实验性2型糖尿病大鼠模型的研究

目的　制作一种与人类 2型糖尿病发病过程类似的动物模型。方法　选体重 16 0～ 180 gWistar大鼠 ,雌雄各半 ,先喂以高脂高糖饲料 4周 ,促发胰岛素抵抗 ,继以小剂量链脲佐菌素 (STZ) (30mg/kg ,每周 1次 )连续腹腔注射 2次 ,诱导建立 2型糖尿病模型。结果　高脂高糖饲料喂养 4周后大鼠空腹胰岛素显著高于对照组(P <0 0 5 ) ,出现胰岛素抵抗 (胰岛素敏感指数ISI =- 5 72± 0 4 3,对照组ISI =- 4 37± 0 6 1,P <0 0 1) ,第 2次注射STZ后大鼠于 1周始出现葡萄糖负荷后 6 0、12 0min血糖显著升高 (P <0 0 1) ,造模成功 ;18周时出现空腹和葡萄糖负荷后血糖均明显升高 (P <0 0 5 ) ,而空腹胰岛素分泌与对照组相比差异无显著性 (P >0 0 5 )。结论　本实验方法建立的 2型糖尿病大鼠模型 ,与人类 2型糖尿病代谢特征相似 ,是研究人类 2型糖尿病较理想的动物模型     

实验性糖尿病肾病大鼠模型建立的优化选择Ⅱ

目的比较几种不同因素组合对大鼠实验性糖尿病肾病(DN)模型建立中几种主要指标的影响,确定建立DN大鼠模型的最佳方案。方法SD大鼠30只,随机分为5组,每组6只,A组为正常对照组,B组为高糖高脂饲料组,C组为高糖高脂饲料+链脲佐菌素(STZ)组,D组为高糖高脂饲料+阿霉素+STZ组,E组为高糖高脂饲料+单肾切除+STZ组。造模12wk后处死大鼠,取血测血脂、糖化血红蛋白、肾功能、醛糖还原酶(AR)、肾小球滤过率(GFR)、超氧化物歧化酶(SOD)及丙二醛(MDA)等各项指标。结果E组大鼠血脂明显升高,GFR及氧自由基水平不仅与正常组有显著差异,并且与其它几个模型组比较也都有显著性差异,尤以AR升高显著。结论以大鼠喂养高糖高脂饲料4wk后单肾切除,2wk后小剂量腹腔注射STZ的模型为最佳。     

链脲佐菌素和高脂肪饲料诱导的实验性2型糖尿病大鼠模型

目的 制备一种发病过程类似人类2型糖尿病的动物模型。方法 雌性Wistar大鼠喂以高脂饲料9周后，继以小剂量链服佐菌素(STZ，25mg／kg，腹腔注射)诱发胰岛素代偿分泌障碍，使之产生高血糖症。结果 高脂饮食后一个月，大鼠出现胰岛素抵抗、高血糖、肥胖。结论 本研究通过饮食方法成功复制出2型糖尿病模型。     

成年SD大鼠糖尿病心肌病模型的建立

目的：探索成年SD大鼠糖尿病心肌病（DCM）模型建立的方法。方法20只健康SD成年大鼠作随机分为DCM组（n=10）、对照组（n=10）。对照组喂养普通饲料,DCM组高脂饲料喂养12周。DCM模型的建立：对照组以枸橼酸缓冲液腹腔注射,DCM组使用等量1%链脲菌素腹腔注射。通过病理组织学证实为DCM心肌病理学改变。结果与对照组比较,DCM组的血清FBG、TC、LDL-C、TG均明显增高（P〈0.05）,而对照组的血清HDL-C较DCM组高（P〈0.05）。与对照组比较,DCM组的大鼠心肌细胞排列紊乱,间质基质集聚与纤维化增多。第6周末,两组的空腹血糖差异无统计学意义（P〉0.05）,DCM组的IRI、胰岛素均高于对照组（P〈0.05）。结论高脂、高糖膳食并小剂量STZ腹腔注射建立DCM模型,其方法成功率高,简单易行。     

