醛固酮对大鼠主动脉bax基因表达的影响

目的 研究醛固酮对大鼠主动脉bax基因表达的影响.方法 32只SD大鼠随机分为空白对照组、腺瘤组、腺瘤+依普利酮组和腺瘤+肼苯哒嗪组.在每只大鼠皮下埋植的微量渗透泵内注入空白溶剂或醛固酮.8周后通过免疫组化、RT-PCR和Western 印迹检测主动脉bax基因的表达.结果 与对照组相比,腺瘤组大鼠主动脉bax mRNA和蛋白表达都显著上调(P＜0.05);依普利酮能够抑制醛固酮对bax基因的诱导作用(P＜0.05);而肼苯哒嗪虽然可以使大鼠收缩压下降,但不能阻止醛固酮对bax基因的作用.结论 醛固酮通过诱导bax基因表达,调节血管平滑肌细胞凋亡和干预细胞周期进程,可能是其导致血管重构的机制之一.     

依普利酮对高盐诱导的高血压大鼠主动脉内皮型一氧化氮合酶表达及活性的影响

目的:探讨依普利酮对高盐诱导的高血压大鼠主动脉内皮型一氧化氮合酶(e NOS)的表达及活性的影响。方法:50~60 g 4周龄雄性Wistar大鼠随机分为3组:对照(control,C)组用普通饲料饲养16周,高盐饮食(high salt diet,HS)组及依普利酮(eplerenone,Epl)组用5%高盐饲料饲养16周,C组和HS组于末4周给予同等剂量生理盐水灌胃,而Epl组于末4周给予依普利酮40 mg·kg-1·d-1灌胃。每2周检测各组大鼠尾动脉收缩压,16周后处死大鼠,留取主动脉。ELISA法检测醛固酮含量,蛋白免疫印迹法检测盐皮质激素受体(MR)及e NOS蛋白表达水平,化学比色法测定一氧化氮合酶活性,免疫组化染色法观察主动脉e NOS、神经型一氧化氮合酶(n NOS)及MR蛋白表达与定位。结果:(1)高盐饲料饲养8周后,大鼠收缩压即明显升高,并逐渐上升,16周时HS组收缩压较同时点C组明显升高(P0.05);依普利酮灌胃4周后,收缩压比灌胃前明显下降(P0.05)。(2)与C组比较,HS组、Epl组主动脉醛固酮含量明显增加(P0.05),且MR表达明显增加(P0.05)。(3)HS组较C组e NOS蛋白表达减少(P0.05)、结构型一氧化氮合酶(c NOS)活性也降低(P0.05);Epl组较HS组e NOS蛋白表达增加(P0.05)、c NOS活性增高(P0.05)。结论:(1)高盐诱导高血压大鼠的主动脉醛固酮含量明显增加,醛固酮可能通过激动MR降低主动脉e NOS蛋白表达及酶活性。(2)选择性MR拮抗剂依普利酮可恢复e NOS蛋白表达及活性,改善e NOS功能。     

醛固酮及其受体拮抗剂对大鼠主动脉平滑肌TGF-β1表达的影响

目的 观察醛固酮及其受体拮抗剂对大鼠主动脉平滑肌转化生长因子-β1(TGF-β1)表达的影响,初步探讨原发性醛固酮增多症发生血管重构的可能机制.方法 采用皮下给药的方法建立醛固酮增多症模型,其中醛固酮组经微量渗透泵持续释放醛固酮(1 μg/h);拮抗组除给予等量醛固酮外,每日行螺内酯灌胃100 mg/(kg·d);对照组仅泵空白溶剂.尾套法检测大鼠血压,4周后处死所有大鼠,测定血钾、钠、醛固酮浓度及血浆肾素活性.分别采用RT-PCR、Western印迹检测主动脉平滑肌TGF-β1基因的表达.结果 ① 醛固酮组大鼠血压明显升高,血钾下降,血浆肾素活性降低,与对照组相比差异具统计学意义(P<0.01);② 醛固酮组主动脉平滑肌TGF-β1基因的表达水平明显高于对照组(P<0.01).螺内酯可抑制醛固酮的上述作用(P<0.01).结论 醛固酮及其受体拮抗剂螺内酯可能通过调节血管平滑肌TGF-β1的表达,从而影响血管重构的发生.     

