静脉输液微粒体内分布的模拟研究

目的：考察输液微粒进入体内后的主要分布。方法：用微粒计数仪分别检测活性炭和硫酸钡混悬液中的粒径分布,并用其模拟静脉输液微粒分别通过尾静脉给小鼠注射3.62×10⁷,1.13×10⁸,2.72×10⁸个微粒,采用CT断层扫描分析硫酸钡微粒在小鼠体内的分布,以组织器官HE染色观察各组织器官中活性炭的分布情况。结果：活性炭和硫酸钡微粒粒径主要分布在2~10 μm之间。影像学结果显示静脉输入的硫酸钡微粒主要分布在肺脏和肝脏;组织学观察表明活性炭微粒主要分布在肺脏、肝脏和脾脏,少量分布在肾脏和心脏。粒径0~2 μm、>2~4 μm和>4~6 μm的活性炭微粒分别主要分布在脾脏、肝脏和肺脏,肾脏和心脏组织中分别分布着少量2~6 μm和4~8 μm的微粒。结论：粒径<10 μm的输液微粒主要分布在肺脏、肝脏和脾脏,少量分布在肾脏和心脏;在肺脏、肾脏和心脏可观察到极少量粒径≥10 μm的微粒分布。     

Sustained release characteristics of rifampin-loaded microsphere formulations in nonhuman primates

Controlled release rifampin-loaded microspheres were evaluated for the first time in nonhuman primates. Animals received either 2.0 g of a large formulation (10-150 μm, 23 wt% rifampin) injected subcutaneously at Day 0 (118-139 mg rifampin/kg), 4.0 g of a small formulation (1-10 μm, 5.8 wt% rifampin) administered intravenously in 2.0 g doses on Day 0 and 7 (62.7-72.5 mg rifampin/kg), or a combination of small and large microspheres (169-210 mg rifampin/kg). Extended rifampin release was observed up to 48 days. Average rifampin concentrations remaining in the liver, lung, and spleen at 30 days were 14.03, 4.09, and 1.98 μg/g tissue, respectively.     

Are beta-adrenoreceptors involved in the intestinal absorption and tissue distribution of iron in the rat?

⁵⁹Fe was incorporated in vivo into intestinal sacs prepared in iron deficient rats and ⁵⁹Fe counts were detected in blood, spleen, liver, femur and intestine. The i.v. injection of isoproterenol (i.v. 2 μg/rat) or N′,O′-dibutyryladenosine 3′,5′-cyclic monophosphate (10 μM/100 g b.w.) enhanced significantly the iron counts in blood, spleen, liver and femur but not in intestine. (−)-Propranolol (2 mg · kg⁻¹ b.w.i.v.) antagonized the stimulatory effect of isoproterenol. It is suggested that isoproterenol increases iron absorption via the stimulation of β-adrenoreceptors of the intestinal mucosa.     

