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Investigation of gender differences in the cardiovascular actions of direct and indirect sympathomimetic stimulants including cathinone in the anaesthetized rat 麻醉大鼠直接和间接拟交感神经兴奋剂(包括卡西酮)心血管作用的性别差异研究
Pub Date : 2016-08-18 DOI: 10.1111/aap.12043
H. A. Alsufyani, J. R. Docherty

  1. We have studied gender differences in the direct and indirect sympathomimetic cardiovascular effects of the stimulant cathinone (from Khat) (and for comparison methylenedioxymethamphetamine [MDMA]) and the archetypal indirect sympathomimetic agent tyramine, employing male and female Wistar rats.
  2. Animals were sympathectomized by treatment with 6-hydroxydopamine or treated with vehicle.
  3. In male and female vehicle-treated pentobarbitone-anaesthetized rats, all three agonists (0.001–1 mg/kg) produced significant tachycardia, tyramine produced large pressor, and in high doses small depressor responses, MDMA produced small pressor responses, and cathinone produced only minor pressor effects.
  4. In sympathectomized rats, pressor responses, even those to tyramine, were virtually abolished, and depressor responses to tyramine were abolished.
  5. In vehicle-treated rats, the tachycardia to tyramine, but not the tachycardia to cathinone or MDMA, was significantly greater in male than female rats. This may suggest that the mechanism of the tachycardia to tyramine differs from those of the stimulants cathinone and MDMA. Following sympathectomy, there were no differences between male and female rats in the tachycardia to any agent.
  6. Hence, there were gender differences in the tachycardia response for tyramine, but no gender differences in the cardiovascular responses to the widely used recreational stimulants cathinone and MDMA. Cardiac stimulant actions of cathinone and MDMA were similar in male and female rats.
我们利用雄性和雌性Wistar大鼠,研究了兴奋剂卡西酮(来自阿拉伯茶)(以及亚甲基二氧甲基苯丙胺[MDMA]的比较)和原型间接拟交感神经剂乳胺的直接和间接拟交感神经心血管作用的性别差异。用6-羟多巴胺或载药治疗交感神经切除动物。在雄性和雌性戊巴比妥麻醉大鼠中,所有三种激动剂(0.001-1 mg/kg)均产生明显的心动过速,乳胺产生较大的升压反应,高剂量时产生较小的降压反应,MDMA产生较小的升压反应,卡西酮仅产生较小的升压作用。在交感神经切除的大鼠中,压迫反应,甚至对酪胺的反应,实际上都被消除了,对酪胺的抑制反应也被消除了。在给药的大鼠中,雄性大鼠对酪胺的心动过速明显高于雌性大鼠,而对卡西酮或MDMA的心动过速则没有。这可能表明酪胺引起心动过速的机制不同于兴奋剂卡西酮和MDMA。交感神经切除后,雄性和雌性大鼠对任何药物的心动过速均无差异。因此,对酪胺的心动过速反应存在性别差异,但对广泛使用的娱乐性兴奋剂卡西酮和MDMA的心血管反应没有性别差异。卡西酮和MDMA对雄性和雌性大鼠的心脏刺激作用相似。
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引用次数: 6
The safety assessment of saffron (Crocus sativus L.) on sympathovagal balance and heart rate variability; a comparison with amiodarone 藏红花(Crocus sativus L.)对交感迷走神经平衡和心率变异性的安全性评价与胺碘酮的比较
Pub Date : 2016-06-21 DOI: 10.1111/aap.12040
Siyavash Joukar, Mohammad-Moein Dehesh

  1. Dry stigmas of the Crocus sativus L. (Saffron) are well known in world as a popular flavouring and therapeutic agent. The anxiolytic, antidepressant, anticonvulsant and antiarrhythmic effects of saffron suggest that it may affect the autonomic control of the heart.
  2. This study assessed its safety on cardiac sympathovagal balance and heart rate variability in rat.
  3. Experimental groups were control, Saf50, Saf100, Saf200 (received saffron at dosages of 50 and 100 and 200 mg/kg/d, orally, respectively) and Amio (received 30 mg/mL/kg/d of amiodarone, orally, for 7 days) groups. On day 8, the frequency domain and time domain indices of animals' electrocardiograms were calculated.
