吡格列酮对糖尿病大鼠心肌肥厚的改善作用

目的探讨噻唑烷二酮(th iazolid ined ione,TZD)类药物吡格列酮对糖尿病大鼠心肌的保护作用。方法应用链脲佐菌素(streptozotoc in,STZ)诱导大鼠糖尿病模型后,吡格列酮组按20 mg.kg-1.d-1混入大鼠饮用水中。大鼠治疗5wk后,检测左心室重量指数(LVI)、心肌细胞面积及横径、心肌组织羟脯氨酸含量和胶原容积分数(CVF);行HE染色观察实质细胞肥大情况,MASSON染色观察胶原纤维增生情况;透射电镜观察心肌超微结构变化。结果吡格列酮组较糖尿病模型组LVI、心肌细胞面积及横径、左心室羟脯氨酸含量及CVF明显降低(P<0.05);光镜下,吡格列酮组较糖尿病模型组心肌实质细胞肥大和间质胶原蛋白增生程度都明显降低;电镜观察,糖尿病模型组心肌细胞明显肥大、间质胶原纤维大量增生、线粒体肿胀,吡格列酮组结构明显改善。结论吡格列酮对早期糖尿病大鼠心肌肥厚有改善作用。     

吡格列酮的不良反应

通过检索《中国知网》等相关数据库,对吡格列酮的不良反应进行整理和分析,供临床参考.结果应用吡格列酮时可出现水肿、低血糖、贫血、头痛、体重增加等不良反应.医务工作者必须重视其不良反应,以保证患者用药安全、有效.     

吡格列酮对自发性IGT-OLETF大鼠胰岛素抵抗的改善作用

目的研究胰岛素增敏剂吡格列酮（pioglitazone）对自发性IGT-OLETF大鼠胰岛素抵抗的改善作用。方法血糖测定采用葡糖氧化酶法，血胰岛素测定采用放射免疫法，游离脂肪酸（FFA）采用铜试剂显色法。结果 IGT-OLETF大鼠具有明显糖耐量、胰岛素耐量异常，脂代谢紊乱，胰岛素敏感指数显著降低等特征。吡格列酮可明显提高IGT-OLETF大鼠对外源性胰岛素的反应性，改善其高胰岛素血症，降低血甘油三酯（TG）、FFA水平，降低肝脂含量及骨骼肌TG含量，使胰岛素敏感指数基本恢复正常。结论吡格列酮可明显改善IGT-OLETF大鼠的胰岛素抵抗。     

吡格列酮对培养的心肌细胞肥大的抑制作用

目的利用体外培养的乳鼠心肌细胞,观察吡格列酮对高浓度葡萄糖与去甲肾上腺素共同诱导的肥大心肌细胞的影响,进一步推测吡格列酮对糖尿病性心肌肥大的可能作用及作用机制。方法以培养的乳鼠心肌细胞为模型分组给药后,用显微镜目镜计数心肌细胞搏动的频率;用Lowry’s法测心肌细胞的蛋白质含量;用[3H]leucine标记法测定心肌细胞蛋白的合成;利用计算机图象分析系统测心肌细胞的体积。结果吡格列酮在1～10μmol·L-1浓度对25.5mmol·L-1高糖与1μmol·L-1去甲肾上腺素联合诱导的肥大心肌细胞的蛋白含量、蛋白合成及体积均有显著的抑制作用。其抑制肥大的效果比1μmol·L-1维拉帕米更为显著;同时观察到10μmol·L-1吡格列酮同1μmol·L-1维拉帕米一样有抑制心肌细胞搏动的作用。结论吡格列酮能有效抑制高糖与去甲肾上腺素联合诱导的心肌细胞肥大。这种作用可能是通过作用于PPARγ来实现的。     

