L—精氨酸和牛磺酸治疗40例慢性心功能不全

慢性充血性心功能不全（ＣＨＦ）冠脉存在ＮＯ缺陷。本研究以ＮＯ前体Ｌ－Ａｒｇ作为ＮＯ药物治疗观察４０例ＣＨＦ。结果显示，静滴Ｌ－Ａｒｇ和牛磺酸治疗ＣＨＦ，显效率达９２．５％，症状及心功能各项指标改善，血小板，ｃＧＭＰ较对照组升高５０％，与对照组比较有较显著差异（Ｐ〈０．０５）。这提示Ｌ－精氨酸和联用牛磺酸治疗ＣＨＦ可能与其促进ＮＯ释放有关，同时推测血管紧张素转换酶抑制剂治疗ＣＨＦ也与促进ＮＯ释放有关     

在正常和多囊性卵巢综合征卵巢编码胰岛素样生长因子（IGF－I，II），IGF及胰岛素受体和IGF结合蛋白1－6的其基因表达及基因产物的定位

在正常和多囊性卵巢综合征卵巢编码胰岛素样生长因子（ＩＧＦ－Ｉ，ＩＩ），ＩＧＦ及胰岛素受体和ＩＧＦ结合蛋白１－６的其基因表达及基因产物的定位ＡＬＢＥＲＴＥＬ－ＲＯＥＩＹ，ＸＩＡＯＨＯＵＣＨＥＮ，ＶＥＲＯＮＩＣＡＪ．ＲＯＢＥＲＴＳＳＨＵＮＩＣＨＩＳＨＩＭ...     

巯甲丙脯酸与硝苯吡啶延缓慢性肾衰进展作用的比较

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垂直法,B超引导经皮肾活检成功率比较

垂直法、Ｂ超引导经皮肾活检成功率比较丁尧海，梁俊林，张囊萍，刘文渊，汤俊达ＡＣＯＭＰＡＲＡＴＩＶＥＳＴＵＤＹＯＦＶＥＲＴＩＣＡＬＡＮＤＵＬＴＲＡＳＯＮｌｃＲＥＡＬ－ＴＩＭＥＧＵＩＤＡＮＣＥＲＥＮＡＬＢＩＯＰＳＩＥＳＤｉｎｇＹａｏｈａｉ；ＬｔａｎｇＪｉ...     

一氧化氮与脑缺血缺氧损伤研究进展

一氧化氮（ＮＯ）激活脑血管平滑肌中的鸟苷酸环化酶（ＧＣ），ｃＧＭＰ合成增加，引起脑血管舒张，ＮＯ参与基础条件下和高碳酸血症等的脑血脑的调节。脑缺血期脑组织中ＮＯ增加，缺血后脑皮质亚硝酸盐和ｃＧＭＰ增加，缺血后ＮＯ全成酶活性明显增，提示Ｌ－Ａｒｇ：ＮＯ通路参与脑缺血再灌注损伤，但ＮＯ在脑缺血再满足灌注损伤中的作用及机理需要进一步研究。     

重组白介素2及重组α肿瘤坏死因子对人胎肾小球系膜细胞产生与表达白介素6的研究

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高浓度葡萄糖对人腹膜间皮细胞的损伤作用及对其增殖的影响

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血透前后甲状腺素、胰岛素、钙调蛋白对红细胞膜钙泵的影响

血透前后甲状腺素、胰岛素、钙调蛋白对红细胞膜钙泵的影响林新伟，刘钟明ＴＨＥＥＦＦＥＣＴＳＯＦＴＨＹＲＯＸＩＮＥ，ＣＡＭ－ＯＤＵＬＩＮ．ＡＮＤＩＮＳＵＬＩＮＯＮＣａ（２＋）ＡＴＰａｓｅＡＣＴＩＶＩＴＹＯＦＲＥＤＢＬＯＯＤＣＥＬＬＭＥＭ－ＢＲＡＮＥＤＵＲ...     

尿NAG活性及尿β_2－MG水平测定对SLE患者近端肾小管功能变化的探讨

尿ＮＡＧ活性及尿β＿２－ＭＧ水平测定对ＳＬＥ患者近端肾小管功能变化的探讨孙艺，杨玉秀，周希静，刘轩军ＵＲＩＮＡＲＹＮＡＧＡＣＴＩＶＩＴＹＡＮＤＵＲＩＮＡＲＹβ－ＭＧＬＥＶＥＬＳＡＮＤＴＨＥＩＲＲＥＮＡＬＴＵＢＵＬＡＲＦＵＮＣ－ＴＩＯＮＩＮＰＡＴＩＥＮ...     