多次低剂量链脲佐菌素诱导大鼠糖尿病模型的方法学研究

目的分别探讨造模后不同时间点禁食、大鼠性别和多次低剂量链脲佐菌素(STZ)对大鼠血糖及糖尿病模型成模率的影响。方法分别一次性腹腔注射(ip)STZ 30 mg.kg-160、62、64 h后,于晚8时、10时、12时禁食,次日晨8时测大鼠空腹血糖,计算糖尿病(空腹血糖≥7.0 mmol.L-1)成模率;记录雌鼠和雄鼠一次性ip STZ 30 mg.kg-1后糖尿病的成模情况;首次分别ip STZ(20、25、30、40和50 mg.kg-1),不成模大鼠再次ip STZ(20 mg.kg-1),比较各组间糖尿病成模情况、血糖水平和6周内大鼠死亡情况。结果晚10时和12时禁食组糖尿病成模数(均为8只)较晚8时禁食组成模数(4只)增加1倍,成模大鼠血糖值进一步升高;雄鼠糖尿病成模数(7只)较雌鼠成模数(4只)增加将近1倍,成模大鼠血糖值进一步升高;首次分别腹腔注射STZ 25、30、40和50 mg.kg-1各组大鼠累计成模率明显高于首剂20 mg.kg-1组;首剂50 mg.kg-1组6周内成模大鼠死亡率明显高于首剂STZ 25和30 mg.kg-1组。结论测大鼠空腹血糖前于晚10～12时禁食优于晚8时禁食;采用雄鼠造模优于雌鼠;首剂采用STZ 25～30 mg.kg-1腹腔注射,未成模大鼠继续采用STZ 20mg.kg-1腹腔注射,糖尿病成模率高,死亡率低。     

大鼠糖尿病肾病模型建立影响因素研究

目的采用高脂饲料喂养联合低剂量链脲菌素(STZ)制备糖尿病肾病(DN)大鼠模型,探讨高脂饲料喂养时间和STZ剂量对模型成模率和死亡率的影响,确定建立DN大鼠模型的最佳方案。方法雄性SD大鼠先给予高脂饲料喂养,诱发胰岛素抵抗,再给予不同剂量STZ腹腔注射,建立DN模型。结果高脂饲料4周+STZ 40 mg·kg-1和高脂6周+STZ 35 mg·kg-1制备的糖尿病大鼠模型,其血糖值、相对肾重、胶原蛋白和TGF-β1的表达和正常组比较都差异有显著性,但高脂饲料4周+STZ40 mg·kg-1的造模死亡率较高。结论高脂喂养6周后腹腔注射低剂量STZ 35 mg·kg-1制备的DN大鼠模型,成模率高,模型稳定。     

克糖特对糖尿病模型小鼠血糖的影响

目的:研究克糖特(KTF)对糖尿病模型小鼠血糖的影响,并初步探讨其降低小鼠血糖的作用机制。方法:建立链脲霉素(STZ)致糖尿病小鼠模型。将小鼠随机分为5组(n=10),分别用格列本脲(50 mg·kg~(-1))、高、中、低剂量克糖特和0.9%氯化钠溶液(0.1 ml/10g体重)灌胃15d。15d后测定正常小鼠的血糖水平,并在相应时间测定STZ致糖尿病小鼠模型空腹血糖(FBG)、药后2h血糖(2h BG)、胰岛素水平,同时对STZ所致糖尿病小鼠进行胰腺病理组织学检查。结果:克糖特对正常小鼠血糖水平无影响,能够显著降低STZ模型小鼠空腹血糖(与模型组比较降糖率可达24.39%,P<0.05～0.01)和药后2 h BG(P<0.05),明显提高胰岛素水平(P<0.05～0.01),保护胰岛β细胞。结论:克糖特对STZ引起的高血糖有较好的降糖作用,其作用机制可能与改善受损的胰岛细胞功能,促进胰岛素分泌有关。     

链脲佐菌素联合高脂高糖饲料诱导糖尿病大鼠模型的建立

目的探讨链脲佐菌素(STZ)联合高脂高糖饲料诱导Wistar大鼠糖尿病模型的方法。方法 Wistar雄性大鼠45只,均分为三组。A组为高脂高糖饲料联合STZ诱导组,B组为高脂高糖饲料喂养组,C组为正常饲料喂养组。高脂高糖饲料喂养4周后,在0.5h内将STZ缓冲液通过腹腔注射至A组大鼠,STZ的剂量为50mg/kg。观察三组大鼠血糖、体重及血胰岛素变化情况。结果A、B组大鼠血糖均升高,与C组比较差异有统计学意义(P<0.05);A组较B组血糖升高更为明显[(20.5±0.5)mmol/L vs.(11.3±0.7)mmol/L](P<0.05)。A、B组大鼠体重及胰岛素水平较C组减低(P<0.05),A组较B组血胰岛素降低更为明显[(26.7±6.8)mmol/L vs.(30.3±11.3)mmol/L](P<0.05)。结论 STZ联合高脂高糖饲料能够成功诱导出糖尿病大鼠模型,方法简便。     

