CPU86017对肥厚豚鼠心室肌细胞L-型钙电流的影响

目的:观察药物CPU86017对左-甲状腺素(L-thy)所致的肥厚豚鼠心室肌细胞L-型钙电流的影响.方法:ip L-thy,诱导豚鼠心肌肥厚,用全细胞膜片钳技术测定CPU86017对心室肌细胞L-型钙电流强度和密度的影响.结果:终浓度为30μmol/L的CPU86017对正常豚鼠心室肌细胞L-型钙电流强度的抑制率达74.21%;肥厚组,终浓度为30.0,10.0,3.3 μmol/LCPU86017均能明显抑制钙电流强度,抑制率分别为67.94%,43.25%,27.07%.结论:CPU86017可抑制正常和肥厚豚鼠心室肌细胞膜上的L-型钙电流,可减轻肥厚所致的钙超载,有利于预防病变心脏的心律失常.     

Endothelin receptor antagonist CPU0213 and vitamin E reverse downregulation of FKBP12.6 and SERCA2a: a role of hyperphosphorylation of PKCepsilon

Downregulation of FKBP12.6 and sarcoplasmic reticulum Ca(2+) ATPase (SERCA2a) contributes to sudden cardiac death and heart failure. We aimed to test the hypothesis that (i) downregulation of FKBP12.6 and SERCA2a can be taken as molecular markers for drug interventions and (ii) such downregulation is produced by crosstalk between endothelin-reactive oxygen species and beta-adrenoceptors stimulation, mediated by hyperphosphorylation of protein kinase Cvarepsilon (PKCvarepsilon). Rat cardiomyocytes were incubated with isoproterenol (1 microM), endothelin-1 (0.1 microM) or hydrogen peroxide (10 microM) for 18 h, resulting in downregulation of mRNA and protein of FKBP12.6 and SERCA2a, as well as upregulation of PKCvarepsilon mRNA and phosphorylated PKCvarepsilon protein. These changes were reversed by an application of either propranolol (1 microM), endothelin receptor antagonist CPU0213 (1 microM) or vitamin E (1 microM). As indicated by the fluorescent dye Fluo3, diastolic [Ca(2+)](i) in rat ventricular myocytes was increased after incubation with isoproterenol (0.1 microM). The increased [Ca(2+)](i) in diastole was dramatically decreased by CPU0213. Thus, the downregulation of FKBP12.6 and SERCA2a, and hyperphosphorylation of PKCvarepsilon, appear to be related to crosstalk between over-activated endothelin-reactive oxygen species and a beta-adrenoceptor pathway. CPU0213 is beneficial in treating cardiac insufficiency and preventing cardiac arrhythmias possibly by normalizing hyperphosphorylation of PKCvarepsilon and abnormal FKBP12.6 and SERCA2a. The antioxidant activity of vitamin E was sufficient to normalize the levels of FKBP12.6 and SERCA2a and phosphorylation of PKCvarepsilon. Thus by testing with biomarkers FKBP12.6 and SERCA2a, we have shown that the endothelin receptor antagonist CPU0213 and the antioxidant vitamin E may relieve risk of lethal arrhythmias and heart failure by suppressing PKCvarepsilon.     

浅谈EDIUS Pro纯软件非线性编辑系统在医学教育中的应用

在医学教育技术中，“CPU＋GPU＋刻录机”模式的纯软件编辑系统已成为实际应用中的主流。文章介绍了EDIUS Pro软件非线性编辑系统在医学教育教学中的应用现状，指出其具有稳定可靠、输出格式灵活等优势，在教学、科研领域发挥着重要的作用。     

CPU 86017 suppression of arrhythmias induced by ischemia/reperfusion,ouabain, aconitine,and elevation of ventricular fibrillatory threshold

Protection by CPU 86017 against reperfusion-induced arrhythmias was studied in Langendorff perfused hearts and anesthetized rats. Inhibition of arrhythmias induced by ouabain and aconitine was observed, and the influence of CPU 86017 on ventricular fibrillation threshold (VFT) was determined. CPU 86017 exerted a dose-dependent antiarrhythmic effect in animal models. In Langendorff's perfused hearts, CPU 86017 significantly reduced the incidence and duration of ventricular fibrillation and ventricular tachycardia, as well as arrhythmic scores in a dose-dependent manner. The approximate ED₅₀ of CPU 86017 against ventricular fibrillation was 2.10 μM. The antiarrhythmic effect of CPU 86017 against arrhythmia persisted for more than 6 h. In anaesthetized rats, CPU 86017 provided potent antiarrhythmic and antifibrillatory effects by po or iv routes. CPU 86017 was similar in potency to propafenone by the po route, and 10 times more potent than lidocaine by the iv route. CPU 86017 significantly attenuated the exaggerated arrhythmia and ventricular fibrillation in hypertrophic hearts induced by 1-thyroxine. Against ouabain-induced arrhythmias CPU 86017 exerted a dose-dependent inhibitory effect, which was 6.5-fold more potent than berberine. CPU 86017 significantly reduced ventricular fibrillation incidence and prevented the further deterioration of ventricular arrhythmias induced by aconitine. In conclusion, CPU 86017 is a potent antiarrhythmic agent with multiple mechanisms of action. Drug Dev. Res. 39:184–190. © 1997 Wiley-Liss, Inc.     

