小鼠肾小球系膜细胞的增龄性改变及油酸对其影响

目的探讨C57BL／6J小鼠肾小球系膜细胞增龄性改变以及油酸对系膜细胞的影响。方法实验动物采用28月龄、3月龄小鼠，测定小鼠血清肿瘤坏死因子α（TNFα）水平，检测系膜细胞的增殖状况，测定肾小球系膜细胞培养上清中胶原Ⅰ、胶原Ⅳ和基质金属蛋白酶2（MMP-2）的含量，观察油酸对系膜细胞的影响。结果28月龄小鼠与3月龄小鼠比较，血清TNFα水平明显增高，分别为（71．6±17．3）μg／L和（59．7±9．7）μg／L，差异有统计学意义（P〈0．05）；肾小球系膜细胞增殖能力明显增强；细胞培养上清中胶原Ⅰ[（52．1±4．6）ng／1万个细胞对（20．3±3．5）ng／1万个细胞]、胶原Ⅳ[（26．3±3．5）ng／1万个细胞对（7．6±1．3）ng／1万个细胞]的水平明显增高；随着鼠龄的增加，细胞培养上清中MMP-2的活性明显下降。油酸可以刺激小鼠肾小球系膜细胞的增殖和胶原Ⅳ的分泌，尤以28月龄小鼠为著。结论与3月龄小鼠比较，28月龄小鼠的肾小球系膜细胞出现明显硬化病变倾向，油酸可刺激28月龄小鼠肾小球系膜细胞的增殖及胶原的分泌。     

灯盏花对自发性高血压大鼠肾脏保护作用的实验研究

目的 :观察蛋白激酶 C ( PKC)抑制剂——灯盏花对自发性高血压大鼠 ( SHR)肾脏的保护作用。方法 :将 12只 10月龄 SHR随机分为灯盏花 ( SHRD)和生理盐水 ( SHRC)组 ,均以 10 m g/ ( kg· d)腹腔内注射 ,连续8周。测定血压、心率 ,用光镜、电镜观察肾脏结构改变。图像分析仪计算肾小球间质胶原面积、含量。结果 :SHRD组肾脏组织结构均有明显改善 ,肾小球面积校正后的胶原面积 ( GCA/ GA) ,SHRD 组较 SHRC 组降低 14 .87%〔( 14 .66± 1.74 ) % vs( 17.2 2± 2 .0 1) % ,差异有显著性意义 ( P <0 .0 5 )〕。结论 :SHRD 能在降低 SHR血压的同时延缓肾小球硬化发展的作用     

自发性高血压大鼠右心室压、肺动脉压变化的观察

目的观察自发性高血压大鼠右室压、肺动脉压的变化。方法36周鼠龄大鼠wky7只，SHR8只。测定两种大鼠的颈动脉压、右室压、肺动脉压，并进行统计学比较。结果SHR的颈动脉压较WKY非常显著升高（225．3±25．6VS127±15．9mmHg，P〈0．001），右室平均压明显升高（23．1±4．8mmHgVS9．1±2．6mmHg，P〈0．001），SHR肺动脉平均压也明显升高（29．1±8．2VS12．4±2．2mmHg，P〈0．001）。结论36周SHR不仅体动脉压升高，并出现右室压及肺动脉压上升。     