苯那普利对高血压大鼠细胞外信号调节激酶和B型钠尿肽的影响

目的：研究苯那普利对自发性高血压大鼠（SHR）细胞外信号调节激酶（ERK）和B型钠尿肽（BNP）的影响。方法：选择Wistar Kyoto（WKY）大鼠作对照，将21只14周龄雄性SHR随机分成3组：未治疗组、肼苯哒嗪组和苯那普利组，每组7只。药物溶于载体（0.5%羧甲基纤维素钠）以灌胃法给予，肼苯哒嗪10 mg·kg-1·d-1，苯那普利10 mg·kg-1·d-1，SHR未治疗组及WKY组灌喂载体，共10周。以左心室重量与体重的比值反映心肌肥厚的程度；用袖带式尾动脉测压法测量大鼠尾动脉血压；分别用Western blotting方法和RT-PCR法半定量测定大鼠心肌中磷酸化ERK（p-ERK）的蛋白表达以及BNP mRNA的含量；酶联免疫吸附法检测大鼠血浆BNP水平。结果：（1） 治疗后SHR苯那普利组和SHR肼苯哒嗪组血压相似，均显著低于SHR未治疗组（P<0.01）。（2） SHR苯那普利组心肌肥厚指数显著低于SHR肼苯哒嗪组和SHR未治疗组(P<0.01) ，与WKY组无显著差异(P>0.05)；SHR肼苯哒嗪组和SHR未治疗组心肌肥厚指数无显著差异(P>0.05)。（3）SHR苯那普利组大鼠心肌p-ERK表达显著低于SHR肼苯哒嗪组和SHR未治疗组(P<0.05) ，与WKY组无显著差异(P>0.05)。SHR肼苯哒嗪组和SHR未治疗组大鼠心肌p-ERK表达无明显差异(P>0.05)。（4） SHR苯那普利组大鼠心肌BNP mRNA和血浆BNP水平显著低于SHR肼苯哒嗪组和SHR未治疗组(P<0.05)，与WKY组无显著差异(P>0.05)；SHR肼苯哒嗪组和SHR未治疗组大鼠心肌BNP mRNA和血浆BNP水平无明显差异(P>0.05)。结论：苯那普利能通过抑制ERK活性逆转心肌肥厚，伴随BNP水平下降；而降压效果相似的肼苯哒嗪不能抑制心肌肥厚，对p-ERK和BNP水平没有影响，提示BNP水平可以反映逆转心肌肥厚药物疗效。     

环孢素A对神经肽Y刺激的大鼠血管平滑肌细胞增殖的影响

目的:观察环孢素A(CsA)对神经肽Y(NPY)诱导的大鼠主动脉平滑肌细胞增殖的影响,以探讨钙调神经磷酸酶(CaN)信号通路在血管平滑肌细胞增殖中的作用。方法:体外培养的大鼠主动脉平滑肌细胞分为3组:(1)NPY组,(2)CsA+NPY组,(3)对照组。检测CaN活性(定磷法)、细胞增殖活度(MTT法)的变化,观察增殖细胞核抗原(PCNA)的表达水平(免疫组化定量技术)。结果:NPY组CaN活性、血管平滑肌细胞增殖活度(吸光度表示),PCNA表达水平(光密度值表示)明显高于对照组(P＜0.01或P＜0.05),CsA+NPY组各项指标明显低于NPY组(P＜0.01或P＜0.05)。结论:环孢素A可显著阻滞神经肽Y刺激的血管平滑肌细胞增殖,这种作用可能通过抑制CaN信号通路所致。     