链脲菌素制备2型糖尿病大鼠模型的研究

目的优化建立操作简便、条件稳定、成模率高、造模周期短、具有胰岛素抵抗的2型糖尿病模型。方法 6周龄大鼠以高糖高脂饲料喂养4周后,禁水禁食18 h,一次性腹腔注射1%链脲菌素(STZ)溶液35mg·kg-1,注射后继续禁水禁食1 h;对照组腹腔注射相同剂量柠檬酸-柠檬酸钠缓冲液。结果 STZ注射后14 d空腹血糖值稳定,口服葡萄糖耐量实验符合糖尿病标准,空腹胰岛素水平接近对照组,成模率93%,模型死亡率0%。结论成功制备了2型糖尿病模型,优化了2型糖尿病造模过程及提高了成模率。     

糖尿病性肥胖大鼠模型的建立及西布曲明对其治疗作用的研究

目的:研究链脲佐菌素(STZ)联合高营养饲料诱导的大鼠糖尿病性肥胖模型的特点,以及盐酸西布曲明对此种模型的治疗作用。方法:先用小剂量STZ(25mg/kg)尾静脉注射诱导大鼠产生糖尿病,再用高营养饲料喂养4个月建立糖尿病性肥胖模型。盐酸西布曲明4mg/kg灌胃治疗17d,给药期间定时测定体重及摄食量,15d时测定糖耐量,实验终点时测定体重、内脏脂肪及右比目鱼肌重量;取血分离血清测定血脂、血糖和血清胰岛素水平,并计算胰岛素抵抗指数。结果:模型组大鼠体重、内脏脂肪重量及系数均显著升高,而右比目鱼肌系数显著降低;空腹血糖、血胰岛素水平显著升高,并出现糖耐量异常及胰岛素抵抗;TG水平显著升高,而高密度脂蛋白胆固醇(HDL-C)水平显著降低。盐酸西布曲明可减轻糖尿病肥胖大鼠的体重、内脏脂肪含量和系数,改善高胰岛素血症和胰岛素抵抗,降低血TG水平,同时升高HDL-C水平。对右比目鱼肌系数,血糖、总胆固醇和低密度脂蛋白胆固醇(LDL-C)水平,以及糖耐量无明显影响。结论:STZ联合高营养饲料可成功诱导糖尿病性肥胖的大鼠模型,盐酸西布曲明对大鼠糖尿病肥胖具有一定的治疗作用。     

畅胃胶囊对肝郁症大鼠治疗作用的实验研究

目的：观察畅胃胶囊对肝郁症大鼠的治疗作用。方法：采用长期夹大鼠尾部，并同时用肾上腺素复制肝郁症动物模型，以畅胃胶囊灌胃治疗。结果：肝郁症大鼠皮毛疏松无光泽，性情暴躁，相互嘶咬，精神不振，食欲减退，胃浆膜血管增大，增粗等，肾上腺重量显著增加，经畅胃肠囊治疗后，大鼠的异常症状显著减轻，肾上腺重量显著降低。结论：畅胃胶囊对肝郁症大鼠具有治疗作用。     

THE EFFECTS OF MAZINDOL AND 46-034 (SANDOZ) ON GLUCOSE OXIDATION AND INSULIN BINDING BY RAT ISOLATED FAT CELLS

1. The anorexic agent mazindol and its major metabolite 46-034 (Sandoz) in high concentrations (>0·4 mM) abolished basal and insulin-stimulated conversion of 1-¹⁴C-glucose to ¹⁴CO₂ by rat isolated fat cells. 2. High concentrations (1 mM) also inhibited specific binding of ¹²⁵I-insulin to fat cells. 3. The observed effects appeared to be due in part to perturbation of the plasma membrane since there was a rise in the lactate dehydrogenase content of the incubation medium, increased ¹²⁵I-insulin degradation and a reduction in cellular tritiated water space. 4. These effects are unlikely to be relevant to the therapeutic action of mazindol.     

金牡蛎对大鼠高脂血症脂肪肝的防治作用

探讨金牡蛎、牛磺酸对肥胖性高脂血症脂肪肝的防治作用。金牡蛎和牛磺酸在适当减轻造模的物体重的同时,显著降低共血脂和肝组织脂肪含量,并显著改善肝组织病理学变化,结论：金牡蛎及其提取物牛磺酸可有效防治大鼠实验性高脂血症和脂肪肝。     

Anti-diabetic effects of DA-11004, a synthetic idpc inhibitor in high fat high sucrose Diet-Fed C57BL/6J mice