瑞马唑仑与丙泊酚对乳腺癌根治术患者围术期细胞免疫功能的影响比较

目的:比较瑞马唑仑与丙泊酚静脉麻醉对乳腺癌根治术患者围术期细胞免疫功能的影响。方法:将择期行乳腺癌根治术的患者80例,采用随机数字表法分为瑞马唑仑组(R组)和丙泊酚组(P组)。麻醉诱导时,R组患者静脉推注瑞马唑仑0.2 mg/kg+舒芬太尼0.3μg/kg+顺阿曲库铵0.2 mg/kg;P组患者静脉推注丙泊酚2 mg/kg+舒芬太尼0.3μg/kg+顺阿曲库铵0.2 mg/kg。麻醉维持时,R组患者静脉泵注瑞马唑仑0.4~1.2 mg(/kg·h)+瑞芬太尼0.1~0.2μg(/kg·min);P组患者静脉泵注丙泊酚4~10 mg(/kg·h)+瑞芬太尼0.1~0.2μg(/kg·min);两组患者均间断静脉推注顺阿曲库铵。术中监测患者麻醉深度并据此调整瑞马唑仑、丙泊酚和瑞芬太尼的泵注速度。记录两组患者术中输液量、失血量、手术时间、阿片类药物用量,术后24、72 h时的视觉模拟评分法(VAS)评分;同时,测定麻醉诱导前30 min、术后24 h和术后72 h时两组患者T淋巴群CD3⁺、CD4⁺、CD8⁺和自然杀伤(NK)细胞的水平以及不良反应发生率,并计算CD4⁺/CD8⁺比值;记录两组患者不良反应发生情况。结果:两组患者术中输液量、失血量、手术时间、阿片类药物用量,术后24、72 h时的VAS评分以及不良反应发生率比较,差异均无统计学意义(P>0.05)。与麻醉诱导前30 min比较,两组患者在术后24 h时的CD3⁺、CD4⁺、NK细胞水平和CD4⁺/CD8⁺比值均显著降低(P<0.05);与P组比较,R组患者在术后24 h时的CD3⁺、CD4⁺、NK细胞水平和CD4⁺/CD8⁺比值均显著升高(P<0.05)。结论:用于麻醉维持时,瑞马唑仑对乳腺癌根治术患者围术期细胞免疫的抑制作用小于丙泊酚。     

2017 年湖南省肿瘤登记地区恶性肿瘤发病及死亡资料分析

目的分析2017年湖南省肿瘤登记地区恶性肿瘤发病及死亡情况。方法收集2017年湖南省30个肿瘤登记地区上报的肿瘤发病与死亡资料,按照城乡、性别分层,分别计算恶性肿瘤的发病和死亡粗率、中国人口标化率(中标率)、世界人口标化率(世标率)、年龄别率、0~74岁累积率等,中标率和世标率分别采用2000年中国标准人口年龄构成和Segi's世界标准人口年龄构成为标准进行计算。结果2017年湖南省肿瘤登记地区恶性肿瘤发病率为229.03/10万,中标率为159.41/10万,世标率为155.66/10万,0~74岁累积率为18.22%。城市地区恶性肿瘤发病率为278.02/10万,而农村地区为208.67/10万。男性恶性肿瘤发病率为251.40/10万,高于女性的205.20/10万。男性恶性肿瘤发病率排名前5位的是肺癌、肝癌、结直肠肛门癌、胃癌、食管癌,女性发病率排名前5位的是乳腺癌、肺癌、子宫颈癌、结直肠肛门癌、肝癌。2017年湖南省肿瘤登记地区居民恶性肿瘤的死亡率为152.91/10万,中标率为99.38/10万,世标率为98.55/10万,0~74岁累积率为11.78%。城市地区居民恶性肿瘤死亡率为182.71/10万,农村为140.53/10万。男性恶性肿瘤死亡率为192.26/10万,高于女性的111.00/10万。男性恶性肿瘤死亡率排名前5位的是肺癌、肝癌、结直肠肛门癌、胃癌、食管癌,女性死亡率排名前5位的是肺癌、肝癌、结直肠肛门癌、乳腺癌、子宫颈癌。结论肺癌、乳腺癌、结直肠肛门癌、肝癌、子宫颈癌、胃癌、鼻咽癌、食管癌等病种是湖南省发病率、死亡率均较高的恶性肿瘤,应作为湖南省恶性肿瘤防治的主要癌种。湖南省男性居民口腔及咽喉癌的发病率和死亡率均有所上升,且城市男性居民上升幅度更大,需要提早采取防范措施。     