吡格列酮对高糖高胰岛素诱导的心肌细胞肥大的影响

目的　利用体外培养的乳鼠心肌细胞 ,观察吡格列酮对高浓度葡萄糖与高浓度胰岛素共同诱导的肥大心肌细胞的影响 ,进一步推测吡格列酮对糖尿病并发心肌肥大的可能作用及作用机制。方法　以培养的乳鼠心肌细胞为模型分组给药后 ,用Lowrys法测心肌细胞的蛋白质含量 ;用 [3 H]leucine标记法测定心肌细胞蛋白的合成 ;利用计算机图像分析系统测心肌细胞的体积 ;用显微镜目镜计数心肌细胞搏动的频率。结果　 10 μmol·L-1浓度的吡格列酮在对高糖高胰岛素诱导的肥大心肌细胞的蛋白含量、蛋白合成及体积均有显著的抑制作用。其抑制肥大的效果比维拉帕米更为明显 ;同时观察到吡格列酮同维拉帕米一样有抑制心肌细胞搏动的作用。结论　吡格列酮能有效抑制高糖高胰岛素诱导的心肌细胞肥大。这种作用可能是通过作用于PPARγ来实现的。     

吡格列酮可能致膀胱癌

法国国家健康保险计划（FNHIP）涉及的一项临床研究于2006年—2009年间跟踪随访了150万名糖尿病患者,发现使用Takeda制药公司上市的抗2型糖尿病药物吡格列酮（商品名：Actos）的155535名病人患膀胱癌的风险明显高于使用其他抗糖尿病药物的患者,     

罗格列酮和吡格列酮对大鼠血浆肌钙蛋白Ⅰ水平的影响

目的通过比较给予罗格列酮、吡格列酮后大鼠心脏组织形态、血浆肌钙蛋白(cTnI)的变化,研究罗格列酮和吡格列酮对大鼠心脏的毒性作用。方法健康SD雄性大鼠30只,分为5组,每组6只,分别鼻饲给予罗格列酮10、80mg.kg-1.d-1,吡格列酮4、20mg.kg-1.d-1以及等量蒸馏水,连续4周。给药后麻醉动物,剥离大鼠心脏和胫骨,测定心脏重量指数(心脏重量/体重、心脏重量/胫骨长度);心内取血,测定大鼠cTnI含量。结果与空白对照组比较,罗格列酮80mg.kg-1.d-1组大鼠心脏重量、心脏重量/体重、心脏重量/胫骨长度比值均显著增加(P<0.01),血浆cTnI水平显著升高;罗格列酮10mg.kg-1.d-1组的血浆cTnI水平也明显升高,但低于罗格列酮80mg.kg-1.d-1组,心脏重量指数无显著变化。吡格列酮4和20mg.kg-1.d-1组没有观察到显著的心肌形态学和血浆cTnI水平的变化。结论罗格列酮可呈剂量依赖性的引起大鼠心肌损害和心肌肥大,而吡格列酮未见明显的心肌损害。     

吡格列酮治疗糖耐量异常临床研究

目的评价吡格列酮治疗糖耐量异常的疗效。方法于2004年1—9月,对我科内分泌门诊初诊为糖耐量异常(IGT)患者28例,经饮食控制及运动治疗1个月后,OCTT检查7.8≤2hPG<11.1mmol/L者,给予吡格列酮15mg/d,疗程24周。比较治疗前后BMI、FPG、2hPG、游离脂肪酸、血胰岛素水平等指标。结果IGT经生活方式干预无好转,加用吡格列酮15mg/d治疗后,患者血糖、胰岛素水平均明显降低,游离脂肪酸降低,BMI无明显变化。结论吡格列酮可用于糖耐量异常的干预治疗,疗效可靠,安全性能好。     

吡格列酮对血液透析患者心血管疾病危险因素的影响

【】目的 观察过氧化物酶增殖体激活受体γ(PPARγ)激活剂吡格列酮对维持性血液透析患者心血管疾病危险因素的影响。方法33例维持性血液透析患者应用吡格列酮(30mg/d)治疗8周,分别于用药前、用药8周后观察患者收缩压(SBP)、舒张压(DBP)、血浆低密度脂蛋白(LDLD)、总胆固醇(CHOL)、高敏C反应蛋白(hs-CRP)、超氧化物歧化酶(SOD)、白细胞介素6(IL-6)、同型半胱氨酸(Hcy)、水平。结果 吡格列酮治疗维持性血液透析患者8周后,SBP、DBP、LDLD、CHOL、hs-CRP、IL-6、Hcy水平下降,差异有统计学意义(P＜0.05),SOD水平较治疗前明显上升,差异有统计学意义(P＜0.01)。结论 吡格列酮能改善维持性血液透析患者的心血管疾病危险因素。     