氯沙坦对自发性高血压大鼠阻力血管结构的影响

探讨氯沙坦（Losartan)对自发性高血压大鼠（SHR）阻力血管结构的影响,并观察在高血压血管壁增厚的过程中血管紧张素Ⅱ（AngⅡ）所起的作用。方法：采用6周龄雄性SHR20只,随机分为Losartan治疗组（SHRlos)和对照组（SHR）。另先同系雄性6周龄WKY鼠10只作为正常对照组,6周龄SHRlos给予Losartan30/mg/kg/d,溶于饮水灌胃治疗17周,颈动脉插管,心血电流动力学监护仪测定动脉收缩压,应用计算机图象分析,计算血管壁腔面积经,用光镜和透射电镜观察SHR肠系膜动脉三级分支结构的变化;血管放免法测肾素活性和AngⅡ含量。结果（1）动脉收缩压（SBP）;治疗结束后,SHRlos组血压与SHR组相比明显下降,差异有显著性（P值＜0．05）。（2）肠系膜动脉血管壁腔面积比和透射电镜观察;SHRlos的血管壁腔面积比与SHR相比明显降低,差异有显著性（P＜0．01）,与WKY与SHR相比明显降低,差异有显著性（P＜0．01）,与WKY相比,无显著性差异（P＞0．05）。SHRlos的肠系膜超微结构与WKY相似,SHR的超微结构有异常改变。（3）血浆肾素活性和AngⅡ;血浆肾素活性在WKY和SHR之间无明显差异（P＞0．05）,SHRlot肾素活性高于SHR（P值＜0．05）,SHRlor的AngⅡ水平高于SHR,差异有显著性（P＜0．01）,SHRlos的AngⅡ高于WKY差异有显著性（P＜0．05）。结论：Losartan能有效地降低SHR的血压,同时也掏了SHR在高血压发展过程中伴随的血管壁增厚现象。     

心脏肥大细胞在自发性高血压大鼠心肌重构中的作用

目的探讨心脏肥大细胞在自发性高血压大鼠(SHR)心肌重构中的作用。方法应用病理检查、计算机分析结合逆转录聚合酶链式反应等方法,观察SHR及Wistar-Kyoto大鼠(WKY)收缩压、左室重量指数、心肌细胞直径、肥大细胞密度、心肌胶原容积分数(CVF)、心肌血管周围胶原面积比(PV-CA)和心肌Ⅰ、Ⅲ型胶原mRNA表达水平的变化。肥大细胞密度与左室重量指数、CVF及PVCA之间的关系采用相关分析。结果与WKY比较,SHR收缩压为(206±18)比(108±10)mm Hg(P<0.01);SHR组左室重量指数为(4.6±0.4)比(3.3±0.3)mg/g,(P<0.01);SHR组心肌细胞长径为(17.4±1.9)比(10.0±2.2)μm(P<0.01);SHR组心肌细胞短径为(9.0±2.0)比(5.8±1.7)μm(P<0.01);SHR组肥大细胞密度为(7.4±3.2)比(1.9±1.2)个/mm2(P<0.01),SHR组肥大细胞密度为WKY组的3.9倍。SHR组CVF、PVCA分别为46.4%±7.8%和1.9±0.9,WKY组分别为24.4%±10.7%和0.4±0.1,SHR组明显升高(P<0.01)。SHR组心肌Ⅰ、Ⅲ型胶原mRNA表达相对含量也均明显高于WKY(P<0.01),心脏肥大细胞密度与左室重量指数、CVF及PVCA存在明显的正相关(相关系数分别为0.67、0.87和0.95,P<0.01)。结论心脏肥大细胞密度增加可能是促进SHR心肌重构的重要原因。     

洛沙坦、氨氯地平减轻老年前期自发性高血压大鼠肾小球硬化机制的探讨

目的：探讨洛沙坦（Losartan)与氨氯地平（Amoldipine)对老年前期自发性高血压大鼠（SHR）肾小球损害的保护作用。方法：将SHR随机分为3组，每组10只，实验组给Amlodipine10mg.kg^-1.d^-1或Losartan30 mg.kg^-1.d^-1治疗3个月；未用药组为空白对照，同时以10只WKY大鼠为健康对照组，治疗前后测血压，血尿素氮（BUN），肌酐（Scr)和24h尿蛋白（UP）及血浆血管紧张素II(ATII)，内皮素（ET），心钠素（ANP），利钾脲肽（KP），醛固酮（Ald)水平，观察IV型胶原（CoIV)，层粘连蛋白（LM）在肾脏组织中的表达，结果：SHR大鼠的血压显著增高，有水钠潴留，肾功能明显受损，血浆缩血管物质AT II，ET明显升高；舒血管物质ANP，KP降低；肾组织病理改变显著，肾小球中细胞外基质（ECM）成分CoIV,LM表达显著增加，Amlodipine与Losartan治疗后，血压明显降低，肾功能改善，ATII，KP，ANP升高，Ald，ET降低，肾组织病理改变明显减轻，肾组织中CoIV，LM表达明显减少。结论：ATII，ET，Ald可能参与了SHR肾损害，KP，ANP有拮抗作用，Losartan与Amlodipine能改善已失调的舒／缩血管物质比例，减少肾小球中ECM的聚集，延缓肾硬化，对肾脏具有保护作用。     