DA-11004 is a synthetic, potent NADP-dependent isocitrate dehydrogenase (IDPc) inhibitor where IC50 for IDPc is 1.49 microM. The purpose of this study was to evaluate the effects of DA-11004 on the high fat high sucrose (HF)-induced obesity in male C57BL/6J mice. After completing a 8-week period of experimentation, the mice were sacrificed 1 hr after the last DA-11004 treatment and their blood, liver, and adipose tissues (epididymal and retroperitoneal fat) were collected. There was a significant difference in the pattern of increasing body weight between the HF control and the DA-11004 group. In the DA-11004 (100 mg/kg) treated group the increase in body weight significantly declined and a content of epididymal fat and retroperitoneal fat was also significantly decreased as opposed to the HF control. DA-11004 (100 mg/ kg) inhibited the IDPc activity, and thus, NADPH levels in plasma and the levels of free fatty acid (FFA) or glucose in plasma were less than the levels of the HF control group. In conclusion, DA-11004 inhibited the fatty acid synthesis in adipose tissues via IDPc inhibition, and it decreased the plasma glucose levels and FFA in HF diet-induced obesity of C57BL/6J mice.     

RENAL,BILIARY AND INTESTINAL CLEARANCE OF SOTALOL ENANTIOMERS IN RAT MODEL: EVIDENCE OF INTESTINAL EXSORPTION

Biliary clearance (Cl_b ) of sotalol (STL) enantiomers was assessed in anaesthetized Sprague–Dawley rats (419±9 g, mean±SEM, n=4) following administration of a 10 mg kg⁻¹ IV dose of the racemate. Cl_b for S- and R-STL (0·0675±0·0090 and 0·0662±0·0089 mL min⁻¹ kg⁻¹, respectively) represented approximately 0·3% of systemic clearance (Cl_s ) values for S- and R-STL (20·4±2·2 and 20·7±2·0 mL min⁻¹ kg⁻¹, respectively). Bile:plasma concentration ratios at 1, 2, and 3 h post-dose were approximately 1·4, 1·3, and 1·2 for both STL enantiomers. Renal clearance (Cl_r ) and intestinal clearance (Cl_i ) of STL enantiomers were assessed in conscious Sprague–Dawley rats (325 g, n=4) following administration of a 10 mg kg⁻¹ IV dose of the racemate. STL enantiomers were predominantly eliminated intact in the urine: Cl_r for S- and R-STL (26·3±3·2 and 28·7±4·2 mL min⁻¹ kg⁻¹, respectively) accounted for approximately 96% of Cl_s for S- and R-STL (27·5±3·3 and 29·9±4·2 mL min⁻¹ kg⁻¹, respectively). Approximately 4% of the dose was recovered in the faeces, corresponding to Cl_i values of 1·16±0·17 and 1·26±0·19 mL min⁻¹ kg⁻¹ for S- and R-STL, respectively. Total recovery of the administered dose in urine and faeces was 99·7±0·2 and 99·8±0·5% for S- and R-STL, respectively. It is concluded from these results in the rat model that (i) STL enantiomers are predominantly eliminated intact in urine; (ii) STL enantiomers are excreted intact in bile, and to a much larger extent in the faeces, thus suggesting the presence of intestinal exsorption of STL; (iii) STL does not appear to be metabolized; and (iv) Cl_s , Cl_r , Cl_b , and Cl_i are negligibly stereoselective.     

ON THE ROLE OF SEROTONIN IN THE PATHOGENESIS OF PULMONARY HYPERTENSION INDUCED BY ANORECTIC DRUGS; AN EXPERIMENTAL STUDY IN THE ISOLATED PERFUSED RAT LUNG II. FENFLURAMINE, MAZINDOL, MEFENOREX, PHENTERMINE AND R 800

1. The influence of the anorectic drugs fenfluramine, mazindol, mefenorex, phentermine and R 800, an experimental compound, on pulmonary vascular resistance has been studied in the isolated, perfused rat lung. 2. R 800 caused a strong vasoconstriction, which was not antagonized by methysergide or phentolamine; the other drugs listed did not alter vascular resistance. 3. Mazindol and phentermine significantly prolonged the vasoconstrictive effect of serotonin due to inhibition of its metabolic breakdown. 4. Although fenfluramine inhibited serotonin metabolism it also prevented the vasoconstrictive effect of serotonin, due to its ability to act as a serotonin antagonist. 5. Mefenorex did not affect pulmonary vascular resistance, either directly or indirectly via a serotoninergic mechanism.     