  4. The heart rate decreased and RR interval increased in Saf200 and Amio groups (P<.05 vs other groups). Square root of the mean squared differences of successive RR intervals enhanced in all treated groups, however, was only significant in Amio group (P<.05). The SD1/SD2 ratio was higher in Saf200 and Amio groups. Both low-frequency (LF) and high-frequency (HF) parameters were higher, and the LF/HF ratio was non-significantly lower in treated groups.
  5. The findings suggest that saffron not only has no harmful effect on activity of cardiac autonomic nervous system, but it may improve the stability of heart sympathovagal balance in normal rat.
藏红花(Crocus sativus L.,藏红花)的干柱头作为一种流行的调味品和治疗剂在世界上是众所周知的。藏红花的抗焦虑、抗抑郁、抗惊厥和抗心律失常作用表明,它可能影响心脏的自主控制。本研究评估其对大鼠心脏交感迷走神经平衡和心率变异性的安全性。试验组分为对照组、Saf50组、Saf100组、Saf200组(分别给予藏红花50、100、200 mg/kg/d,口服)和Amio组(给予胺碘酮30 mg/mL/kg/d,口服,连用7 d)。第8天,计算动物心电图频域和时域指数。Saf200组和Amio组大鼠心率降低,RR间期增加(p < 0.05)。05 vs其他组)。所有治疗组连续RR区间的均方根差均增加,但只有Amio组显著(p < 0.05)。Saf200组和Amio组的SD1/SD2比值较高。治疗组的低频(LF)和高频(HF)参数均升高,LF/HF比值无显著降低。研究结果表明,藏红花不仅对心脏自主神经系统的活性无不良影响,而且可能提高正常大鼠心脏交感迷走神经平衡的稳定性。
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引用次数: 11
Autonomic & Autacoid Pharmacology: past, present and future 自主和自体药理学:过去,现在和未来
Pub Date : 2016-06-21 DOI: 10.1111/aap.12039
Peter E. Penson
It is with great pleasure and no little trepidation that I assume my role as the fourth editor of Autonomic & Autacoid Pharmacology. It is a privilege to follow in the footsteps of Michael Day, Kenneth Broadley and William Ford. I hope that I will prove to be a worthy successor to these great custodians of the journal. I look forward to receiving submissions of manuscripts describing original work and reviews of the literature. Coincident with my commencement of editorial responsibilities is the introduction by the publishers, John Wiley & Sons, of a new page design. I hope that readers will agree with me that the more modern formatting suits the journal very well. Contributors should please note that the new style necessitates some changes in the formatting of manuscripts for submission. The journal started life in 1980 as The Journal of Autonomic Pharmacology. Michael Day’s inaugural editorial makes fascinating reading as a brief overview of the development of autonomic pharmacology as a discipline.1 Day was keen to encourage the submission of articles designated as ‘Historical Perspectives’. He explained: ‘These will be concerned with the historical development of autonomic pharmacology and may take the form of a description of a particular discovery of of the work of an individual or group. The historical aspects of a subject are more than merely of curiosity value, since they form the intellectual base on which the subject continues to grow and often contain valuable clues and hints which did not fit the contemporary framework of knowledge’. This is clearly as important today, as it was in 1980, and I would be delighted to receive submissions of this type. Authors of ‘Historical Perspectives’ will find themselves in very good company. The first publication of this type in this journal was written by no less than Raymond Ahlquist, and readers will nor be surprised to learn that it discussed the classification of adrenoceptors.2 The current title, Autonomic & Autacoid Pharmacology, was adopted in 2002, by the journal’s second editor, Ken Broadley. This was not a conscious decision to change direction, but a ‘formalizing of the natural evolution of the scope of the journal’;3 indeed, the most highly cited article published in the journal (693 citations according to Google Scholar) is the paper ‘Tachykinin receptors and Tachykinin receptor antagonists’ by Maggi et al.4, published in 1993, which illustrates that the scope of the journal had moved beyond strictly ‘autonomic’ pharmacology sometime previously. Nevertheless, in contrast to ‘autonomic pharmacology’ which can be defined and limited reasonably easily, the definition of ‘autacoid’ is perhaps harder to pin down. It is possible that authors may have been reluctant to submit their work, not knowing whether the subjects of their papers could be considered ‘autacoids’. I am very pleased therefore that Jan Keppel Hesselink has contributed an article entitled ‘The terms ‘autacoid,’ ‘hormone’ an
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引用次数: 5
Proliferation of the human urothelium is induced by atypical β1-adrenoceptors 非典型β1-肾上腺素受体可诱导人尿路上皮的增殖
Pub Date : 2016-05-31 DOI: 10.1111/aap.12036
M. Winder, C. Wasén, P. Aronsson, D. Giglio

  1. We wanted to assess whether β-adrenoceptors mediate proliferation in the normal and malignant urothelial cell lines UROtsa and T24, respectively.