血脂变化对OLETF糖尿病大鼠肾小球细胞外基质成分含量的影响

目的：采用OLETF大鼠来观察血脂变化对2型糖尿病鼠肾小球细胞外基质含量的影响。方法：实验动物分为三组即正常对照组，糖尿病和非诺贝特治疗的糖尿病组，非诺贝特20mg.kg^-1.d^-1灌胃22周，用免疫组化的方法检测肾小球细胞外基质成分含量的变化，结果：糖尿病组血清总胆固醇，甘油三酯，极低密度脂蛋白和高密度脂蛋白水平明显高于正常对照（P＜0．05），同时细胞外基质成分（Ⅳ型胶原，层粘连蛋白，纤维连接蛋白）含量亦较正常对照组增加（三者P＜0．01），降脂治疗后肾脏细胞外基质积聚明显减少（与糖尿病未治疗组比P＜0．05），结论：高脂血症可能与糖尿病肾小球硬化的发生有关，降脂治疗能够减缓肾脏的损害从而起到保护肾脏的作用。     

自发性高血压大鼠心肌丝裂素活化蛋白激酶活性增加

新近研究表明丝裂素活化蛋白激酶（MAPK）是细胞增殖肥大的重要酶类，为各种细胞外的生长刺激信号引起细胞内信息传递的共同通路或汇聚点。本文通过观察自发性高血压大鼠（SHR）心肌MAPK活性和心肌肥大的关系，探讨SHR心肌肥大发生的可能细胞内信息传递机制。方法：4个月的SHR和WKY大鼠各8只，以心重／体重的比值表示心肌肥厚的程度，采用胶内磷酸化法测定心肌MAPK活性。结果：与WKY大鼠比较，SHR心肌MAPK活性增加107.0％（P＜0．01），心肌肥大程度增加38．3％（P＜0．01）。心肌MAPK活性与心肌肥大程度呈显著正相关（r=0．708，P＜0．05）。结论：SHR心肌肥厚可能涉及MAPK。     

心脏肥大细胞在自发性高血压大鼠心肌重构中的作用

目的探讨心脏肥大细胞在自发性高血压大鼠(SHR)心肌重构中的作用.方法应用病理检查、计算机分析结合逆转录-聚合酶链式反应等方法,观察SHR及Wistar-Kyoto大鼠(WKY)收缩压、左室重量指数、心肌细胞直径、肥大细胞密度、心肌胶原容积分数(CVF)、心肌血管周围胶原面积比(PV-CA)和心肌Ⅰ、Ⅲ型胶原mRNA表达水平的变化.肥大细胞密度与左室重量指数、CVF及PVCA之间的关系采用相关分析.结果与WKY比较,SHR收缩压为(206±18)比(108±10)mm Hg(P<0.01);SHR组左室重量指数为(4.6±0.4)比(3.3±0.3)mg/g,(P<0.01);SHR组心肌细胞长径为(17.4±1.9)比(10.0±2.2)μm(P<0.01);SHR组心肌细胞短径为(9.0±2.0)比(5.8±1.7)μm(P<0.01);SHR组肥大细胞密度为(7.4±3.2)比(1.9±1.2)个/mm2(P<0.01),SHR组肥大细胞密度为WKY组的3.9倍.SHR组CVF、PVCA分别为46.4%±7.8%和1.9±0.9,WKY组分别为24.4%±10.7%和0.4±0.1,SHR组明显升高(P<0.01).SHR组心肌Ⅰ、Ⅲ型胶原mRNA表达相对含量也均明显高于WKY(P<0.01),心脏肥大细胞密度与左室重量指数、CVF及PVCA存在明显的正相关(相关系数分别为0.67、0.87和0.95,P<0.01).结论心脏肥大细胞密度增加可能是促进SHR心肌重构的重要原因.     

