of 4 diets for 45 days: basal diet, basal diet + 1.25% L‐Leu, basal diet + 1.25% KIC‐Ca, basal diet + 0.62% HMB‐Ca. Results indicated that relative to the basal diet and HMB groups, Leu and KIC groups exhibited increased Leu concentrations and decreased concentrations of isoleucine, valine and EAAs in selected muscle (p < 0.05) and had lower mRNA levels of MyHC I and higher expression of MyHC IIx/IIb (p < 0.05), and there was no significant difference between the basal and HMB‐supplemented groups. Moreover, the mRNA expression levels of AMPKα and UCP3 were higher but the myostatin mRNA levels were lower in the soleus muscle of the HMB group than those from other groups (p < 0.05). These findings demonstrated that doubling dietary Leu content exerted growth‐depressing effects in growing pigs; dietary KIC supplementation induced muscular branched‐chain amino acid imbalance and promoted muscle toward a more glycolytic phenotype; while dietary HMB supplementation promoted the generation of more oxidative muscle types and increased muscle growth specially in oxidative skeletal muscle, and these effects of HMB might be associated with the AMPKα‐Sirt1‐PGC‐1α axis and mitochondrial biogenesis.     

Effects of maternal treatment with β‐hydroxy‐β‐metylbutyrate and 2‐oxoglutaric acid on femur development in offspring of minks of the standard dark brown type

The aim of the study was to evaluate the effect of the diet, mother type and sex of the offspring on the mechanical and geometric parameters of long bones as well as bone tissue density in minks. Primiparous and multiparous dams were supplemented with β‐hydroxy β‐methylbutyrate (a metabolite of leucine, at the daily dosage of 0.02 g/kg of body weight) and/or 2‐oxoglutaric acid (a precursor of glutamine, at the daily dosage of 0.4 g/kg of body weight) during gestation. The diet did not influence bone tissue density and the length of the humerus. An increase in the length of the femur was noted in male offspring delivered by multiparous dams. The diet resulted in an increase in the weight of the humerus in males from multiparous dams and a decrease in offspring from primiparous dams. Heavier femora were noted in male offspring delivered by both types of dams. The maximum elastic strength of the humerus was higher in the offspring delivered by multiparous than primiparous dams, irrespective of the offspring sex. The diet resulted in reduction in the ultimate strength of the femur in the male offspring delivered by primiparous dams. Only females born by multiparous dams, irrespective of the diet, showed a significant increase in the cross‐sectional area of the humerus, while a significant decline was noted in males delivered by multiparous dams and in all the offspring delivered by primiparous dams. An increase in the cross‐sectional area of the femur was noted in the offspring delivered by multiparous dams, while reduction was observed in the offspring delivered by primiparous dams. These results have shown for the first time that the presence of β‐hydroxy‐β‐methylbutyrate or 2‐oxoglutaric acid in the diet of pregnant primiparous or multiparous dams unambiguously affects the geometry and mechanical properties of offspring's long bones.     

Dietary supplementation of β‐hydroxy‐β‐methylbutyrate in animals – a review

The leucine metabolite β‐hydroxy‐β‐methylbutyrate (HMB) has been studied by many researchers over the last two decades. In particular, the utility of HMB supplementation in animals has been shown in numerous studies, which have demonstrated enhanced body weight gain and carcass yield in slaughter animals; positive immunostimulatory effect; decreased mortality; attenuation of sarcopenia in elderly animals; and potential use in pathological conditions such as glucocorticoid‐induced muscle loss. The aim of this study was to summarize the body of research on HMB supplementation in animals and to examine possible mechanisms of HMB action. Furthermore, while the safety of HMB supplementation in animals is well documented, studies demonstrating efficacy are less clear. The possible reasons for differences in these findings will also be examined.     

Expression analysis of an α‐1, 3‐galactosyltransferase,an enzyme that creates xenotransplantation‐related α–Gal epitope,in pig preimplantation embryos

α‐1,3‐Galactosyltransferase (α‐GalT), an enzyme creating Galα1‐3Gal (α‐Gal) epitope on the cell surface in some mammalian species such as pigs, is known to be a key factor that causes hyperacute rejection upon transplantation from pigs to humans. To establish the RNA interference‐based suppression of endogenous α‐GalT messenger RNA (mRNA) synthesis in porcine preimplantation embryos, we determined the suitable embryonic stage at which stage such approach is possible by using the semi‐quantitative RT‐PCR (qRT‐PCR) and the cytochemical method using a fluorescence‐labeled Bandeiraea simplicifolia Isolectin B₄ (BS‐I‐B₄). Staining with BS‐I‐B₄ demonstrated that α‐Gal epitope expression was first recognized at the 8‐cell stage, and increased up to the hatched blastocyst stage. Single embryo‐based qRT‐PCR also confirmed this pattern. These results indicate that creation of α‐Gal epitope is proceeded by de novo synthesis of α‐GalT mRNA in porcine preimplantation embryos with peaking at the blastocyst stage.     