依普利酮通过下调VEGF表达抑制UUO模型大鼠对侧肾脏血管新生并减轻肾脏纤维化

目的:观察依普利酮抑制单侧输尿管结扎(UUO)模型大鼠对侧肾脏血管新生及肾脏纤维化的作用。方法:30只雄性Wistar大鼠随机分为假手术组、UUO组和依普利酮组,每组10只。除假手术组外,其余各组大鼠行UUO手术复制梗阻性肾病模型。依普利酮组以100 mg·kg~(-1)·d~(-1)加入饲料中喂养,连续给药180 d后摘取对侧肾脏。天狼星红染色观察大鼠肾脏组织纤维化改变;免疫荧光检测血管新生标志物CD34、血管内皮生长因子A(VEGF-A)和VEGF受体2(VEGFR2)的表达;免疫组化检测血清/糖皮质激素调节激酶1(SGK1)、转化生长因子β1(TGF-β1)、肿瘤坏死因子α(TNF-α)、核因子κB(NF-κB)和结缔组织生长因子(CTGF)等促炎、促纤维化细胞因子的表达;RT-qPCR检测SGK1、TGF-β1和NF-κB的mRNA表达;Western blot检测VEGF-A、VEGFR2、SGK1、TNF-α、TGF-β1和CTGF的蛋白表达。结果:UUO大鼠对侧肾脏胶原纤维沉积明显增多,血管增生明显,VEGF-A、VEGFR2、SGK1、TNF-α、TGF-β1和CTGF的表达均显著增强(P0.05);RT-qPCR结果显示,UUO组SGK1、TGF-β1和NF-κB的mRNA表达较假手术组显著升高(P0.05)。依普利酮治疗后,CD34、VEGF-A、VEGFR2、SGK1、TGF-β1和NF-κB的表达均受到抑制(P0.05)。结论:依普利酮可通过下调VEGF的表达抑制UUO大鼠对侧肾脏病理性血管新生并减轻纤维化损伤。     

阿托伐他汀对实验性大鼠心肌纤维化的干预作用及可能机制

目的:探讨阿托伐他汀对醛固酮诱导大鼠心肌纤维化的干预作用及相关机制。方法:40只雄性SD大鼠实验初始阶段行右肾切除,术后给予1%氯化钠饮水4周并随机将大鼠分为4组:对照组(CON组);醛固酮组(ALD组);安体舒通+醛固酮组(SPI+ALD组);阿托伐他汀+醛固酮组(ATO+ALD组)。颈动脉插管测大鼠血压,大鼠心脏组织经苦味酸-天狼猩红染色观察心肌间质胶原容积分数(CVF)和心肌血管周围胶原面积比(PVCA),免疫组化法观察血小板衍生生长因子(PDGF-A,PDGF-B)、血小板衍生生长因子受体(PDGFR-α,PDGFR-β)及单核巨噬细胞抗原(ED-1)的表达,免疫印迹(Western blotting)检测骨桥蛋白(OPN)表达。结果:ALD组、SPI+ALD组和ATO+ALD组大鼠平均动脉压(MABP)均显著高于对照组(P0.01或P0.05);ALD组出现明显纤维化,ALD组的CVF和PVCA指标显著高于其它各组(P0.01或P0.05),SPI+ALD组与ATO+ALD组的CVF和PVCA指标无明显差异(P0.05);ALD组PDGF-A、PDGF-B、PDGFR-α、ED-1及OPN的表达显著高于其它各组(P0.01或P0.05),SPI+ALD组与ATO+ALD组的PDGF-A、PDGF-B、PDGFR-α及OPN指标的表达无明显差异(P0.05),但ATO+ALD组的ED-1指标表达明显低于SPI+ALD组(P0.05),各组PDGFR-β均无显著差异(P0.05)。结论:阿托伐他汀具有抗醛固酮诱导大鼠心肌纤维化作用,其机制可能与减少巨噬细胞浸润及炎症因子OPN表达、部分抑制血小板衍生生长因子及其受体表达有关。     