高血压机体外周动脉G-蛋白偶联受体对缩血管物质的反应

目的研究高血压患者及自发性高血压大鼠(SHR)阻力动脉G-蛋白偶联受体对缩血管介质的反应性。方法将实验动脉血管分成高血压患者大网膜动脉组、非高血压患者大网膜动脉组、SHR肠系膜动脉组和Wistar-Kyoto(WKY)大鼠肠系膜动脉组4组。分别将4组动脉切成环置于浴槽中,累加浓度法加入去甲肾上腺素(NE),测定动脉环张力的变化,作量效曲线,考察α受体介导的收缩功能;分别加入5-羟色胺(5-HT)、蛇毒类似物(Sarafotoxin,S6c)、内皮素1(ET-1)3种物质,依次考察5-HT、ETB、ETA3种受体介导的收缩功能。同样试验方法在SHR组及WKY大鼠组用特异性5-HT2A受体拮抗剂氟哌喹酮(Ketanserin),α1受体拮抗剂哌唑嗪和α2受体拮抗剂西萝芙木碱(Rauwolscine)考察5-HT2A受体、α1受体、α2受体在血管收缩中的作用,作量效曲线。结果1)高血压患者大网膜动脉ETB、ETA、α受体激动剂量效曲线的Emax均明显高于非高血压患者(P均<0·01);高血压患者ETB、5-HT、α受体激动剂量效曲线的pEC50明显高于非高血压患者(P<0·01或P<0·05);2)在SHR肠系膜动脉α受体和5-HT受体激动剂量效曲线的Emax明显高于WKY大鼠(P均<0·01);SHRETB、ETA、5-HT受体激动剂量效曲线的pEC50明显高于WKY大鼠(P<0·05或P<0·01),而α受体激动剂量效曲线pEC50明显降低(P<0·01);3)应用氟哌喹酮引起5-HT量效曲线平行右移,在SHR和WKY大鼠,pA2值分别为(9·5±0·1)和(9·4±0·1);哌唑嗪引起NE量效曲线平行右移,在SHR和WKY大鼠,pA2值分别为(11·0±0·2)和(10·9±0·2);西萝芙木碱引起NE量效曲线平行右移,pA2值SHR(7·2±0·2)和WKY大鼠(7·1±0·2)。结论1)高血压机体外周阻力血管的ETB、ETA、5-HT以及α受体介导的收缩作用明显增强;2)在外周阻力血管5-HT主要通过激动5-HT2A受体引起血管收缩,NE主要通过激动α1受体引起血管收缩。     

The presence of genetic hypertension stimulates early renal accumulation of fibronectin in experimental diabetes mellitus

Aims/hypothesis: To investigate the interaction between hypertension and diabetic nephropathy, we studied the renal accumulation of fibronectin in a genetic model of hypertension with streptozotocin-induced diabetes mellitus. Methods: Spontaneously hypertensive rats (SHR) and their genetically normotensive control Wistar Kyoto rats (WKY) were studied at 4 weeks of age. The rats were killed 20 days after the induction of diabetes mellitus. The renal accumulation of fibronectin was estimated using Western blot analysis as well as immunofluorescence technique and confocal microscopy. Results: Blood glucose concentrations were similar in diabetic SHR rats (27 ± 3.3 mmol/l) and WKY rats (25.5 ± 2.7 mmol/l). The systolic blood pressure was higher in both groups of SHR rats than in the control rats. The abundance of renal fibronectin as detected by Western blot analysis was (p < 0.05) higher in the diabetic SHR rats (41.4 ± 15.0 densitometric U, n = 8) than in the control rats, and no difference was observed between diabetic and control WKY rats (20.8 ± 6.2, n = 8) and (27.8 ± 17.2, n = 8). The mean peak intensity of fibronectin signal within the glomerulus as estimated by confocal microscopy was higher (p < 0.05) in the diabetic SHR rats (32.9 ± 3.5) than in control SHR rats (11.9 ± 5.7) or diabetic (7.4 ± 2.2) and control (15.2 ± 7.9) WKY rats. Conclusion/interpretation: In experimental diabetes the presence of genetic hypertension promotes earlier accumulation of renal fibronectin, a matrix protein implicated in renal glomerulosclerosis. [Diabetologia (2001) 44: 2088–2091] Received: 11 January 2001 and in revised form: 30 May 2001     