  2. Urothelial cells were cultured for 24 h in the presence of the β-adrenoceptor agonists isoprenaline (β1/2/3), dobutamine (β1), salbutamol (β2), BRL 37344 (β3), CGP 12177 (a partial β-agonist) or β-adrenoceptor antagonists (metoprolol; β1, propranolol; β1/2). Phosphorylation of kinases was screened with a Human Phospho-Kinase Array Kit (R&D systems). Intracellular pathways activated by proliferation of urothelial cells were characterized by incubating cells with the MEK1/2 inhibitor PD 98,059, the p38 kinase inhibitor losmapimod or with the Akt 1/2 kinase inhibitor. Proliferation was assessed with the MTT proliferation assay (ATCC). Western blot and immunocytochemistry were used for detection of the β1-adrenoceptor.
  3. Isoprenaline and dobutamine induced proliferation, while salbutamol and BRL 37344 did not. Dobutamine-induced proliferation was not affected by metoprolol or propranolol but was instead antagonized by CGP 12177 in T24 but not in UROtsa. In response to stimulation with dobutamine, Akt1/2/3 was phosphorylated in UROtsa, while ERK1/2 and p38 were phosphorylated in T24. MEK1/2 inhibition blocked basal and dobutamine-induced proliferation in T24 but only basal proliferation in UROtsa. Losmapimod slightly inhibited basal proliferation in T24 but not dobutamine-induced proliferation. Akt 1/2 inhibitor blocked basal and dobutamine-induced proliferation in UROtsa. Immunocytochemistry and Western blot revealed expression of β1-adrenoceptors in both urothelial cell lines.
  4. The present data show that the urothelium expresses atypical β1-adrenoceptors that activate intracellular kinases inducing urothelial proliferation.
我们想要评估β-肾上腺素受体是否分别介导正常和恶性尿路上皮细胞系UROtsa和T24的增殖。尿路上皮细胞在β-肾上腺素受体激动剂异丙肾上腺素(β1/2/3)、多巴酚丁胺(β1)、沙丁胺醇(β2)、BRL 37344 (β3)、CGP 12177(部分β激动剂)或β-肾上腺素受体拮抗剂(美托洛尔;β1、普萘洛尔;β1/2)。使用Human Phospho-Kinase Array Kit (R&D systems)筛选激酶的磷酸化。通过MEK1/2抑制剂PD 98059、p38激酶抑制剂losmapimod或Akt 1/2激酶抑制剂孵育细胞,研究了尿路上皮细胞增殖激活的细胞内通路。用MTT增殖试验(ATCC)评估增殖情况。Western blot和免疫细胞化学检测β1-肾上腺素能受体。异丙肾上腺素和多巴酚丁胺可诱导细胞增殖,而沙丁胺醇和BRL 37344则无此作用。美托洛尔和心得安对多巴酚丁胺诱导的增殖没有影响,而CGP 12177对T24有拮抗作用,而对UROtsa无拮抗作用。多巴酚丁胺刺激后,UROtsa中Akt1/2/3被磷酸化,而T24中ERK1/2和p38被磷酸化。MEK1/2抑制可阻断T24细胞基底细胞和多巴酚丁胺诱导的增殖,但仅阻断UROtsa细胞基底细胞的增殖。Losmapimod对T24的基底细胞增殖有轻微抑制作用,但对多巴酚丁胺诱导的增殖没有抑制作用。Akt 1/2抑制剂阻断基底和多巴酚丁胺诱导的UROtsa细胞增殖。免疫细胞化学和Western blot显示两种尿路上皮细胞系均表达β1-肾上腺素受体。目前的数据表明,尿路上皮表达非典型β1-肾上腺素受体,激活细胞内激酶,诱导尿路上皮增殖。
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引用次数: 4
Role of α1D-adrenoceptors in vascular wall hypertrophy during angiotensin II-induced hypertension α 1d肾上腺素受体在血管紧张素ii诱导的高血压中血管壁肥厚的作用
Pub Date : 2016-05-31 DOI: 10.1111/aap.12035
I. A. Gallardo-Ortíz, S. N. Rodríguez-Hernández, J. J. López-Guerrero, L. Del Valle-Mondragón, P. López-Sánchez, R. M. Touyz, R. Villalobos-Molina