stathmin和P27kip1在大肠癌中的表达及意义

目的:探讨stathmin蛋白与p27kip1蛋白在大肠癌组织中的表达及意义.方法:应用免疫组织化学SABC法检测25例正常大肠黏膜组织、25例大肠腺瘤组织、47例大肠癌组织中stathmin蛋白及p27kip1蛋白的表达情况.结果:①stathmin蛋白在正常大肠黏膜组织、大肠腺瘤组织及大肠癌组织中的阳性表达率分别为20％、48％、74.47％;正常大肠黏膜组分别与大肠腺瘤组及大肠癌组比较,差异均有统计学意义(P＜0.05);大肠腺瘤组与大肠癌组比较,差异亦有统计学意义(P＜0.05):stathmin蛋白的表达与肿瘤的分化程度、有无淋巴结转移及TNM分期显著相关(P＜0.05).②p27kap1蛋白在正常大肠黏膜组织、大肠腺瘤组织及大肠癌组织中的阳性表达率分别为92％、80％、31.91％.正常大肠黏膜组与大肠癌组比较,差异有统计学意义(P＜0.05);大肠腺瘤组与大肠癌组比较,差异亦有统计学意义(P＜0.05);正常大肠黏膜组与大肠腺瘤组比较,差异无统计学意义(P＞ 0.05);p27kip1蛋白的表达与肿瘤的分化程度及淋巴结转移有关(P＜0.05).③stathmin蛋白的表达与p27kip1蛋白的表达呈负相关(r=--0.695 3,P＜0.01).结论:stathmin蛋白在大肠癌组织中高表达,其表达程度与肿瘤的分化程度、淋巴结转移及TNM分期显著相关,p27kip1蛋白在大肠癌组织中低表达,其表达程度与肿瘤的分化程度及淋巴结转移显著相关,提示stathmin及p27kip1蛋白共同参与了大肠癌的发生、发展;stathmin蛋白可作为一种判断大肠癌恶性程度及侵袭转移的生物学指标.     

辛伐他汀对大鼠血管平滑肌细胞增殖及bFGF与ERK1/2表达的干预作用

目的:观察辛伐他汀对大鼠血管平滑肌细胞(VSMC)碱性成纤维细胞生长因子(bFGF)与细胞外信号调节激酶1/2(ERK1/2)蛋白表达的影响.方法:体外培养大鼠胸主动脉VSMC,MTT法测定细胞增殖活力;Western blot法检测bFGF与ERK1/2蛋白的表达.结果:与对照组比较,辛伐他汀各浓度组细胞增殖活力均显著降低(P＜0.05).与对照组比较,低、中剂量组bFGF、ERK1/2蛋白表达均显著降低(P＜0.05),高剂量组bFGF、ERK1/2蛋白表达进一步降低(P＜0.01);与低剂量组比较,中剂量组bFGF、ERK1/2蛋白的表达均无统计学意义(P＞0.05),高剂量组则显著降低(P＜0.05);高剂量组bFGF、ERK1/2蛋白的表达又较中剂量组显著降低(P＜0.05),并呈剂量依赖性.结论:辛伐他汀能抑制平滑肌细胞增殖,该作用是通过抑制bFGF及其相应信号通路ERK1/2蛋白的表达来实现的,这可能是辛伐他汀治疗动脉粥样硬化、再狭窄及高血压等心血管疾病的重要机制之一.     