两种肺动脉高压模型大鼠肺动脉和尾动脉血管活性变化及药物体外干预

目的：考察缺氧及皮下注射野百合碱诱导肺动脉高压模型大鼠肺动脉和尾动脉血管活性变化及药物CPU0213和CPU86017的体外急性给药疗效。方法：建立缺氧及皮下注射野百合碱所致大鼠肺动脉高压模型。造模5周后，大鼠乌拉坦麻醉，经右颈静脉插管，进行血流动力学实验，记录中心静脉压、右心室收缩压等血流动力学指标。随后，处死大鼠，分离肺内动脉和尾部腹侧动脉，进行离体血管环实验，观察分别由乙酰胆碱和苯肾上腺素所致大鼠肺动脉和尾动脉血管舒缩活性的变化以及经CPU0213和CPU86017温孵对病损血管的离体治疗作用。结果：慢性缺氧可致大鼠肺动脉及尾动脉血管收缩增强，而野百合碱致血管收缩削弱。慢性缺氧和注射野百合碱均可致大鼠肺动脉和尾动脉血管舒张削弱。CPU0213和CPU86017温孵能不同程度地改善两种模型大鼠的血管收缩和内皮依赖性舒张功能，CPU0213能部分恢复而CPU86017却进一步削弱两种模型大鼠中KATP介导的血管舒张活性。结论：慢性缺氧和注射野百合碱均损伤血管活性，同时造成尾动脉KATP功能障碍，且慢性缺氧对肺动脉损伤的选择性高于野百合碱。CPU0213体外急性给药对血管活性有较好的改善作用，而CPU86017可部分改善血管活性，但对KATP有阻断作用。     

Reversal of isoproterenol-induced downregulation of phospholamban and FKBP12.6 by CPU0213-mediated antagonism of endothelin receptors

Aim： The downregulation of phospholamban （PLB） and FKBP12.6 as a result of β- receptor activation is involved in the pathway（s） of congestive heart failure. We hypothesized that the endothelin （ET）-1 system may link to downregulated PLB and FKBP12.6. Methods： Rats were subjected to ischemia/reperfusion （I/R） to cause heart failure （HF）. 1 mg/kg isoproterenol （ISO） was injected subcutaneously （sc） for 10 d to worsen HF. 30 mg/kg CPU0213 （sc）, a dual ET receptor （ETAR/ETBR） antagonist was given from d 6 to d 10. On d 11, cardiac function was assessed together with the determination of mRNA levels of ryanodine receptor 2, calstabin-2 （FKBP12.6）, PLB, and sarcoplasmic reticulum Ca^2＋-ATPase. Isolated adult rat ventricular myocytes were incubated with ISO at 1 × 10^-6 mol/L to set up an in vitro model of HF. Propranolol （PRO）, CPU0213, and darusentan （DAR, an ETAR antagonist） were incubated with cardiomyocytes at 1× 10^-5 mol/L or 1× 10^-6 mol/L in the presence of ISO （1×10^-6 mol/L）. Immunocytochemistry and Western blotting were applied for measuring the protein levels of PLB and FKBP12.6. Results： The worsened hemodynamics produced by I/R were exacerbated by ISO pretreatment. The significant downregulation of the gene expression of PLB and FKBP12.6 and worsened cardiac function by ISO were reversed by CPU0213. In vitro ISO 1× 10^-6 mol/L produced a sharp decline of PLB and FKBP12.6 proteins relative to the control. The downregulation of the protein expression was significantly reversed by the ET receptor antagonist CPU0213 or DAR, comparable to that achieved by PRO. Conclusion： This study demonstrates a role of ET in mediating the downregulation of the cardiac Ca^2＋-handling protein by ISO.     

内皮素受体拮抗剂抑制异丙肾上腺素诱导大鼠心肌细胞搏动加速及凋亡

观察内皮素受体拮抗剂CPU0213能否阻断异丙肾上腺素(isoprenaline,ISO)所致大鼠心肌细胞搏动加速及凋亡。分离大鼠心肌细胞。给ISO(10-7M)的同时给CPU0213(10-7、10-6、10-5M),并以普萘洛尔(10-6M)作为阳性药对照,观察各组心肌细胞的搏动次数。采用吖啶橙/碘化丙啶(AO/PI)染色法检测成年大鼠心肌细胞凋亡率的变化。普萘洛尔明显抑制ISO效应(P<0.001)。内皮素受体拮抗剂CPU0213明显抑制ISO所致的心肌细胞搏动和细胞凋亡,且呈浓度依赖性。大剂量CPU0213对ISO生物效应的阻断作用(P<0.001)与普萘洛尔相仿。内皮素受体拮抗剂CPU0213阻断ISO所致的心肌细胞搏动加速和增加细胞凋亡率等生物学效应,提示内皮素介导β-受体效应。     

复方黄芪注射液对小鼠多能造血干细胞(CFU—S)影响的实验研究

将经(60)~Coγ射线和环磷酰胺联合处理后的贫血小鼠随机分为两组,分别腹腔注射复方黄芪注射液及生理盐水,连续6天.第9天检测脾结节、血红蛋白、红细胞、白细胞和骨髓有核细胞,结果显示,用药组的脾结节、白细胞和骨髓有核细胞数明显高于对照组(P<0.01).而血红蛋白含量和红细胞数两组未见明显差异(P>O.05).