Rat striatum contains pure population of ETB receptors

In most organs of the body, endothelin acts on endothelin ET_A and ET_B receptors that co-exist (albeit often on different cell types). Although virtually pure endothelin ET_A receptors have been identified in some tissues (e.g., lung), no essentially pure endothelin ET_B receptor tissue has been reported to date. [¹²⁵I]Endothelin-1 bound to striatal membrane preparations with a K_d of 19.4 ± 0.2 pM and B_max of 496 ± 8 fmol/mg protein. Endothelin-1 displaced [¹²⁵I]endothelin-1 receptor binding with an IC₅₀ of 23 pM. The endothelin ET_B-selective antagonist BQ788 (N-cis-2,6-dimethylpiperidinocarbonyl- -γ-methyl-leucyl- -l-methoxycarbonyltryptophanyl- -norleucine) and agonist sarafotoxin 6C displaced [¹²⁵I]endothelin-1 monophasically with IC₅₀ values of 25 nM and 110 pM, respectively, whereas that of the endothelin ET_A-selective antagonist BQ123 (cyclo( -Trp- -Asp-Pro- -Val-Leu)) was 24 μM, values agreeing with cloned human endothelin ET_B but not ET_A receptors. Receptor autoradiography confirmed that rat striatum (but not white matter) contains essentially exclusively endothelin ET_B receptors.     

Effects of ochratoxin a on the mouse immune system after subchronic exposure

The effects on the immune system of oral, subchronic exposure to ochratoxin A (OA) at 6, 250 or 2600 μg/kg diet were studied in female Balb/c mice. After 28 days of exposure, antibody production to sheep red blood cells, as measured in the plaque-forming cell assay and expressed as number of plaque-forming cells/spleen, was suppressed in a dose-dependent manner which was significant in the two highest exposure groups. In addition, a decrease in thymocyte cell counts was seen in the 250-μg/kg group. After 90 days of exposure, flow cytometry analysis of thymic lymphocyte subpopulations revealed a decreased proportion of mature (CD4⁺ or CD8⁺) cells. Furthermore, the mitogenic responsiveness of thymocytes and splenocytes to concanavalin A (Con A) was significantly decreased. This effect was observed in all three treatment groups. Interleukin-2 production of Con A-stimulated lymphocytes, natural killer cell activity, and humoral antibody titres to a viral antigen were not affected by OA treatment. The present results indicate that subchronic, oral exposure to OA affects certain immune functions in mice at exposure levels that may be found in contaminated food products.     

Biphasic effects of mianserin and desipramine on serotonin-evoked current and Cl- efflux in Xenopus oocytes.

Serotonin (5-HT, 1 μM) elicited two phases of Cl⁻ inward current in Xenopus oocytes injected with rat brain mRNA: a transient current (T-current), which was generated rapidly (within 1 min), and a sustained current (S-current), which persisted for 10 min. Each type of 5-HT-evoked response was time-dependent after mRNA injection. The T-current was generated at 20-30 h and the S-current at 30–40 h. Although mianserin at 0.1 μ M completely inhibited the T-current, 10 μ M mianserin was required to suppress the S-current. 5-HT also caused Cl⁻ efflux from oocytes preloaded with ³⁶Cl⁻, Cl⁻ efflux during 1 min, corresponding to the T-current, was inhibited by 0.1 μ M mianserin. A higher concentration of mianserin (10 μ M) was required to block the efflux for 10 min, corresponding to the S-current, as well as the current response. Desipramine selectively inhibited the T-current and Cl⁻ efflux for 1 min. The mechanisms underlying the different sensitivity to mianserin of oocytes injected with rat brain mRNA are discussed.     

In vitro and in vivo biological activities of SR140333, a novel potent non-peptide tachykinin NK1 receptor antagonist

(S)1- {;2-[3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenylacetyl)piperidin-3-yl]ethyl };-4-phenyl-1-azoniabicyclo[2.2.2]octane chloride (SR140333) is a new non-peptide antagonist of tachykinin NK₁ receptors. SR140333 potently, selectively and competitively inhibited substance P binding to NK₁ receptors from various animal species, including humans. In vitro, it was a potent antagonist in functional assays for NK₁ receptors such as [Sar⁹,Met(O₂)¹¹]substance P-induced endothelium-dependent relaxation of rabbit pulmonary artery and contraction of guinea-pig ileum. Up to 1 μM, it had no effect in bioassays for NK₂ ([βAla⁸]neurokinin A-induced contraction of endothelium-deprived rabbit pulmonary artery) and NK₃ ([MePhe⁷]neurokinin B-induced contraction of rat portal vein) receptors. The antagonism exerted by SR140333 toward NK₁ receptors was apparently non-competitive, with pD'₂ values (antagonism potency evaluated by the negative logarithm of the molar concentration of antagonist that produces a 50% reduction of the maximal response to the agonist) between 9.65 and 10.16 in the different assays. SR140333 also blocked in vitro [Sar⁹,Met(O₂)¹¹]substance P-induced release of acetylcholine from rat striatum. In vivo, SR140333 exerted highly potent antagonism toward [Sar⁹,Met(O₂¹¹]substance P-induced hypotension in dogs (ED₅₀ = 3 μg/kg i.v., bronchoconstriction in guinea-pig (ED₅₀ = 42 μg/kg i.v.) and plasma extravasation in rats (ED₅₀ = 7 μg/kg i.v.). Finally, it also blocked the activation of rat thalamic neurons after nociceptive stimulation (ED = 0.2 μg/kg i.v.).     