  1. The in vivo effect of continuous angiotensin II (Ang II) infusion on arterial blood pressure, vascular hypertrophy and α1-adrenoceptors (α1-ARs) expression was explored.
  2. Alzet® minipumps filled with Ang II (200 ng kg−1 min−1) were subcutaneously implanted in male Wistar rats (3 months-old). Groups of rats were also treated with losartan, an AT1R antagonist, or with BMY 7378, a selective α1D-AR antagonist. Blood pressure was measured by tail-cuff; after 2 or 4 weeks of treatment, vessels were isolated for functional and structural analyses.
  3. Angiotensin II increased systolic blood pressure. Phenylephrine-induced contraction in aorta was greater (40% higher) in Ang II-treated rats than in the controls, and similar effect occurred with KCl 80 mm. Responses in tail arteries were not significantly different among the different groups.
  4. Angiotensin II decreased α1D-ARs without modifying the other α1-ARs and induced an increase in media thickness (hypertrophy) in aorta, while no structural change occurred in tail artery. Losartan prevented and reversed hypertension and hypertrophy, while BMY 7378 prevented and reversed the aorta's hypertrophic response, without preventing or reversing hypertension. Findings indicate that Ang II-induced aortic hypertrophic response involves Ang II-AT1Rs and α1D-ARs. Angiotensin II-induced α1D-AR-mediated vascular remodeling occurs independently of hypertension.
  5. Findings identify a α1D-AR-mediated process whereby Ang II influences aortic hypertrophy independently of blood pressure elevation.
探讨持续输注血管紧张素II (Ang II)在体内对动脉血压、血管肥大及α1-肾上腺素受体(α1-ARs)表达的影响。在雄性Wistar大鼠(3个月大)皮下植入充满Ang II (200 ng kg−1 min−1)的Alzet®微型泵。各组大鼠也用AT1R拮抗剂氯沙坦或选择性α1D-AR拮抗剂BMY 7378治疗。用尾袖测量血压;治疗2或4周后,分离血管进行功能和结构分析。血管紧张素II增加收缩压。苯肾上腺素诱导的大鼠主动脉收缩比对照组更大(高出40%),KCl 80mm也有类似的效果。尾动脉的反应在不同组间无显著差异。血管紧张素II降低α1D-ARs,但不影响其他α1-ARs,导致主动脉中膜厚度增加(肥厚),尾动脉未发生结构改变。氯沙坦预防和逆转高血压和肥厚,而BMY 7378预防和逆转主动脉肥厚反应,但未预防或逆转高血压。结果表明,Ang ii诱导的主动脉肥厚反应涉及Ang II-AT1Rs和α1D-ARs。血管紧张素ii诱导的α - 1d - ar介导的血管重构与高血压无关。研究结果确定了α 1d - ar介导的过程,其中Ang II独立于血压升高影响主动脉肥厚。
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引用次数: 17
The terms ‘autacoid’, ‘hormone’ and ‘chalone’ and how they have shifted with time 术语“类自体”、“激素”和“chalone”以及它们是如何随着时间而变化的
Pub Date : 2016-03-29 DOI: 10.1111/aap.12037
J. M. Keppel Hesselink

  1. The increase of knowledge in a particular field (endocrinology) can be understood if one follows how certain key concepts were constructed and transformed over time. To explore such construction and transformation (shifts in meaning), we studied the use of the concepts ‘autacoid’ and ‘chalone’ in a period of one century (1916–2016), since the introduction of these concepts by the British professor of physiology Sir Sharpey-Schäfer.