PHARMACOKINETICS OF THE ENANTIOMERS OF VERAPAMIL AFTER INTRAVENOUS AND ORAL ADMINISTRATION OF RACEMIC VERAPAMIL IN A RAT MODEL

Verapamil is a chiral calcium channel blocking drug which is useful clinically as the racemate in treating hypertension and arrhythmia. The published pharmacokinetic data for verapamil enantiomers in the rat model are limited. Utilizing a stereospecific high-performance liquid chromatographic (HPLC) assay, the enantiomeric disposition of verapamil is reported after intravenous (1·0 mg kg⁻¹) and oral (10 mg kg⁻¹) administration of racemic verapamil to the rat model. After intravenous administration the systemic clearance of R-verapamil was significantly greater than that of S-verapamil; 34·9 ± 7 against 2·7 ± 3·7 mL min⁻¹ kg⁻¹ (mean ± SD), respectively. After oral administration, the clearance of R-verapamil was significantly greater than that of S-verapamil, 889 ± 294 against 351 ± 109 mL min⁻¹ kg⁻¹, respectively. The apparent oral bioavailability of S-verapamil was greater than that of R-verapamil, 0·074 ± 0·031 against 0·041 ± 0·011, respectively. These data suggest that the disposition of verapamil in the rat is stereoselective; verapamil undergoes extensive stereoselective first-pass clearance after oral administration and the direction of stereoselectivity in plasma is opposite to that observed in the human. © 1997 John Wiley & Sons, Ltd.     

MOBILIZATION OF LEAD BY CALCIUM VERSENATE AND DIMERCAPTOSUCCINATE IN THE RAT

1. Calcium disodium ethylenediaminetetraacetate (CaNa₂ EDTA) and meso-2,3-dimercaptosuccinic acid (DMSA) individually and in permutation-combination in various doses (0.1,0.2 and 0.4 mmol/kg bodyweight) were investigated for their efficacy to mobilize lead from vital tissues into urine and faeces and to restore the lead-sensitive biochemical parameters in lead pre-exposed rats with a view to develop the most acceptable treatment regimen for lead poisoning with a minimal loss of endogenous essential elements. 2. The combined therapy was more effective than a single chelator treatment. 3. The combination of 0.2 mmol/kg CaNa₂EDTA + 0.4 mmol/kg DMSA caused a lower depletion of zinc, calcium and iron but possessed almost equal capability to that of 0.4 mmol/kg CaNa₂EDTA + 0.4 mmol/kg DMSA to produce urinary as well as faecal excretion of lead, to reduce the tissue burden of lead, including that of the brain, and to reverse lead-induced biochemical alterations. 4. The combination of 0.2 mmol/kg CaNa₂EDTA + 0.4 mmol/kg DMSA has shown a definite improvement over previously reported combinations in terms of removal of lead from tissues, particularly the brain, restoration of urinary delta-aminolevulinic acid levels and a decrease in the loss of body zinc and is, therefore, recommended for the treatment of lead intoxication.     

INFLUENCE OF CIMETIDINE COADMINISTRATION ON THE PHARMACOKINETICS OF SOTALOL ENANTIOMERS IN AN ANAESTHETIZED RAT MODEL: EVIDENCE SUPPORTING ACTIVE RENAL EXCRETION OF SOTALOL

Sotalol (STL) is an amphoteric, chiral β-adrenergic blocking drug useful in the treatment of both hypertension and ventricular arrhythmias. In the human and rat, STL enantiomers are predominantly cleared from the body by the kidney as intact drug. The renal clearance (Cl_r) of STL enantiomers substantially exceeds the glomerular filtration rate (GFR) in the human and rat. In this report, the hypothesis that STL enantiomers are excreted by an active renal transport system was investigated in the rat by coadministering racemic STL (10 mg kg⁻¹) with cimetidine, an inhibitor of renal tubular secretion of organic cations. To compare the effects of short-term and sustained cimetidine exposure on STL enantiomer disposition, cimetidine was administered either as a single bolus (30 mg kg⁻¹, n=7) immediately prior to the STL dose, or as a 30 mg kg⁻¹ bolus plus a 50 mg kg⁻¹ infusion over the 6 h study period (n=7). Blood and urine samples were collected over 6 h, during which time anaesthesia was maintained via intraperitoneal administration of pentobarbital. Cimetidine bolus and cimetidine infusion reduced STL enantiomer Cl_r by 43 and 59%, respectively, compared with respective saline controls. Significant stereoselectivity was observed in the cimetidine infusion group: systemic clearance, Cl_r (R>S), and AUC (S>R), although the magnitude of stereoselectivity was less than 5%. This study supports the hypothesis that STL enantiomers are predominantly cleared from the rat via a renal cationic transport mechanism, and that this system can be competitively inhibited by the presence of cimetidine.