肾移植患者血清α_1-微球蛋白测定的临床价值

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Icariin stimulates the osteogenic differentiation of rat bone marrow stromal cells via activating the PI3K–AKT–eNOS–NO–cGMP–PKG

Icariin, a prenylated flavonol glycoside isolated from Epimedii herba, has been found to be a potent stimulator of osteogenic differentiation and has potential application in preventing bone loss. However, the signaling pathway underlying its osteogenic effect remains unclear. We hypothesized that the osteogenic activity of icariin is related to the nitric oxide (NO) signal pathway and PI3K/AKT pathway in its upstream. Rat bone marrow stromal cells (rBMSCs) were cultured in osteogenic medium and treated with icariin or together with L-NAME, ODQ, PDE5, and/or LY294002 (the inhibitor of NOS, sGC, cGMP, and PI3K respectively), and effects were examined on the expression of signal messengers (NOS, NO, sGC, cGMP, PKG and PI3K) and the levels of osteogenic markers (alkaline phosphatase or ALP, osteocalcin and calcified nodules). It was found that icariin dose-dependently increased ALP activity, and treatment at the optimal concentration (10^− 5 M) increased NOS activity, iNOS and eNOS expression, NO production, sGC and cGMP contents and PKG expression besides the phosphorylation of AKT. The addition of L-NAME, ODQ and PDE5 significantly inhibited the icariin effects on above markers respectively. The addition of LY294002 decreased the p-AKT level, NOS activity, eNOS expression and NO production significantly, but had no significant effect on iNOS expression. The addition of any of the four inhibitors also abolished the osteogenic effect of icariin on rBMSCs as indicated by ALP activity, osteocalcin synthesis, calcium deposition and the number and areas of calcified nodules. These results suggest that the osteogenic effect of icariin involves the PI3K–AKT–eNOS–NO–cGMP–PKG signal pathway. Furthermore, dosage response studies showed that icariin at 10^− 6 M (a physiologically achievable concentration in vivo) also activated this signal pathway.     

Nitric oxide generation from L-arginine is required for optimal human peripheral blood lymphocyte DNA synthesis.

We examined whether L-arginine is a substrate for nitric oxide (NO) production by peripheral blood mononuclear cells (MNC) in vitro. Minimal extracellular arginine (0.04 mmol/L) is required for maximal lymphocyte proliferation after phytohemagglutinin stimulation. In the absence of arginine, proliferation was 41% of normal without loss of viability. In contrast, MNC total protein synthesis (as assessed by tritiated leucine incorporation) or lymphokine synthesis (interleukin-2, as assessed by cytotoxic lymphoid line (CTLL) proliferation) were not affected by the absence or presence of arginine in the medium. Exogenous nitric oxide provided as sodium nitroprusside could replace L-arginine for maximal blastogenic proliferation. The addition of NG-monomethyl-L-arginine (NMMA; 0.1 mmol/L), a specific inhibitor of the NO synthetic pathway, significantly reduced DNA synthesis both at 0 and 0.1 mmol/L arginine concentrations; this effect was reversed to 91% of normal by excess arginine (1.0 mmol/L). Homoarginine (0.1 mmol/L; a known substrate for NO production) partially substituted for arginine, and this effect was also abrogated by NMMA. Nitrite levels (an end product of NO metabolism) were reduced when L-arginine was absent or NMMA was added to L-arginine-containing media. Cytosol from phytohemagglutinin-stimulated MNC-enhanced cyclic guanosine monophosphate production in the presence of L-arginine as substrate. The data suggest that the inductive effects of L-arginine on MNC DNA synthesis are not related to its nutrient requirement for protein synthesis, but rather caused by its role as a substrate for NO production. MNC actively synthesize NO during mitogenic proliferation. NO appears to be a promoter of MNC DNA synthesis, probably by its well-known effect as an activator of guanylate cyclase, which increases cyclic guanosine monophosphate levels.     