Effects of β‐carotene‐enriched dry carrots on β‐carotene status and colostral immunoglobulin in β‐carotene‐deficient Japanese Black cows

Data from 18 β‐carotene‐deficient Japanese Black cows were collected to clarify the effects of feeding β‐carotene‐enriched dry carrots on β‐carotene status and colostral immunoglobulin (Ig) in cows. Cows were assigned to control or carrot groups from 3 weeks before the expected calving date to parturition, and supplemental β‐carotene from dry carrots was 138 mg/day in the carrot group. Plasma β‐carotene concentrations in the control and carrot groups at parturition were 95 and 120 μg/dL, and feeding dry carrots slightly improved plasma β‐carotene at parturition. Feeding dry carrots increased colostral IgA concentrations in cows and tended to increase colostral IgG₁, but colostral IgM, IgG₂, β‐carotene and vitamin A were not affected by the treatment. Feeding dry carrots had no effects on plasma IgG₁, IgA and IgM concentrations in cows, but plasma IgG₁ concentrations decreased rapidly from 3 weeks before the expected calving date to parturition. These results indicate that feeding β‐carotene‐enriched dry carrots is effective to enhance colostral IgA and IgG₁ concentrations in β‐carotene‐deficient cows.     

A possible solution to model nonlinearity in elimination and distributional clearances with α2‐adrenergic receptor agonists: Example of the intravenous detomidine and methadone combination in sedated horses

The alpha(α)₂‐agonist detomidine is used for equine sedation with opioids such as methadone. We retrieved the data from two randomized, crossover studies where detomidine and methadone were given intravenously alone or combined as boli (STUDY 1) (Gozalo‐Marcilla et al., 2017, Veterinary Anaesthesia and Analgesia, 2017, 44 , 1116) or as 2‐hr constant rate infusions (STUDY 2) (Gozalo‐Marcilla et al., 2019, Equine Veterinary Journal, 51 , 530). Plasma drug concentrations were measured with a validated tandem Mass Spectrometry assay. We used nonlinear mixed effect modelling and took pharmacokinetic (PK) data from both studies to fit simultaneously both drugs and explore their nonlinear kinetics. Two significant improvements over the classical mammillary two‐compartment model were identified. First, the inclusion of an effect of detomidine plasma concentration on the elimination clearances (Cls) of both drugs improved the fit of detomidine (Objective Function Value [OFV]: ?160) and methadone (OFV: ?132) submodels. Second, a detomidine concentration‐dependent reduction of distributional Cls of each drug further improved detomidine (OFV: ?60) and methadone (OFV: ?52) submodel fits. Using the PK data from both studies (a) helped exploring hypotheses on the nonlinearity of the elimination and distributional Cls and (b) allowed inclusion of dynamic effects of detomidine plasma concentration in the model which are compatible with the pharmacology of detomidine (vasoconstriction and reduction in cardiac output).     

Olive leaves (Olea europea L.) and α‐tocopheryl acetate as feed antioxidants for improving the oxidative stability of α‐linolenic acid‐enriched eggs

Ninety‐six brown Lohmann laying hens were equally assigned into four groups with six replicates. Hens within the control group were fed a corn–soybean‐based diet supplemented with 4% linseed oil. Two other groups were given the same diet further supplemented with 5 or 10 g ground olive leaves/kg feed, while the diet of the fourth group was further supplemented with 200 mg α‐tocopheryl acetate/kg. Supplementing diets with olive leaves had no effect on egg production, feed intake and egg traits. Eggs collected 28 days after feeding the experimental diets were analysed for lipid hydroperoxides and malondialdehyde (MDA) content, fatty acid profile, α‐tocopherol concentrations and susceptibility to iron‐induced lipid oxidation. Olive leaves were also analysed for total and individual phenolics, and total flavonoids, whereas their antioxidant capacity was determined using both the DPPH (1,1‐diphenyl‐2‐picrylhydrazyl) and ABTS (2,2‐azinobis3‐ethylbenzothiazoline‐6‐sulphonic acid) radical scavenging activity assays. Results showed that neither α‐tocopheryl acetate nor olive leaves supplementation exerted (p > 0.05) any effect on the fatty acid composition of n‐3 eggs. Supplementing the diet with 5 g olive leaves/kg had no (p > 0.05) effect on the hydroperoxide levels of n‐3 eggs, while supplementing with 10 g olive leaves/kg or 200 mg α‐tocopheryl acetate/kg, the lipid hydroperoxide levels were reduced (p ≤ 0.05) compared to control. However, although hydroperoxides were reduced, MDA, a secondary lipid oxidation product, was not affected (p > 0.05). Iron‐induced lipid oxidation increased MDA values in eggs from all groups, the increase being higher (p ≤ 0.05) in the control group and the group supplemented with 5 g olive leaves/kg. The group supplemented with 10 g olive leaves/kg presented MDA values lower (p ≤ 0.05) than the control but higher (p ≤ 0.05) than the α‐tocopheryl acetate group, which presented MDA concentrations lower (p ≤ 0.05) than all other experimental diets at all incubation time points.     