吡格列酮对脂多糖所致大鼠学习记忆障碍的改善作用及其机制

目的研究吡格列酮(Pioglitazone,Pio)对脂多糖引起的大鼠学习记忆障碍和海马CA1区锥体神经元损伤的保护作用。方法大鼠灌胃给予Pio(408、0 mg/kg)3周,脑室内注射LPS(5、30μg),2 d后进行Mor-ris水迷宫定位航行实验,连续训练5 d,第6天进行空间探索实验。行为学实验后,取脑组织,制成石蜡切片,进行尼氏(Nissl)染色和胶质纤维酸蛋白(Glial fibrillary acidic protein,GFAP)免疫组织化学染色,研究海马CA1区锥体神经元形态学改变和星型胶质细胞的活化浸润情况。结果脑内注射LPS可以引起大鼠学习和记忆障碍,表现为大鼠逃避潜伏期较对照组明显延长,大鼠在平台所在象限游泳距离百分比明显较对照组低,这些行为学改变伴随海马CA1区星型胶质细胞和锥体神经元的损伤。治疗组LPS所致的学习记忆损伤减轻,Pio能明显减轻海马CA1区锥体神经元的损伤和星型胶质细胞的浸润。结论吡格列酮能对抗LPS引起的锥体神经元的损伤和星型胶质细胞的活化浸润,从而改善大鼠的学习记忆能力。     

ANP is cleared much faster than BNP in patients with congestive heart failure

Objective To obtain a better understanding of the pharmacokinetics of atrial and brain natriuretic peptides (ANP and BNP, respectively), two peptide mediators used in the treatment of congestive heart failure (CHF). Although both peptides exert their effects by binding to a common receptor (natriuretic peptide receptor A) with about the same affinity, their respective loading and maintenance doses differ. Methods Sixteen CHF patients were randomized to be infused for 2 h with α-human ANP (0.05 μg/kg per minute) or BNP (0.01 μg/kg per minute). Plasma concentrations of both peptides were measured 0, 2, 5, 15, 30, 60 and 120 min post-infusion. The pharmacokinetic parameters were then calculated using a 1-compartment model. Results The plasma BNP concentrations in the ANP and BNP groups before infusion were 464.7 ± 339.8 and 506.8 ± 332.5 pg/ml, respectively. Following infusion, ANP disappeared from the circulation more rapidly than BNP: their plasma half-lives were 2.4 ± 0.7 and 12.1 ± 3.0 min, and their total body clearance volumes were 48.2 ± 24.1 and 10.1 ± 2.7 ml/min per kilogram, respectively. Conclusion ANP has a shorter half-life in the plasma of CHF patients than BNP, which suggests that it controls hemodynamics more readily than BNP.     

Inhibition of Jak2 phosphorylation attenuates pressure overload cardiac hypertrophy

RATIONALE: We examined the role of Jak2 kinase phosphorylation in the development of pressure overload hypertrophy in mice subjected to transverse aortic constriction (TAC) and treated with tyrphostin AG490, a pharmacological inhibitor of Jak2. METHODS: Control mice (sham), subjected to TAC for 15 days (TAC) or to TAC and treated with 48 microg/kg/day i.p. of tyrphostin AG490 (TAC+AG490) were evaluated for morphological, physiological, and molecular changes associated with pressure overload hypertrophy. RESULTS: Mice subjected to TAC alone developed concentric hypertrophy that accompanied activation of the components of the Jak/STAT signaling pathway manifested by an increase in phosphorylation of Jak2 and STAT3. We also observed increased phosphorylation of MAPK p44/p42, p38 MAPK and JNK in the TAC group, as well as, an increase in expression of MKP-1 phosphatase which negatively regulates MAPK kinases. Treatment of aortic constricted mice with tyrphostin AG490 failed to develop hypertrophy and showed a marked reduction in phosphorylation of Jak2 and STAT3. There was, however, in TAC and AG490 treated mice, a notable increase in the phosphorylation state of the MAPK p44/42, whereas MKP-1 phosphatase was downregulated. CONCLUSION: These findings suggest that Jak2 kinase plays an important role in left ventricular remodeling during pressure overload hypertrophy. Pharmacological inhibition of Jak2 kinase during pressure overload blocks the development of concentric hypertrophy.     