Lobeline inhibits nicotine-evoked [H]dopamine overflow from rat striatal slices and nicotine-evoked Rb efflux from thalamic synaptosomes

The present study evaluated the interaction of lobeline with neuronal nicotinic acetylcholine receptors using two in vitro assays, [³H] overflow from [³H]dopamine ([³H]DA)-preloaded rat striatal slices and ⁸⁶Rb⁺ efflux from rat thalamic synaptosomes. To assess agonist interactions, the effect of lobeline was determined and compared to S(−)-nicotine. To assess antagonist interactions, the ability of lobeline to inhibit the effect of S(−)-nicotine was determined. Both S(−)-nicotine (0.1–1 μM) and lobeline (>1.0 μM) evoked [³H] overflow from superfused [³H]DA-preloaded striatal slices. However, lobeline-evoked [³H] overflow is mecamylamine-insensitive, indicating that this response is not mediated by nicotinic receptors. Moreover, at concentrations (<1.0 μM) which did not evoke [³H] overflow, lobeline inhibited S(−)-nicotine (0.1–10 μM)-evoked [³H] overflow, shifting the S(−)-nicotine concentration–response curve to the right. S(−)-Nicotine (30 nM–300 μM) increased (EC₅₀ VALUE=0.2 μM) ⁸⁶Rb⁺ efflux from thalamic synaptosomes. In contrast, lobeline (1 nM–10 μM) did not evoke ⁸⁶Rb⁺ efflux, and the lack of intrinsic activity indicates that lobeline is not an agonist at this nicotinic receptor subtype. Lobeline completely inhibited (IC₅₀ VALUE=0.7 μM) ⁸⁶Rb⁺ efflux evoked by 1 μM S(−)-nicotine, a concentration which maximally stimulated ⁸⁶Rb⁺ efflux. Thus, the results of these in vitro experiments demonstrate that lobeline inhibits the effects of S(−)-nicotine, and suggest that lobeline acts as a nicotinic receptor antagonist.     

The in vivo assessment of safety and gastrointestinal survival of an orally administered novel probiotic, Propionibacterium jensenii 702, in a male Wistar rat model

This study aimed to evaluate in vivo gastrointestinal survival and safety of orally administered probiotic bacterium, Propionibacterium jensenii 702, using a male Wistar rat model. A high dose of 10¹⁰ cfu/rat/day of P. jensenii 702 was fed to each rat for 81 days. The repeated dose toxicity and translocation of P. jensenii 702 into rat tissues were evaluated, along with the rat faecal β-glucuronidase activities and dairy propionibacteria counts. Results showed that P. jensenii 702 had no adverse effect on general health status, body weight gain, visceral organs and faecal β-glucuronidase activities. No viable cells of P. jensenii 702 were recovered from blood and tissue samples (mesenteric lymph nodes, liver and spleen) of rats, and no treatment-associated illness or death was observed. Faecal dairy propionibacteria counts reached 10⁸ cfu/g after 36 days treatment and remained between 10⁸–10⁹ cfu/g till the end of 81 days treatment. The results indicate that P. jensenii 702 was able to survive the in vivo gastrointestinal tract transit of rats, with no adverse affects on the animals. However, further human clinical trials are required before strain P. jensenii 702 could be incorporated into food for human consumption as probiotics.     