脂蛋白相关磷脂酶A_2与兔易损斑块的相关性研究

目的:建立易损斑块动物模型,观察探讨脂蛋白相关磷脂酶A2(Lp-PLA2)、超敏C反应蛋白(hs-CRP)、基质金属蛋白酶(MMP-9)在易损斑块中的表达规律。方法:实验新西兰雄兔48只随机分为对照组、稳定斑块组、p53基因组和p53+药物组。对照组假手术后普通饲料喂养;稳定斑块组、p53基因和p53+药物组行腹主动脉球囊拉伤后高脂喂养12周,p53基因和p53+药物组于10周末行腹主动脉斑块形成处转染人野生型p53基因重组腺病毒载体,p53+药物组于12周末给与中国圆斑蝰蛇毒和组胺药物触发斑块破裂。4组兔于实验第1d和处死前检测Lp-PLA2、hs-CRP、MMP-9、HDL、LDL、VLDL血清指标,处死后取腹主动脉斑块处病理标本并做局部原位杂交、免疫组织化学分析。结果:稳定斑块组、p53基因组和p53基因+药物触发组血清Lp-PLA2、MMP-9第12周末明显高于对照组和实验第1d(P0.05);p53基因组和p53基因+药物触发组血清Lp-PLA2及hs-CRP水平明显高于对照组和稳定斑块组,差别显著(P0.05);p53基因+药物触发组与p53基因组比较血清Lp-PLA2、hs-CRP、MMP-9水平均差别明显(P0.05)。第12周末,病理结果示4组兔分别为正常动脉血管、稳定粥样硬化斑块、易损斑块、破裂斑块模型,在p53基因组和p53基因+药物触发组纤维帽厚度明显低于稳定斑块组(P0.05);p53基因+药物触发组斑块破裂、血栓形成明显高于p53基因组。血清Lp-PLA2与斑块纤维帽厚度呈明显负相关性(r=-0.710,P0.01),hs-CRP、MMP-9与纤维帽厚度无明显相关关系(P0.05)。结论:在已建立的动脉粥样硬化动物易损斑块模型上,动脉血清与组织Lp-PLA2、hs-CRP、MMP-9的表达规律表明,Lp-PLA2与斑块的不稳定性相关性好,结合hs-CRP、MMP-9检测可更好阐释斑块的性质;为发现易损斑块并预测斑块稳定性提供了基础实验依据。     

Eplerenone reduces oxidative stress and enhances eNOS in SHR: vascular functional and structural consequences

The aim of the present study was to evaluate the effect of the aldosterone receptor antagonist eplerenone on endothelial function, oxidative stress, and structural alterations present in spontaneously hypertensive rats (SHR). To carry out the study, male SHR (18 weeks old) were treated with two doses of eplerenone (30 and 100 mg/kg/day) for 10 weeks. A group of n = 8 untreated SHR was used as a control-vehicle group, and a group of Wistar Kyoto rats (n = 8) was used as a reference of normotensive conditions. Systolic arterial pressure (SAP) was measured by the tail-cuff method. Endothelium-dependent and -independent relaxations, as well as endothelial nitric oxide synthase (eNOS) and the subunit p22phox of NAD(P)H oxidase mRNA expressions, were studied in aorta from SHR untreated or treated with eplerenone. Media/lumen ratio was also calculated in aortic preparations. In addition, levels of reduced glutathione (GSH), oxidized glutathione (GSSG), and malonyl dialdehyde (MDA) were evaluated in liver homogenates. Treatment with eplerenone reduced (p < 0.05) SAP and normalized aortic media/lumen ratio and acetylcholine relaxations. Both doses of the drug enhanced (p < 0.05) eNOS and reduced p22phox mRNA expressions. Similarly, eplerenone increased (p < 0.05) hepatic GSH/GSSG ratio, and reduced (p < 0.05) hepatic MDA levels in a comparable manner. Consequently, it could be concluded that aldosterone participates in the functional and structural vascular alterations of SHR through the diminution of nitric oxide availability and an enhancement of vascular and systemic oxidative stress.     

Aldosterone Modulates Cell Proliferation and Apoptosis in the Neonatal Rat Heart

In the present study, we investigated whether and how the mineralocorticoid receptor antagonist spironolactone affects cardiac growth and development through apoptosis and cell proliferation in the neonatal rat heart. Newborn rat pups were treated with spironolactone (200 mg/kg/d) for 7 days. The cell proliferation was studied by PCNA immunostaining. The treatment with spironolactone decreased proliferating myocytes by 32% (P<0.05), and reduced myocytes apoptosis by 29% (P<0.05). Immunoblot and immunohistochemistry for the expression of p38, p53, clusterin, TGF-β2, and extracellular signal-regulated kinase were performed. In the spironolactone group, p38, p53, clusterin, and TGF-β2 protein expression was significantly decreased (P<0.05). These results indicate that aldosterone inhibition in the developing rat heart induces cardiac growth impairment by decreasing proliferation and apoptosis of myocytes.     