  2. We could identify that the use of ‘autacoid’ shifted from a very broad category encompassing both stimulating and inhibiting hormones, in the period 1916–1960, to a much more specific use of the term for locally produced bioactive molecules, from the 1960s onwards.
  3. Histamine was the first compound seen as an ‘autacoid’, followed by prostaglandins, ATP, ADP and bradykinin, and from 1993 onwards, compounds such as ‘palmitoylethanolamide’ were also classified as ‘autacoids’. For ‘chalone’, a comparable shift was noticed around the 1960s, when the concept suddenly changed from the category of inhibiting hormones into a substance that is produced within a tissue, inhibiting mitosis of the cells of that tissue. For both concept shifts, we could not find any argument.
  4. Around 1980, authors started to relate autacoids to various promising indications in the field of inflammation and immune modulation. The Nobel laureate Rita Levi-Montalcini gave an extra dimension to the concept autacoid in 1993, and introduced a new class of compounds modulating mast cells, the ALIAmides (from Autacoid Local Inflammation Antagonist), of which palmitoylethanolamide was the prototype. Our exploration demonstrates that biomedical concepts can be constructed and defined differently as time goes by, while concept transformations seem to emerge without arguments.
一个特定领域(内分泌学)的知识增长可以理解,如果一个人遵循某些关键概念是如何随着时间的推移而构建和转变的。为了探索这种结构和转换(意义的转变),我们研究了一个世纪(1916-2016)期间“autotacoid”和“chalone”概念的使用,因为这些概念是由英国生理学教授Sir Sharpey-Schäfer引入的。我们可以确定,在1916-1960年期间,“自体类”的使用从一个非常广泛的类别,包括刺激和抑制激素,转变为更具体的术语,用于本地生产的生物活性分子,从20世纪60年代开始。组胺是第一个被视为“类自身”的化合物,其次是前列腺素、ATP、ADP和缓激素,从1993年起,“棕榈酰乙醇酰胺”等化合物也被归类为“类自身”。“chalone”在20世纪60年代前后出现了类似的变化,当时这个概念突然从抑制激素的范畴转变为组织内产生的一种物质,可以抑制该组织细胞的有丝分裂。对于这两种观念的转变,我们都找不到任何论据。1980年前后,作者开始将类自身素与炎症和免疫调节领域的各种有希望的适应症联系起来。1993年,诺贝尔奖得主丽塔·列维-蒙塔奇尼(Rita levy - montalcini)给自体类细胞的概念增加了一个维度,并介绍了一类调节肥大细胞的新化合物ALIAmides(来自自体类局部炎症拮抗剂),其中棕榈酰乙醇酰胺是其原型。我们的探索表明,随着时间的推移,生物医学概念可以被不同地构建和定义,而概念转换似乎没有争论。
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引用次数: 8
Protective effect of proteins derived from Calotropis procera latex against acute inflammation in rat 原角鹿乳蛋白对大鼠急性炎症的保护作用
Pub Date : 2015-04-17 DOI: 10.1111/aap.12022
V. L. Kumar, B. Guruprasad, P. Chaudhary, S. M. A. Fatmi, R. S. B. Oliveira, M. V. Ramos

  1. The non-dialysable proteins present in the latex of plant Calotropis procera possess anti-inflammatory and analgesic properties.
  2. The aim of this study was to evaluate the effect of latex proteins (LP) on the level of inflammatory mediators, oxidative stress markers and tissue histology in the rat model of carrageenan-induced acute inflammation. This study also aimed at evaluating the anti-inflammatory efficacy of LP against different mediators and comparing it with their respective antagonists.