Propofol stimulates ciliary motility via the nitric oxide-cyclic GMP pathway in cultured rat tracheal epithelial cells

BACKGROUND: Airway ciliary motility is impaired by inhaled anesthetics. Recent reports show that nitric oxide (NO) induces upregulation in ciliary beat frequency (CBF), and others report that propofol, an intravenous anesthetic, stimulates NO release; this raises the possibility that propofol increases CBF by stimulating the NO-cyclic guanosine monophosphate (cGMP) signal pathway. In this study, the authors investigated the effects of propofol on CBF and its relation with the NO-cGMP pathway using the pharmacologic blockers NG-monomethyl-l-arginine (l-NMMA), an NO synthase inhibitor; 1H-[1,2,4]oxidazole[4,3-a]quinoxalin-1-one (ODQ), a soluble guanylyl cyclase inhibitor; and KT5823, a cGMP-dependent protein kinase inhibitor, in cultured rat tracheal epithelial cells. METHODS: Rat tracheal tissues were explanted and cultured for 3-5 days. Images of ciliated cells were videotaped using a phase-contrast microscope. Baseline CBF and CBF 25 min after exposure to propofol or blocker were measured using video analysis. RESULTS: Vehicle (0.1% dimethyl sulfoxide; n = 11) increased CBF by 0.2 +/- 1.7% (mean +/- SD) from baseline. Propofol stimulated CBF significantly (P < 0.01) and dose dependently (1 microM, 2.0 +/- 1. 9%, n = 6; 10 microM, 8.2 +/- 6.7%, n = 9; 100 microM, 14.0 +/- 4.7%, n = 10). Intralipid (0.05%), the clinical vehicle of propofol, did not affect CBF (-0.2 +/- 2.2%; n = 5). The enhancement of CBF with use of 100 microm propofol was abolished (P < 0.01) by coadministration of 10 mmicroM l-NMMA (2.4 +/- 3.6%; n = 5), 100 microM ODQ (-0.3 +/- 2.2%; n = 6) or 30 microM KT5823 (-0.1 +/- 4. 1%; n = 8). l-NMMA, ODQ, or KT5823 alone did not change CBF. CONCLUSIONS: These results show that propofol stimulates CBF viathe NO-cGMP pathway in rat tracheal epithelial cells, suggesting a possible advantage of propofol in decreasing respiratory risk.     

Propofol Stimulates Ciliary Motility via the Nitric Oxide-Cyclic GMP Pathway in Cultured Rat Tracheal Epithelial Cells

Background: Airway ciliary motility is impaired by inhaled anesthetics. Recent reports show that nitric oxide (NO) induces upregulation in ciliary beat frequency (CBF), and others report that propofol, an intravenous anesthetic, stimulates NO release; this raises the possibility that propofol increases CBF by stimulating the NO-cyclic guanosine monophosphate (cGMP) signal pathway. In this study, the authors investigated the effects of propofol on CBF and its relation with the NO-cGMP pathway using the pharmacologic blockers NG-monomethyl-l-arginine (l-NMMA), an NO synthase inhibitor; 1 H-[1,2,4]oxidazole[4,3-a]quinoxalin-1-one (ODQ), a soluble guanylyl cyclase inhibitor; and KT5823, a cGMP-dependent protein kinase inhibitor, in cultured rat tracheal epithelial cells.

Methods: Rat tracheal tissues were explanted and cultured for 3-5 days. Images of ciliated cells were videotaped using a phase-contrast microscope. Baseline CBF and CBF 25 min after exposure to propofol or blocker were measured using video analysis.

Results: Vehicle (0.1% dimethyl sulfoxide; n = 11) increased CBF by 0.2 +/- 1.7% (mean +/- SD) from baseline. Propofol stimulated CBF significantly (P < 0.01) and dose dependently (1 [mu]m, 2.0 +/- 1.9%, n = 6; 10 [mu]m, 8.2 +/- 6.7%, n = 9; 100 [mu]m, 14.0 +/- 4.7%, n = 10). Intralipid (0.05%), the clinical vehicle of propofol, did not affect CBF (-0.2 +/- 2.2%; n = 5). The enhancement of CBF with use of 100 [mu]m propofol was abolished (P < 0.01) by coadministration of 10 m[mu]m l-NMMA (2.4 +/- 3.6%; n = 5), 100 [mu]m ODQ (-0.3 +/- 2.2%; n = 6) or 30 [mu]m KT5823 (-0.1 +/- 4.1%; n = 8). l-NMMA, ODQ, or KT5823 alone did not change CBF.     