Inhibition of Jak2 phosphorylation attenuates pressure overload cardiac hypertrophy

RationaleWe examined the role of Jak2 kinase phosphorylation in the development of pressure overload hypertrophy in mice subjected to transverse aortic constriction (TAC) and treated with tyrphostin AG490, a pharmacological inhibitor of Jak2.MethodsControl mice (sham), subjected to TAC for 15 days (TAC) or to TAC and treated with 48 μg/kg/day i.p. of tyrphostin AG490 (TAC + AG490) were evaluated for morphological, physiological, and molecular changes associated with pressure overload hypertrophy.ResultsMice subjected to TAC alone developed concentric hypertrophy that accompanied activation of the components of the Jak/STAT signaling pathway manifested by an increase in phosphorylation of Jak2 and STAT3. We also observed increased phosphorylation of MAPK p44/p42, p38 MAPK and JNK in the TAC group, as well as, an increase in expression of MKP-1 phosphatase which negatively regulates MAPK kinases. Treatment of aortic constricted mice with tyrphostin AG490 failed to develop hypertrophy and showed a marked reduction in phosphorylation of Jak2 and STAT3. There was, however, in TAC and AG490 treated mice, a notable increase in the phosphorylation state of the MAPK p44/42, whereas MKP-1 phosphatase was downregulated.ConclusionThese findings suggest that Jak2 kinase plays an important role in left ventricular remodeling during pressure overload hypertrophy. Pharmacological inhibition of Jak2 kinase during pressure overload blocks the development of concentric hypertrophy.     

AP-811, a novel ANP-C receptor selective agonist

AP-811 is a derivative of the Phe8-Ile15 region of atrial natriuretic peptide (ANP) and is one of the smallest linear ligands for ANP receptors. The binding and agonist activities of AP-811 have been compared with those of other ANP analogs for the ANP-A and ANP-C receptors. AP–811 binds with a high binding affinity to and is a strong agonist for the ANP-C receptor, indicating that the binding and agonist sites for this receptor are the same or near each other in the ANP sequence. In contrast, AP-811 showed no agonistic effect for the ANP-A receptor, although it could bind to this receptor. Comparing the biological activities of AP-811 with those of other ANP analogs, we propose that the binding and agonist sites for the ANP-A receptor may consist of separate regions of ANP. In conclusion, AP-811 is the smallest C-receptor-selective agonist.     

Inhibition of matrix metalloproteinases prevents cardiac hypertrophy induced by beta-adrenergic stimulation in rats

Insulin-like growth factor (IGF) -I is one of the candidates for cardiac hypertrophy induced by beta-adrenergic stimulation. However, the mechanisms by which the biologic actions of IGF-I are regulated under this condition remain unclear. IGF-I becomes bioavailable for its receptors upon its dissociation from IGF-binding protein (IGFBP) through IGFBP degradation. Because matrix metalloproteinases (MMPs) have been implicated in the degradation of IGFBPs, the authors investigated the role of MMPs in the regulation of the IGF-I action through the degradation of IGFBPs in cardiac hypertrophy induced by beta-adrenergic stimulation. They examined the expression of MMPs in cardiac tissues of rats infused with isoproterenol (3 mg/kg per day), the effect of a MMP inhibitor, SI-27 (5 mg/rat per day), on cardiac hypertrophy, and the expression of IGF-I and IGFBP-3. MMP-1 and -2 activities increased and IGFBP-3 was degraded in heart hypertrophied by isoproterenol. MMP inhibition caused a regression in the myocyte hypertrophy in association with the suppression of both IGF-I protein in myocytes and the degradation of IGFBP-3 protein. These results suggest that the induction of myocyte hypertrophy by isoproterenol is mediated, at least in part, by a modulation of the IGF-I axis.     