  3. Paw inflammation was induced by subplantar injection of carrageenan, and the effect of LP was evaluated on oedema volume, level of TNF-α, PGE2, myeloperoxidase, nitric oxide, reduced glutathione, thiobarbituric acid-reactive substances and tissue histology at the time of peak inflammation.
  4. Paw inflammation was also induced by histamine, serotonin, bradykinin and PGE2, and the inhibitory effect of LP against these mediators was compared with their respective antagonists at the time of peak effect.
  5. Treatment with LP produced a dose-dependent inhibition of oedema formation, and its anti-inflammatory effect against carrageenan-induced paw inflammation was accompanied by reduction in the levels of inflammatory mediators, oxidative stress markers and normalization of tissue architecture.
  6. LP also produced a dose-dependent inhibition of oedema formation induced by different inflammatory mediators, and its efficacy was comparable to their respective antagonists and more pronounced than that of diclofenac.
  7. Thus, our study shows that LP has a potential to be used for the treatment of various inflammatory conditions where the role of these mediators is well established.
植物原角鹿角乳乳中的非透析蛋白具有抗炎和镇痛的特性。本研究旨在探讨乳胶蛋白(latex protein, LP)对卡拉胶致急性炎症大鼠模型炎症介质、氧化应激标志物及组织组织学的影响。本研究还旨在评估LP对不同介质的抗炎作用,并将其与各自的拮抗剂进行比较。通过足底注射角叉菜胶诱导足跖炎症,观察LP对炎症峰值时足跖水肿量、TNF-α、PGE2、髓过氧化物酶、一氧化氮、还原性谷胱甘肽、硫代巴比妥酸反应性物质水平及组织组织学的影响。组胺、5 -羟色胺、缓激肽和PGE2也可诱导足跖炎症,比较LP对这些介质的抑制作用及其拮抗剂在作用峰值时的抑制作用。LP治疗对水肿形成具有剂量依赖性的抑制作用,其抗卡拉胶诱导的足跖炎症的抗炎作用伴随着炎症介质、氧化应激标志物水平的降低和组织结构的正常化。LP对不同炎症介质诱导的水肿形成也有剂量依赖性的抑制作用,其效果与各自的拮抗剂相当,比双氯芬酸更明显。因此,我们的研究表明,LP具有用于治疗各种炎症条件的潜力,其中这些介质的作用已经得到了很好的确立。
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引用次数: 19
Evaluating the effect of oral administration of Echinacea hydroethanolic extract on the immune system in dog 评价口服紫锥菊水乙醇提取物对犬免疫系统的影响
Pub Date : 2015-03-30 DOI: 10.1111/aap.12024
S. Torkan, F. Khamesipour, S. Katsande

  1. This study was designed to evaluate the effects of oral administration of Echinacea hydroethanolic extract on the dog's immune system.
  2. The study was performed on 14 dogs that were referred to the veterinary clinic. These dogs were randomly allocated to two equal treatment groups. The first group received 1 ml of 5% Echinacea hydroethanolic extract two times a day for 2 months, and the second group received a placebo (water). To do haematology and immunology tests, the dogs were bled on days 0, 30 and 60. Blood tests, including packed cell volume (PCV), haemoglobin (Hb), red blood cell count (RBC), white blood cell count (WBC), counting neutrophils (Nut), lymphocytes (Lym), monocytes (Mon), eosinophils (Eos), basophils (Baso) and B cell, were performed. Furthermore, safety factor IgM and per cent of phagocytosis and phagocyte were measured from the blood sample.
  3. The results showed that in the group which received Echinacea PCV, Hb, RBC count, WBC count, Lym, Nut, the per cent of phagocytosis and IgM significantly increased (P < 0.05). Moreover, positive effects of Echinacea plant on the immune system were observed. There was a significant change in HTC, RBC, Hb over time in the group that received Echinacea and the per cent of phagocytosis and IgM (P < 0.05).
  4. The study establishes that these extracts might have appreciable immunostimulatory activity. However, further studies are required to confirm these findings.