The soluble guanylyl cyclase inhibitor ODQ, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, dose-dependently reduces the threshold for isoflurane anesthesia in rats

Nitric oxide (NO), a cell messenger for activating soluble guanylyl cyclase, is produced by activation of the enzyme NO synthase (NOS) in a wide variety of tissues, including the central nervous system. We have previously demonstrated that inhibition of NOS decreased the minimum alveolar anesthesia concentration (MAC) for isoflurane anesthesia. Moving more distally in the NOS-guanylyl cyclase signaling pathway, we investigated the effects of the specific soluble guanylyl cyclase inhibitor ODQ, 1H-(1,2,4)oxadiazolo[4,3-a]quinoxalin-1-one, on anesthetic requirements. The effect of ODQ on the MAC of isoflurane anesthesia was investigated in Sprague-Dawley rats while concurrently monitoring the their arterial blood pressure and heart rate. After determining control MAC, ODQ 20-500 mg/kg was administered intraperitoneally 30 min before re-determining MAC in the presence of the soluble guanylyl cyclase inhibitor. In one series, the effect of 250 mg/kg of ODQ on neuronal cyclase guanosine monophosphate production was determined by microdialysis. ODQ produced a statistically significant, dose-dependent decrease from isoflurane control MAC (maximal effect 52.4% +/- 2.7%). No ceiling effect was observed over the dose-range studied. This reduction in isoflurane MAC was not accompanied by changes in either heart rate or blood pressure. Inhibition of the NOS-guanylyl cyclase signaling pathway decreased the MAC for isoflurane, which suggests that inhibition of this pathway may play a role in the anesthetic state. The MAC reduction by the soluble guanylyl cyclase inhibitor ODQ was devoid of any significant hemodynamic effects. The current findings, along with the previous observations that structurally distinct NOS inhibitors and the nonspecific soluble guanylyl cyclase inhibitor methylene blue decrease the MAC for volatile anesthetics, support that this is an effect specific to the NOS-guanylyl cyclase signaling pathway.     

一氧化氮在门静脉高压症高动力循环中作用的实验研究

目的研究一氧化氮（ＮＯ）在门静脉高压症高血流动力学中的作用。方法用ＳＤ大鼠制备肝内型（ＩＨＰＨ）、肝前型门静脉高压（ＰＨＰＨ）和门腔分流（ＰＣＳ）三组模型,并以正常鼠作为对照组。每一组实验动物再分成三个亚组：ＮＯ生物合成抑制剂左旋单甲基精氨酸（Ｌ－ＮＭＭＡ）组、Ｌ－ＮＭＭＡ加ＮＯ生物合成底物Ｌ－精氨酸组以及生理盐水安慰组。血流动力学研究用放射性微球注射技术。结果ＩＨＰＨ、ＰＨＰＨ和ＰＣＳ鼠均具有心输出量和内脏血流量增加,平均动脉压、周围血管总阻力和内脏血管阻力降低等高血流动力学特征。Ｌ－ＮＭＭＡ能逆转门静脉高压鼠和门腔分流鼠的高血流动力学状态,使之恢复至正常鼠的基础水平,但并未达到正常鼠用Ｌ－ＮＭＭＡ后的水平。如先给予Ｌ－精氨酸,则使Ｌ－ＮＭＭＡ对门静脉高压鼠和门腔分流鼠的心血管作用消失。结论门静脉高压症中ＮＯ过多产生是高动力循环重要的、但并不是唯一的介质。     

Guanylate cyclase activators influence reactivity of human mesenteric superior arteries retrieved and preserved in the same conditions as transplanted kidneys

INTRODUCTION: This study sought to investigate the mechanisms of relaxation induced by the (nitric oxide (NO)-independent soluble guanylyl cyclase (sGC) stimulators 3-[5'-hydroxymethyl-2'-furyl]-1-benzylindazole (YC-1) in human mesenteric arteries relaxed and precontracted with 1 micromol/L 5-hydroxytryptamine (serotonin). MATERIAL AND METHODS: Human mesenteric arteries obtained during kidney retrieval were preserved in the same conditions as transplanted kidneys. All experiments were performed after reperfusion with Krebs buffer in 37 degrees C and 100% oxygen exposure. RESULTS: In endothelium-intact rings, YC-1 (0.001 to 30 mmol/L) caused concentration-dependent relaxation (pEC(50): 6.59 +/- 0.12), which shifted to the right in endothelium-denuded rings. The sGC inhibitor 1H- [1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ 10 mmol/L) partially attenuated the maximal responses to YC-1 (E(max) = 51.30% +/- 3.70%; n = 6) and displaced its curve to the right in intact and denuded vessels. Both, the NO synthesis inhibitor N-nitro-L-arginine methyl ester (100 mmol/L) and the NO scavenger carboxy-2-[4-carboxyphenyl]-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (100 mmol/L) significantly reduced YC-1 relaxation. The sodium pump inhibitor ouabain (1 micromol/L) produced a greater decrease in the vasodilator response of YC-1 (E(max) = 18.7% +/- 4.55%; n = 9). ODQ (10 micromol/L) plus 1 mumol/L ouabain abolished the relaxant response of YC-1 (E(max) = 9.4% +/- 2.94%, n = 9). CONCLUSIONS: This study demonstrated that sodium pump stimulation by YC-1 as an additional mechanism of sGC activation independent of cGMP relaxed human mesenteric artery, including blockade of Ca(2+) influx. Furthermore, this study suggested an ability of NO to mediate relaxation of resistance-like arteries through the activation of soluble guanylate cyclase and K(+) channels.     