ARDS急性期大鼠心脏局部RAS的变化与BNP水平相关性研究

目的观察急性呼吸窘迫综合征（ARDS）急性期大鼠心脏局部肾素-血管紧张素系统（RAS）与脑钠素（BNP）水平的变化,并探讨其间的相关性。方法健康雄性sD大鼠54只,鼠龄12～16周,随机分为三组（每组18只）：假手术组（A组）仅进行气管切开插管和右颈总动脉穿刺置管,尾静脉注射生理盐水0．15mL／kg;ARDS未干预纽（B组）尾静脉注射油酸0．15mL／kg,建立油酸诱导的大鼠ARDS模型;ARDS机械通气治疗组（C组）VT-6mL／kg,RR=60次／min,Fi02—50％,I：E-1：2,PEEP=5cmH20。各组按造模成功后时间又分为a、b、C三个亚组,每组6只。于大鼠ARDS后1h、ARDS后2h、ARDS后4h取左室心肌组织放射免疫法检测血管紧张素I（AngI）、血管紧张素II（AngⅡ）含量及肾素（Renin）活性;ELISA测定血清中BNP水平。将数据进行统计学分析。结果同时间点与A组相比,B、C组AngI、AngII含量及Renin活性均显著增加（P〈0．05）,血清BNP水平明显升高（P〈O．05）。同时间点C组与B组相比,C组AngI、AngII含量及Renin活性均有降低倾向,但差异无统计学意义（P〉0．05）。大鼠心肌局部AngⅡ含量及Renin活性与血清BNP含量呈正相关。结论ARDS可导致激活大鼠心脏局部的RAS。ARDS急性期大鼠心脏局部RAS的变化与BNP水平的变化呈正相关。     

High concentrations of atrial natriuretic peptide and brain natriuretic peptide in rat pericardial fluid and their reduction by reserpine in vivo

We determined concentrations and molecular sizes of natriuretic peptides in rat pericardial fluid and plasma by use of specific radioimmunoassays (RIA) and gel filtration HPLC. Our study shows that pericardial fluid forms a local extracellular storage of immunoreactive (ir) atrial natriuretic peptide (irANP) and brain natriuretic peptide (irBNP) near the heart where these peptides can be found in high concentrations in vivo. The concentrations of irANP, irBNP and NH₂-terminal fragment of proANP (irNT-proANP) in pericardial fluid were 9.8 ± 3.7, 0.49 ± 0.47 and 28.9 ± 11.8 nmol/l, respectively. IrBNP had the lowest (20 ± 11) and irANP the highest (90 ± 32) concentration ratio between pericardial fluid and plasma. The elution positions of irANP, irBNP and irNT-proANP in pericardial fluid and plasma were similar as examined by gel filtration HPLC. Furthermore, we show that the reduction of noradrenaline content of the heart muscle by reserpine reduces concentration of irANP in pericardial fluid by 39.6% and in plasma by 30.3% when compared to respective control group values. The concentration of irBNP is reduced by 44.1 % in pericardial fluid but in plasma its reduction was not statistically significant. Vasoactive peptides released into the interstitial space and from there into pericardial fluid may have a more active role in the regulation of cardiac function than previously considered.     