本研究旨在评估口服紫锥菊水乙醇提取物对狗免疫系统的影响。这项研究是在转介到兽医诊所的14只狗身上进行的。这些狗被随机分配到两个平等的治疗组。第一组给予5%紫锥菊水乙醇提取物1 ml,每天2次,连续2个月;第二组给予安慰剂(水)。在第0、30和60天进行血液学和免疫学测试。进行血液检查,包括细胞体积(PCV)、血红蛋白(Hb)、红细胞计数(RBC)、白细胞计数(WBC)、中性粒细胞(Nut)、淋巴细胞(Lym)、单核细胞(Mon)、嗜酸性粒细胞(Eos)、嗜碱性粒细胞(Baso)和B细胞计数。此外,从血液样本中测量安全系数IgM和吞噬率和吞噬细胞的百分比。结果表明,紫锥菊组PCV、Hb、RBC、WBC、Lym、Nut、吞噬率和IgM均显著升高(P <0.05)。此外,还观察到紫锥菊对免疫系统的积极作用。服用紫锥菊组的HTC、RBC、Hb随时间变化显著,吞噬率和IgM (P <0.05)。研究表明,这些提取物可能具有明显的免疫刺激活性。然而,需要进一步的研究来证实这些发现。
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引用次数: 12
Functional and radioligand binding characterization of the α1L-adrenoceptor subtype of the human vas deferens 人输精管α 1l -肾上腺素能受体亚型的功能和放射配体结合特性
Pub Date : 2015-03-19 DOI: 10.1111/aap.12023
B. J. Davis, M. Wiener, C. R. Chapple, D. J. Sellers, R. Chess-Williams

  1. Alpha1-adrenoceptor antagonists can cause ejaculatory dysfunction as an adverse effect. Contractions of the human vas deferens are mediated via α1A-adrenoceptors, and this study investigated whether the low affinity state of this receptor (α1L-adrenoceptor) is involved in mediating contractions of this tissue.
  2. The potency of agonists and the affinity of receptor subtype selective antagonists were determined in functional experiments and in [3H]tamsulosin binding experiments to identify the α1-adrenoceptor subtype population present in the human vas deferens.
  3. The α1A-adrenoceptor selective agonist A61603 was a full agonist and was 250-fold more potent than noradrenaline. Prazosin antagonized contractile responses to phenylephrine with a low affinity (pKd = 8.6). Only high concentrations of RS17053 antagonized responses to phenylephrine and yielded a relatively low affinity estimate of 7.0. BMY7378 (α1D-adrenoceptor selective) gave a low affinity estimate (pKd = 6.7), whilst tamsulosin (α1A- and α1D-adrenoceptor selective) had a high affinity (pKd = 9.9).
  4. [3H]Tamsulosin bound to human vas deferens membranes with a high affinity (pKd = 10.0). Prazosin, RS17053 and BMY7378 competed with [3H]tamsulosin with low affinities for a single population of binding sites (pKd values of 8.5, 7.2 and 6.3, respectively).
  5. These functional and radioligand binding data indicate that the human vas deferens possesses a homogeneous population of α1-adrenoceptors which have the pharmacological properties of the putative α1L-adrenoceptor, the same functional receptor previously identified in the human prostate.