Differential anxiolytic effect of enalapril and losartan in normotensive and renal hypertensive rats

The effect of angiotensin-converting enzyme (ACE) inhibitor enalapril (EPL) (2 and 4 mg/kg), angiotensin (AT) II receptor antagonist losartan (LRN) (5 and 10 mg/kg), and anxiolytic drug diazepam (DZP) (0.5 mg/kg) on anxiety parameters were evaluated in experimentally induced renal hypertensive rats (RHR). Renal hypertension was induced in Wistar strain male albino rats weighing 200-250 g by following the method of Goldblatt. The animals having systolic blood pressure more than 180-210 mm Hg were subjected to open-field exploratory behaviour, elevated plus maze behaviour, and social interaction tests of anxiety. The RHR showed hyperactivity in open-field behaviour and anxiogenicity in elevated plus maze and social interaction tests. Losartan (5 and 10 mg/kg) and DZP (0.5 mg/kg) significantly attenuated the hyperactivity and anxiogenic behaviour in experimentally induced hypertensive rats and induced anxiolysis in normotensive rats (NTR). Enalapril reversed the hypertension-induced alteration only at higher dose (4 mg/kg) and failed to show any effect in NTR. It can be concluded that renin angiotensin aldosterone system (RAAS) has a significant role on behaviour, and LRN has shown better effect in reversing the hyperactivity and anxiogenicity in the experimentally induced hypertensive rats, indicating a possible role of AT receptor in the mediation of anxiolysis.     

ERK在慢性哮喘大鼠气道平滑肌细胞增殖中的作用

目的：观察细胞外信号调节蛋白激酶(ERK)在慢性哮喘大鼠气道平滑肌细胞的表达，以探讨ERK信号通路在气道平滑肌增殖中的作用。方法：病理图像分析慢性哮喘大鼠气道重塑，免疫组化法检测ERK和PCNA在肺内表达，激光共聚焦显微镜分析ERK1/2、磷酸化ERK1/2和PCNA在气道平滑肌的共表达，免疫印迹和原位杂交检测气道平滑肌中ERK和PCNA蛋白以及mRNA的表达。结果：慢性哮喘大鼠有气道平滑肌层增厚，出现结构重塑。ERK和PCNA在肺内表达增强，同时在气道平滑肌上有ERK和PCNA蛋白与mRNA表达增加。结论：ERK可能是介导慢性哮喘气道重建中平滑肌增殖的重要信号通路之一。     

Spironolactone prevents alterations associated with cardiac hypertrophy produced by isoproterenol in rats: involvement of serum- and glucocorticoid-regulated kinase type 1

Persistent β-adrenergic receptor stimulation with isoproterenol is associated with cardiac hypertrophy as well as cardiac synthesis of angiotensin II. Serum- and glucocorticoid-regulated kinase type 1 (SGK-1) is a key mediator in structural, functional and molecular cardiac effects of aldosterone in rats. This study was designed to investigate the cardiac effects of the mineralocorticoid receptor antagonist spironolactone on the response to isoproterenol treatment in rats, as well as the involvement of the main mediator of cellular aldosterone action, SGK-1, in the heart. Male Wistar rats received isoproterenol (3 mg kg(-1) day(-1)) or vehicle for 15 days. Half of the animals in each group were simultaneously treated with spironolactone (200 mg kg(-1) day(-1)). Systolic and diastolic blood pressures were not significantly different among groups. Treatment with spironolactone normalized the increased left ventricular end-diastolic pressure observed in isoproterenol-treated rats. Isoproterenol treatment induced cardiac hypertrophy and increased collagen content, both of which were normalized by spironolactone treatment. The mRNA levels of transforming growth factor β, connective tissue growth factor, matrix metalloprotease 2, matrix metalloprotease inhibitor 2, tumour necrosis factor α, interleukin 1β, p22phox and xanthine dehydrogenase were increased (P < 0.05) in isoproterenol-treated rats, and this effect was prevented by spironolactone (P < 0.05). Spironolactone also reduced the elevated SGK-1 expression in isoproterenol-treated rats. The observed reduction of the principal mediator of aldosterone cellular actions, SGK-1, by spironolactone in hearts from isoproterenol-treated rats suggests a role of mineralocorticoids in the cardiac hypertrophy, fibrosis, inflammation, oxidation and diastolic dysfunction induced by isoproterenol treatment in rats.     