腺苷A1受体激活在钙调磷酸酶信号通路上对异丙肾上腺素诱导的心肌细胞肥大的抑制作用

目的观察腺苷A1受体激活在钙调磷酸酶(CaN)通路上对异丙肾上腺素(Iso)诱导的心肌细胞肥大的抑制作用及机制。方法体外培养大鼠乳鼠心肌细胞,以Iso 10μmol.L-1诱导心肌细胞肥大,观察腺苷A1受体激动剂R(-)-N6-(2-phenylIsopropyl)adenosine(R-PIA)1μmol.L-1对其作用,进一步探讨钙调神经磷酸酶特异性抑制剂环孢菌素A(CSA)1μmol.L-1、PKA抑制剂cAMP三乙胺盐(RP-cAMPS)1μmol.L-1、百日咳毒素(PTX)5 mg.L-1存在时,腺苷A1受体的激活对心肌细胞肥大的影响。通过Lowry法测心肌细胞蛋白含量;RT-PCR法检测心肌细胞心钠素(ANP)的mRNA表达;Western blot法测心肌细胞CaN的相对表达水平;以Fluo-3/AM为荧光探针,共聚焦显微镜下测量心肌细胞[Ca2+]i瞬变。结果 10μmol.L-1 Iso可以诱导心肌细胞肥大,腺苷A1受体激动剂R-PIA可以使其蛋白含量降低、ANP的mRNA表达减少、CaN相对表达降低、[Ca2+]i荧光强度减小,CSA、RP-cAMPS有类似抑制作用,PTX预处理的情况下,R-PIA对Iso诱导的心肌肥大的抑制作用消失。结论腺苷A1受体可以通过钙调磷酸酶通路抑制Iso诱导的心肌肥大,其机制与降低细胞内[Ca2+]i浓度及CaN表达有关。     

盐酸吡格列酮对鼠心脏成纤维细胞增殖的影响

目的 观察胰岛素增敏剂盐酸吡格列酮(PIO)对Wistar大鼠心脏成纤维细胞(CFs)增殖的抑制作用,探讨其与一氧化氮合酶-一氧化氮(NOS-NO)系统活性的关系.方法 采用胶原酶消化法培养Wistar大鼠的CFs、四氮唑蓝(MTT)比色法测定CFs的增殖情况、硝酸还原酶法测定CFs培养上清NO含量、分光光度计法测定CFs培养上清NOS活性.结果 CFs吸光值(A490值)随PIO干预浓度增加和作用时间延长而减低,呈浓度和时间依赖性;5×10-6 mol/L的PIO干预48 h后,CFs培养上清NO含量(221.7±35.3) μmol/L和NOS活性(15.38±1.82) U/mL高于对照组[(112.1±8.9 μmol/L)和(11.24±0.49) U/mL](P＜0.01).结论 PIO能够抑制大鼠CFs的增殖,具有浓度和时间依赖性,其效应可能是通过上调NOS-NO系统的活性来实现的.     

Effect of pioglitazone on the expression of inflammatory cytokines in attenuating rat cardiomyocyte hypertrophy

Pioglitazone, one of the synthetic peroxisome proliferator-activated receptor (PPARgamma) agonists, has been found to inhibit inflammatory response. However, it is not known yet whether the preventive effect of pioglitazone on cardiac hypertrophy is related to its antiinflammatory function. The objective of this study was to investigate the role of pioglitazone in attenuation of cardiac hypertrophy and its relation to the inhibitory effect on the inflammatory cytokine expression in cultured neonatal rat cardiomyocytes. The mRNA expression of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), interleukin (IL)-1beta, IL-6, and PPARgamma was measured by using RT-PCR. Cardiomyocyte hypertrophy was induced by stimulating angiotensin II (Ang II) and evaluated both by measuring surface area of cardiac myocyte and 3H-leucine incorporation. The expressions of IL-1beta, IL-6, ANP, and BNP were significantly enhanced, whereas that of PPARgamma was significantly reduced in Ang II-induced hypertrophic cardiomyocytes. Pioglitazone decreased cardiac myocyte surface area and inhibited 3H-leucine incorporation into cardiomyocytes. Furthermore, pioglitazone upregulated the suppressed expression of PPARgamma and attenuated the increased IL-1beta and IL-6 expression. The effect of pioglitazone might be associated with PPARgamma activation and the consequent antiinflammatory function in prevention and treatment of cardiac hypertrophy.