α -肾上腺素受体拮抗剂可引起射精功能障碍。人输精管的收缩是通过α 1a -肾上腺素受体介导的,本研究探讨了α 1l -肾上腺素受体的低亲和力状态是否参与了输精管收缩的介导。在功能实验和[3H]坦索罗辛结合实验中,测定了受体亚型选择性拮抗剂的效价和受体亚型选择性拮抗剂的亲和力,以鉴定人输精管中存在的α1-肾上腺素能受体亚型群体。α α -肾上腺素受体选择性激动剂A61603是一种完全激动剂,比去甲肾上腺素强250倍。哌唑嗪对苯肾上腺素的收缩反应具有低亲和力(pKd = 8.6)。只有高浓度的RS17053对苯肾上腺素产生拮抗反应,并且产生相对较低的亲和力估计为7.0。BMY7378 (α 1d -肾上腺素受体选择性)具有低亲和力(pKd = 6.7),而坦索罗新(α1A-和α 1d -肾上腺素受体选择性)具有高亲和力(pKd = 9.9)。[3H]坦索罗辛以高亲和力与人输精管膜结合(pKd = 10.0)。Prazosin、RS17053和BMY7378与[3H]tamsulosin在单个群体结合位点上的亲和力较低(pKd值分别为8.5、7.2和6.3)。这些功能和放射配体结合数据表明,人类输精管具有均匀的α1-肾上腺素受体,这些α1-肾上腺素受体具有假定的α 1l -肾上腺素受体的药理特性,与先前在人类前列腺中发现的功能受体相同。
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引用次数: 5
A high-fat plus fructose diet produces a vascular prostanoid alterations in the rat 高脂肪加果糖的饮食会使大鼠的血管前列腺素发生改变
Pub Date : 2015-03-12 DOI: 10.1111/aap.12021
H. A. Peredo, H. Lee, A. S. Donoso, V. Andrade, N. Sánchez Eluchans, A. M. Puyó

  1. In the rat, a high-fat (HF) plus fructose (F) diet produces cardiovascular and metabolic alterations that resemble human metabolic syndrome. Prostanoids (PR), cyclo-oxygenase-derived arachidonic acid metabolites, have vasoactive properties and mediate inflammation.
  2. The aim of this study was to analyse the effect of a HF+F diet on blood pressure (BP), metabolic parameters and mesenteric vascular bed PR production in male Sprague–Dawley rats.
  3. Four groups were studied over 9 weeks (n = 6 each): control (C), standard diet (SD) and tap water to drink; F+SD and 10% w/v F solution to drink; HF 50% (w/w) bovine fat added to SD and tap water; and HFF, both treatments. PR were determined by HPLC.
  4. Blood pressure was elevated in all experimental groups. Triglyceridaemia, insulinaemia and HOMA-IR were increased in the F and HF groups. HF+F animals showed elevated glycaemia, insulinaemia, HOMA-IR and triglyceridaemia. F decreased the vasodilator prostanoids PGI2 and PGE2 in the mesenteric vascular bed. Body weight was not significantly altered. In HFF, production of PGE2, PGF2alpha and TXB2 was elevated.
  5. The increased BP in HF and HFF could be partly attributed to the imbalance in vascular PR production towards vasoconstrictors. On the other hand, this dietary modification could induce inflammation, which would explain the elevation of PGE2. In the F group, hypertension could be related to decreased vasodilator PRs.
  6. The simultaneous administration of HF and F in the rat produces deleterious effects greater than observed when treatments are applied separately.
在大鼠中,高脂肪(HF)加果糖(F)的饮食会产生类似于人类代谢综合征的心血管和代谢变化。Prostanoids (PR)是环加氧酶衍生的花生四烯酸代谢物,具有血管活性并介导炎症。本研究旨在分析HF+F饮食对雄性Sprague-Dawley大鼠血压(BP)、代谢参数和肠系膜血管床PR生成的影响。四组研究时间为9周(每组n = 6):对照组(C)、标准饮食组(SD)和自来水饮用组;F+SD和10% w/v F溶液饮用;HF 50% (w/w)牛脂肪添加到SD和自来水中;和HFF,两种治疗方法。高效液相色谱法测定PR。所有实验组的血压都升高了。F和HF组甘油三酯血症、胰岛素血症和HOMA-IR升高。HF+F动物出现血糖、胰岛素、HOMA-IR和甘油三酯血症升高。F降低肠系膜血管床血管舒张剂前列腺素PGI2和PGE2。体重没有明显改变。在HFF中,PGE2、PGF2alpha和TXB2的产生升高。HF和HFF患者血压升高的部分原因可能是血管PR生成向血管收缩剂的不平衡。另一方面,这种饮食改变可能会引起炎症,这可以解释PGE2的升高。在F组,高血压可能与血管扩张剂pr降低有关。在大鼠体内同时施用HF和F产生的有害影响比单独施用时观察到的更大。
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引用次数: 13
期刊
Autonomic and Autacoid Pharmacology
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