Integrin heterodimer α9β1 is localized on the surface of porcine spermatogonial stem cells in the undifferentiated state

A previous study found that undifferentiated porcine spermatogonial stem cells (SSCs) did not adhere to tenascin C, indicating that the integrin α₉ and β₁ subunits are inactive on the surface of porcine SSCs. However, that study used recombinant tenascin C without FNIII‐like repeats. Therefore, this study re‐evaluated the existence of integrin α₉β₁ actively functioning on the plasma membrane of porcine SSCs using full‐length native tenascin C with FNIII‐like repeats. The localization and function of the integrin heterodimer were confirmed using immunocytochemistry, attachment and antibody inhibition assays. In undifferentiated porcine SSCs with integrin α₉β₁ on the cell surface, adhesion to native tenascin C was significantly higher compared with cells lacking native tenascin C and functional blocking of integrin α₉β₁ significantly inhibited the attachment to native tenascin C compared with no functional blocking. Accordingly, we confirmed that the integrin α₉ and β₁ subunits function as an active heterodimer on the surface of porcine SSCs in the undifferentiated state.     

The impact of MK‐467 on plasma drug concentrations,sedation and cardiopulmonary changes in sheep treated with intramuscular medetomidine and atipamezole for reversal

The effect of MK‐467, a peripheral α₂‐adrenoceptor antagonist, on plasma drug concentrations, sedation and cardiopulmonary changes induced by intramuscular (IM) medetomidine was investigated in eight sheep. Additionally, the interactions with atipamezole (ATI) used for reversal were also evaluated. Each animal was treated four times in a randomized prospective crossover design with 2‐week washout periods. Medetomidine (MED) 30 μg/kg alone or combined in the same syringe with MK‐467 300 μg/kg (MMK) was injected intramuscular, followed by ATI 150 μg/kg (MED + ATI and MMK + ATI) or saline intramuscular 30 min later. Plasma was analysed for drug concentrations, and sedation was subjectively assessed with a visual analogue scale. Systemic haemodynamics and blood gases were measured before treatments and at intervals thereafter. With MK‐467, medetomidine plasma concentrations were threefold higher prior to ATI, which was associated with more profound sedation and shorter onset. No significant differences were observed in early cardiopulmonary changes between treatments. Atipamezole reversed the medetomidine‐related cardiopulmonary changes after both treatments. Sedation scores decreased more rapidly when MK‐467 was included. In this study, MK‐467 appeared to have a pronounced effect on the plasma concentration and central effects of medetomidine, with minor cardiopulmonary improvement.     

Effects of supplemental β‐carotene on colostral immunoglobulin and plasma β‐carotene and immunoglobulin in Japanese Black cows

Data from 26 Japanese Black cows were collected to clarify the effects of supplemental β‐carotene on colostral immunoglobulin (Ig) and plasma β‐carotene and Ig in the cows. Cows were assigned to control or β‐carotene groups from 21 days before the expected calving date to 60 days after parturition. Supplemental β‐carotene was provided at 500 mg/day in the β‐carotene group. Supplemental β‐carotene drastically increased plasma β‐carotene concentrations in the cows from parturition to 60 days after parturition, and plasma β‐carotene concentrations in the control and β‐carotene groups at parturition were 202 and 452 μg/dl, respectively. Supplemental β‐carotene had no effects on plasma IgG₁, IgA or IgM concentrations at parturition. Supplemental β‐carotene increased colostral IgG₁ concentrations in the cows, but colostral β‐carotene, IgA and IgM concentrations were not affected by supplemental β‐carotene. These results indicate that supplemental β‐carotene is effective to enhance colostral IgG₁ concentrations and plasma β‐carotene concentrations in Japanese Black cows.     

Effects of transforming growth factor‐β1 treatment on muscle regeneration and adipogenesis in glycerol‐injured muscle

Transforming growth factor (TGF)‐β1 is associated with fibrosis in many organs. Recent studies demonstrated that delivery of TGF‐β1 into chemically injured muscle enhances fibrosis. In this study, we investigated the effects of exogenous TGF‐β1 on muscle regeneration and adipogenesis in glycerol‐injured muscle of normal mice. Tibialis anterior (TA) muscles were injured by glycerol injection. TGF‐β1 was either co‐injected with glycerol, as an ‘early treatment’ group, or injected at day 4 after glycerol, as a ‘late treatment’ group and the TA muscles were collected at day 7 after initial injury. Myotube density was significantly lower in the early treatment group than in the glycerol‐injured group (without TGF‐β1 treatment). Moreover, the Oil red O‐positive area was significantly smaller in the early treatment group than in the late treatment group and glycerol‐injured group. Furthermore, TGF‐β1 treatment increased endomysial fibrosis and induced immunostaining of α‐smooth muscle actin. The greater inhibitory effects of early TGF‐β1 treatment than that of late TGF‐β1 treatment during regeneration in glycerol‐injured muscle suggest a more potent effect of TGF‐β1 on the initial stage of muscle regeneration and adipogenesis. Combination of TGF‐β1 with glycerol might be an alternative to enhance muscle fibrosis for future studies.