Activation of latent transforming growth factor-β1 by nitric oxide in macrophages: Role of soluble guanylate cyclase and MAP kinases

The inducible nitric oxide (NO) synthase and the cytokine transforming growth factor-β1 (TGF-β1), both central modulators of wound healing, interact reciprocally: TGF-β1 generally suppresses iNOS expression, while NO can induce and activate latent TGF-β1. We have shown that chemical NO activates recombinant human latent TGF-β1 by S-nitrosation of the latency-associated peptide (LAP), a cleaved portion of pro-TGF-β1 that maintains TGF-β1 in a biologically-inactive state. We hypothesized that cell-associated TGF-β1 could be activated by NO via known NO-inducible signaling pathways (soluble guanylate cyclase [sGC] and mitogen-activated protein [MAP] kinases). Treatment of mouse RAW 264.7 macrophage-like cells with the NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP) led to a dose- and time-dependent increase in cell-associated active and latent TGF-β1, as assessed by quantitative immunocytochemistry for active TGF-β1 vs. LAP and partially validated by western blot analysis. Treatment with the sGC inhibitor 1,H-[1,2,4]oxadiazole[4,3-a]quinoxalon-1-one (ODQ) reduced both active and latent TGF-β1 dose-dependently. SNAP, in the presence or absence of ODQ or the MAP kinase inhibitors, did not affect steady-state TGF-β1 mRNA levels. Treatment with inhibitors specific for JNK1/2, ERK1/2, and p38 MAP kinases suppressed SNAP-induced active and latent TGF-β1. Treatment with the cell-permeable cGMP analog 8-Br-cGMP increased both active and latent TGF-β1. However, TGF-β1 activation induced by 8-Br-cGMP was not blocked by MAP kinase inhibitors. Our findings suggest that NO activates latent TGF-β1 via activation of sGC and generation of cGMP and separately via MAP kinase activation, and may shed insight into the mechanisms by which both cGMP production and MAP kinase activation enhance wound healing.     

Symmetrical dimethylarginine: a new combined parameter for renal function and extent of coronary artery disease

Symmetrical dimethylarginine (SDMA) is the structural isomer of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine. Whereas the major route of asymmetric dimethylarginine elimination is the hydrolytic degradation by dimethylarginine dimethylaminohydrolase, SDMA is eliminated by renal excretion. SDMA does not directly inhibit NOS but is a competitor of arginine transport. This study showed for the first time that measurement of SDMA can be a marker of estimated GFR and extent of coronary artery disease (CAD). In 97 patients with CAD, SDMA was a marker of estimated GFR. On multiple regression analysis of the CAD parameter stenosis score, SDMA was the only parameter retained. In addition, endothelial cells from the third passage were cultured in medium that contained 70 micromol/L arginine and was incubated for 24 h in the presence of various concentration of SDMA (0, 2, 5, 10, and 100 micromol/L). The levels of nitrate and nitrite in conditioned media, the protein expression of NOS, and the content of reactive oxygen species in endothelial cells were determined. SDMA inhibited dose dependently the NO synthesis in intact endothelial cells, whereas it had no effect on protein expression of NOS. This effect was associated with an increase in reactive oxygen species. Co-incubation with L-arginine but not D-arginine reversed the effect of SDMA on NOS pathway. Our data suggest that SDMA reduced the endothelial NO synthesis, probably by limiting L-arginine supply to NOS. It is concluded that SDMA might be a useful parameter for detecting patients in very early stages of chronic kidney disease and for determining their risk for developing cardiovascular disease.