Behavioral and biochemical effects of the dopamine D3 receptor-selective ligand, 7-OH-DPAT, in the normal and the reserpine-treated rat

In normal rats, the dopamine D₃ receptor-selective ligand, 7-hydroxy-2-(di-n-propylamino)tetralin (7-OH-DPAT), produced biphasic effects on spontaneous locomotor activity, i.e. suppression at low doses (0.06–0.25 μmol kg⁻¹ s.c.), followed by a gradual increase in motor activity (1.0–4.0 μmol kg⁻¹). The core temperature was decreased at these latter high doses only. The reserpine-induced (8.2 μmol kg⁻¹ s.c.) increase in neostriatal 3,4-dihydroxyphenylalanine (DOPA) accumulation, following treatment with m-hydroxybenzylhydrazine-(NSD-1015) (475 μmol kg⁻¹ i.p.), was dose dependently antagonized by 7-OH-DPAT in the dose range 0.02–4.0 μmol kg⁻¹. The reserpine-induced suppression of spontaneous locomotor activity, however, was antagonized at higher doses only (1.0–4.0 μmol kg⁻¹). Finally, there were no region-selective effects of 7-OH-DPAT on DOPA accumulation in the neustriatum. Thus, it appears that the dopamine D₃ receptor-preferring ligand, 7-OH-DPAT, displays the profile of a dopamine D₂ receptor agonist, pre- and postsynaptically.     

Interaction between accumulation of cadmium selenium in the tissues of turbot Scophthalmus maximus

The interaction between accumulation of waterborne cadmium and selenite in juvenile turbot, Scophthalmus maximus, was investigated in the laboratory. Intestine, kidney and liver of turbot exposed to 150 μg Cd 1⁻¹ accumulated cadmium linearly with time over 5 wk at rates of 0.50, 0.014 and 0.11 μg Cd g⁻¹ dry wt. d⁻¹, respectively. Gills, skin and muscle reached steady-state cadmium levels of ca. 15, 0.8 and 0.25 μg Cd g⁻¹ after 1–3 wk of exposure. Plasma and erythrocytes reached steady-state concentrations of ca. 0.1 and 1–2 μg Cd ml ⁻¹ after 1–2 wk of exposure. Exposure to 105 μg Se-SeO₃²⁻1⁻¹ did not consistently alter selenium concentrations in gills, skin, liver, muscle and erythrocytes of juvenile turbot. Kidneys accumulated selenium linearly (0.029 μg Se g⁻¹ dry wt. d⁻¹) with time over 5 wk, while intestine reached a steady-state level after 2 wk. Selenium concentrations in the plasma were maintained close to the ambient level throughout the exposure time. Concurrent exposure to selenite augmented cadmium accumulation rates in gills, kidney and liver and reduced cadmium accumulation in intestine and erythrocytes; cadmium accumulation in spleen, skin, muscle and plasma was not affected. Concurrent exposure to cadmium depleted erythrocytes and partly skin of selenium and reduced accumulation of selenium in kidney and plasma, whereas selenium accumulation patterns in gills, intestine, liver, muscle and spleen were not affected by exposure to cadmium.     