三七总皂苷通过Notch3/Hes-1/p27Kip1信号通路抑制低氧性肺动脉高压大鼠肺血管重构

目的：探讨Notch3/Hes-1/p27^Kip1信号通路与低氧性肺动脉高压大鼠肺血管重构的关系及三七总皂苷(PNS)的干预作用。方法：将SPF级雄性SD大鼠采用随机编号分为3组：正常组(C组),低氧组(H组)和PNS组(P组),检测肺动脉压,称量右心室重量,HE染色和Masson染色观察肺血管重构情况,RT-qPCR检测大鼠肺组织中Notch3、Hes-1和p27^Kip1的mRNA表达水平,Western blot检测大鼠肺组织中Notch3、Hes-1、p27^Kip1,增殖细胞核抗原(PCNA)和caspase-3的蛋白水平。结果：与C组相比,H组大鼠的肺动脉压和右心室肥厚指数明显增加;肺血管重构现象明显;Notch3、Hes-1和PCNA的蛋白水平增加,p27^Kip1和caspase-3的蛋白水平降低;Notch3和Hes-1的mRNA表达增加,p27^Kip1的mRNA表达降低(P<0.05)。经PNS干预后,与H组相比,P组大鼠的肺动脉压和右心室肥厚指数降低;肺血...     

Cartilage dysplasia and tissue mineralization in the rat following administration of a FGF receptor tyrosine kinase inhibitor

PD176067 is a reversible and selective inhibitor of fibroblast growth factor receptor tyrosine kinase, and was in preclinical development as an angiogenesis inhibitor for the treatment of solid tumors. A 14-day oral toxicity study of PD176067 in young female rats (7 weeks old) was conducted at doses of 2.5, 5, and 10 mg/kg/day (15, 30, and 60 mg/m(2), respectively). Skeletal changes, and vascular and soft tissue mineralization were observed as primary drug-related toxicities. To determine if these changes are specific to young, rapidly growing animals with increased vascular and osseous development, PD176067 was administered to mature (11 months old) rats. Female rats received PD176067 by gavage for 14 days at doses of 2.5, 5, and 10 mg/kg/day and necropsied on day 15. Clinical signs of toxicity were seen at > or =5 mg/kg and one death occurred at 10 mg/kg. Physeal dysplasia (distal femur, proximal tibia, sternum) occurred in all drug-treated animals and was characterized by dose-related increased thickness of the zones of chondrocyte proliferation and hypertrophy, and marked thickening of the zone of ossification. Cartilage hyperplasia was characterized by proliferation of chondrocytes along margins of the synchondrosis and subperiosteum of sternebrae. Serum phosphorus levels increased 47% and 166% at 5 and 10 mg/kg, respectively. Mineralization of cardiac myocytes, aorta, various arteries, renal tubules, and gastric mucosa and muscularis was seen at 10 mg/kg, and consistent with the presence of calcium-phosphorus deposition. Physeal changes occurred at similar plasma PD176067 exposures in young and mature rats (AUC > or = 4.83 microg.hr/mL). PD176067 produced morphologically similar lesions in young and adult rats.