姜黄素对结核小鼠复发及p38丝裂原活化蛋白激酶信号通路的影响

目的研究姜黄素对结核小鼠复发及p38丝裂原活化蛋白激酶(p38 MAPK)信号通路的影响。方法将45只C57BL/6小鼠随机分为模型组(n=15)、实验组(n=15)和对照组(n=15),所有小鼠均尾静脉注射结核分枝杆菌H37RV(1×10⁷ CFU·mL^-1)0.1 mL。4周后,实验组腹腔注射异烟肼10 mg·kg^-1+姜黄素60 mg·kg^-1,对照组腹腔注射异烟肼10 mg·kg^-1,模型组腹腔注射等量生理盐水,qd,连续干预4周。4周后各组小鼠均每周腹腔注射肿瘤坏死因子-α(TNF-α)抗体50μg,每天1次,连续4周。分别于药物干预结束后及诱导结束后用分枝杆菌中性罗氏培养管检测小鼠肺、脾组织荷菌量;以苏木精-伊红(HE)染色法观察各组小鼠肺组织病理学形态;以蛋白质印迹(WB)法检测小鼠肺组织中p-p38 MAPK蛋白的表达水平。结果药物干预结束后,模型组、对照组和实验组小鼠肺组织中荷菌量分别为(3.68±1.15),(1.13±0.12),(1.02±0.29)LgCFU·mL^-1,脾组织中荷菌量分别为(4.26±0.39),(2.12±0.13),(2.05±0.11)LgCFU·mL^-1,与模型组比较,实验组和对照组小鼠肺、脾组织中荷菌量均明显降低(均P<0.05),但实验组和对照组比较差异无统计学意义(P>0.05)。诱导结束后,模型组、对照组和实验组小鼠肺组织中荷菌量分别为(4.43±0.29),(4.03±0.10),(3.72±0.09)LgCFU·mL^-1,脾组织中荷菌量分别为(4.53±0.44),(3.97±0.22),(4.05±0.21)LgCFU·mL^-1,小鼠肺组织中小肉芽肿面积比分别为(8.65±0.32)%,(4.21±0.36)%,(3.98±0.52)%,小鼠肺组织中p-p38 MAPK蛋白相对表达量分别为1.47±0.33,1.13±0.35,0.76±0.25,差异均有统计学意义(均P<0.05)。结论姜黄素可通过降低p38 MAPK信号通路蛋白表达而抑制小鼠结核复发。     

Opioid receptor-mediated inhibition of evoked catecholamine release from cultured neurons of rat ventral mesencephalon and locus coeruleus

The effects of selective opioid agonists on the evoked release of [³H]dopamine and [³H]noradrenaline were studied in cultured dopaminergic neurons of the ventral mesencephalon (containing the substantia nigra and ventral tegmental area) and in cultured neurons of the noradrenergic locus coeruleus, respectively. The cultures were prepared from embroyonic day 15 rat brains. After 9 days in culture, the calcium-dependent release of [³H]dopamine from dopaminergic substantia nigra/ventral tegmental aera neurons induced by 23 mM k⁺ appeared to be inhibited exclusively by activation of κ-opioid receptors, as [³H]dopamine release was inhibited selectively by the κ- agonists U69,593 and dynorphin-(1–13) (EC₅₀ 8 and 5 nM, respectively), and this inhibitory effect was antagonized by the κ-selective antagonist nor-binaltorphine (K_i 0.07 nM). In contrast, cultured noradrenergic locus coeruleus neurons appeared to contain release-inhibitory μ-opioid receptors only, as evoked [³H]noradrenaline release was inhibited selectively by the μ agonist [D-Ala², MePhe⁴, Gly-ol⁵]enkephalin (EC₅₀ 45 nM), a response that was antagonized by the preferential μ antagonist naloxone (K_i = 0.7 nM). The δ-opioid receptor agonist [D-Ser²(O-butyl), Leu⁵]enkephaly-Thr⁶ did not affect catecholamine release. Dopamine release from cultured ventral mesencephalic neurons, induced by 100 μM N-Methyl-D-Aspartate (NMDA), also appeared to be subject to κ receptor-mediated inhibition, whereas NMDA-induced noradrenaline release from cultured locus coeruleus neurons was under the inhibitor control of μ receptors. It is therefore concluded that in rat brain neurotransmitter release from dopaminergic and noradrenergic neurons, originating from the substantia nigra/vental tegmental area and the locus coeruleus, is liable to inhibition by homogenous populations of κ- and μ-opioid receptors, respectively, independent of the input of non-opioid neurons from distict nuclei.     

磷酸川芎嗪乳剂在大鼠体内的药动学及组织分布研究

目的： 通过研究磷酸川芎嗪乳剂在大鼠体内的药动学和组织分布，探究磷酸川芎嗪乳剂的生物利用度和脑靶向性。方法： 大鼠静脉注射50 mg·kg^-1磷酸川芎嗪制剂，给药后，在不同时间采血，最后切除大鼠心脏，肝脏，脾脏，肺，肾，和脑。所有样品均采用液相色谱-质谱/质谱联用法（HPLC/MS/MS）进行检测，用DAS 2.1.1软件使用非房室分析计算药动学参数。结果： 与参比制剂（磷酸川芎嗪注射液）相比，乳剂制剂血浆中的药动学参数无显著差异。在血浆中，乳剂的AUC_0-∞和C_max分别为（4 406.96±977.08）mg·L^-1·min和（52.131±13.61）mg·L^-1。组织分布研究发现磷酸川芎嗪乳剂较参比制剂在脑组织分布更多。结论： 磷酸川芎嗪乳剂在心、肝、脾、肺、肾中有靶向趋势，比参比制剂更易分布在组织中。磷酸川芎嗪乳剂制剂具有脑靶向性。     

Effects of L- and N-type Ca channel antagonists on excitatory amino acid-evoked dopamine release

In thc present study we tested the effect of dihydropyridine (DHP) Ca²⁺ channel antagonists and of ω-conotoxin GVIA on [³H]dopamine (DA) release evoked by the activation of excitatory amino acid (EAA) receptors in cultures of fetal rat ventral mesencephalon, in order to investigate the role of voltage-sensitive L- and N-type Ca²⁺ channels in these EAA-mediated processes. Micromolar concentrations (10–30 μM) of DHP L-type Ca²⁺ channel antagonists inhibited [³H]DA release evoked by N-methyl-D-aspartate (NMDA), kainate, quisqualate or veratridine. [³H]DA release evoked by the L-type Ca²⁺ channel agonist, Bay K 8644, was inhibited by lower concentrations (0.1–1 μM) of the DHP antagonist, nitrendipine, than was the release evoked by EAAs. The DHP antagonist, ( + )-PN 200-110, was more potent than ( − )-PN 200-110 in inhibiting [³H]DA release evoked by Bay K 8644, but the two stereoisomers were equipotent in inhibiting NMDA-evoked release. These results indicate that activation of L-type Ca²⁺ channels is able to evoke [³H]DA release. However activation of L-type channels is not involved in EAA-induced [³H]DA release and therefore inhibition of EAA-induccd [³H]DA release by micromolar concentrations of DHPs must be mediated by actions other than inhibition of L-type Ca²⁺ channels. ω-Conotoxin GVIA (3 μM) had no effect on [³H]DA release evoked by Bay K 8644, indicating that the toxin may selectively inhibit N-type channels in this preparation. ω-Conotoxin GVIA (3 μM) partially inhibited [³H]DA release evoked by NMDA or kainate, suggesting that N-type Ca²⁺ channels could possibly play a role in FAA-mediated responses in these cells.     

Selective effects of [D-Ser(O-t-butyl),Leu]enkephalyl-Thr and [D-Ser(O-t-butyl),Leu]enkephalyl-Thr(O-t-butyl), two new enkephalin analogues, on neurotransmitter release and adenylate cyclase in rat brain slices

The selectivity and potency of two new enkephalin-derived δ-opioid receptor agonists, DSTBULET ([D-Ser²(O-t-butyl), Leu⁵]enkephalyl-Thr⁶) and BUBU ([D-Ser²(O-t-butyl),Leu⁵]enkephalyl-Thr⁶(O-t-butyl)) were determined with functional tests in vitro of μ-, δ-, and κ-opioid receptor activation in the rat brain. Both peptides concentration dependently (1 nM-1 μM) inhibited the release of radiolabeled acetylcholine (ACh) from striatal slices (pD₂ 7.6–7.9), an effect exclusively mediated by δ-opioid receptor activation. Fentanyl isothiocyanate (FIT), an irreversible δ-antagonist, completely blocked the inhibitory effects of DSTBULET and BUBU. Up to a concentration of 1 μM, the peptides did not affect striatal [³H]dopamine (DA) release nor cortical [³H]noradrenaline (NA) release, processes which are known to be inhibited by opioids activating κ and μ-receptors, respectively. Furthermore, both DSTBULET and BUBU caused a strong inhibition (pD₂ 8.2–8.3) of D-1 dopamine receptor-stimulated cyclic AMP efflux from striatal slices, an effect known to be mediated by μ- and/or δ-opioid receptor activation. However, the peptides were without effect when D-1 and D-2 dopamine receptors were stimulated simultaneously, a situation in which only μ-agonists are able to inhibit the resulting cAMP efflux. In conclusion, DSTBULET and BUBU appear to display a high selectivity and potency toward functional δ-opioid receptors in the brain.     

Alterations in retinoid concentrations in several extrahepatic organs of rats by 3,4,3′,4′-tetrachlorobiphenyl

In this study, the effect of polychlorinated biphenyls on retinoid homeostasis was investigated in Sprague—Dawley rats, by analysing [³H]retinoid concentrations in peripheral organs, following exposure to 3,4,3′,4′-tetrachlorobiphenyl (TCB). The rats were rendered retinoid-deficient through dietary restriction, followed by dietary supplementation with [³H]retinol for 14 days, in order to facilitate determination of retinoid concentrations in various tissues. At day 7 of [³H]retinol supplementation the rats were exposed to a single i.p. dose of 15 mg TCB dissolved in corn oil/kg body weight. In corn oil-treated control rats, the highest concentrations of [³H]retinoid radioactivity, consisting mainly of retinol and several retinylesters, were obtained in the liver ( > 10⁶ cpm/g), followed by the kidney and the lung, while only minor concentrations were found in skin and heart. Exposure to TCB resulted in a significant reduction of both retinol and retinylester concentrations in the liver (to 25% of controls) and the lung (to 44% of controls), while in the heart a reduction of retinol to 35% of controls was observed. No significant alterations in retinoid concentrations were observed in the skin and kidney. It is suggested that the reductions in retinoid concentrations might contribute to the toxicological alterations reported in these organs upon exposure to TCB.     

Effects of divalent cations on snake venom cardiotoxin-induced hemolysis and H-deoxyglucose-6-phosphate release from human red blood cells

, and . Effects of divalent cations on snake venom cardiotoxin-induced hemolysis and ³H-deoxyglucose-6-phosphate release from human red blood cells. Toxicon 27, 1297–1305, 1989.—At a low concentration of Naja naja kaouthia cardiotoxin (3 μM) Ca²⁺, Sr²⁺ and Ba²⁺ (2 mM), had little to no effect on ³H-deoxyglucose-6-phosphate (³H-dGlu-6-p) or hemoglobin release. At higher concentrations of N. n. kaouthia cardiotoxin (≥ 10 μM), Ca²⁺ (2 mM), but not Sr²⁺ or Ba²⁺, significantly enhanced ³H-dGlu-6-p and hemoglobin release. Mn²⁺ (2 mM) almost completely inhibited ³H-dGlu-6-p release and hemolysis at both the 3 μM and 10 μM concentrations of cardiotoxin. At a fixed concentration of N. n. kaouthia cardiotoxin (3 μM), Ca²⁺ at low concentrations (0.5 mM) enhanced ³H-dGlu-6-p and hemoglobin release, but at higher concentrations caused a dose-dependent inhibition of cardiotoxin action. The cardiotoxin from N. n. kaouthia venom (3 μM) induced ³H-dGlu-6-p release and hemolysis release with similar time courses and to similar extents. ³H-dGlu-6-p release induced by cardiotoxin was greatly enhanced as the pH of the medium was increased from 7.0 to 8.5. Similarities between ³H-dGlu-6-p and hemoglobin release do not support opening of pores in the plasmalemma of all red blood cells as the mode of action of cardiotoxins, but suggests that complete lysis of a subpopulation of cells occurs. Cardiotoxins have two components of lysis, only one of which is Ca²⁺-dependent. The Ca²⁺-dependent lysis is only evident at higher cardiotoxin concentrations and is likely due to trace phospholipase A₂ contamination in the toxin fraction. Mn²⁺ is an effective antagonist of cardiotoxin action.