氯沙坦对自发性高血压大鼠左心室结构改变的实验研究

目的 :探讨氯沙坦 (Los)对自发性高血压大鼠 (SHR)左心室结构的影响。方法 :6周龄Los治疗组 (SHRlos)管饲法给予Los3 0mg kg天。治疗 17周后 ,观察 3组大鼠动脉收缩压 (SBP)、左心室 (LV)壁的厚度、左心室重量 体重 (LVW BW)以及左心室结构的变化 ;血浆放免法测肾素活性和AngⅡ含量。结果 :1 SBP :治疗结束后 ,SHRlos组血压 10 9 15± 11 3 1mmHg( 1mmHg =0 .13 3kPa) ,与对照组 (SHR)血压167 4± 13 0 1mmHg相比明显下降 (P <0 0 1)。 2 SHRlos组的LVW BW、LV壁厚度与SHR组相比明显减少 (P <0 0 1)。SHRlos心肌的超微结构与正常对照组 (WKY)相似。 3 血浆肾素活性在WKY组和SHR组之间无明显差异 (P >0 0 5 )。SHRlos组肾素活性及AngⅡ水平分别高于SHR组 (P <0 0 5 ,P <0 0 1)。结论 :Los能有效地降低SHR的血压 ,具有预防高血压LVH的作用。     

Glomerular dimensions in spontaneously hypertensive rats: effects of AT1 antagonism

OBJECTIVE: A reduction in glomerular number and/or size has been implicated in the development of hypertension. This study investigated whether differences in glomerular number and/or size occur during the development of hypertension in the spontaneously hypertensive rat (SHR) and whether angiotensin II is responsible for any glomerular differences. METHODS: SHR (n=6) and Wistar-Kyoto (WKY) rats (n=6) were administered the angiotensin II type I receptor antagonist TCV-116 from 4 to 10 weeks of age. At 10 weeks of age, the kidneys from these rats and those from untreated SHR (n=6) and WKY rats (n=6) controls were perfusion fixed at physiological pressures and analysed using unbiased stereological techniques. RESULTS: There were no significant differences in glomerular number, glomerular volume or total glomerular volume between SHR and WKY rats. Treatment of SHR with TCV-116 significantly lowered systolic blood pressure but had no significant effect on glomerular number or volume or total glomerular volume. Treatment of WKY rats with TCV-116 reduced systolic blood pressure, body weight, glomerular volume and total glomerular volume; however, total glomerular volume per body weight of treated WKY rats was not significantly different from that of untreated WKY rats. CONCLUSION: There were no differences in glomerular number or volume in SHR compared with WKY rats at 10 weeks of age. We therefore conclude that glomerular changes are not responsible for the development of hypertension in SHR. Angiotensin II, via the type 1 receptor, does not contribute to glomerular growth during the development of hypertension in the SHR.     

Altered insulin-like growth factor-1 and nitric oxide sensitivities in hypertension contribute to vascular hyperplasia

Vascular medial thickening, a hallmark of hypertension, is associated with vascular smooth muscle cell (VSMC) hypertrophy and hyperplasia. Although the precise mechanisms responsible are elusive, we have shown that strain induced regulation of autocrine insulin-like growth factor-1 (IGF-1) and nitric oxide (NO) reciprocally modulate VSMC proliferation. Therefore, we investigated potential IGF-1 and NO abnormalities in young (10-week-old) spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) and their respective VSMC ex vivo. The SHR had increased mean arterial pressure (173 ± 2 v 128 ± 3 mm Hg, n = 24, P < .05) but similar pulse pressures (31 ± 2 v 30 ± 3 mm Hg; P > .05) v WKY. The SHR exhibited increased aortic wall thickness in comparison with WKY (523 ± 16 v 355 ± 17μm; P < .05). No differences were seen in plasma combined NO₂ and NO₃ (NO_x) (0.48 ± 0.11 mmol/L for WKY v 0.58 ± 0.18 mmol/L for SHR) or plasma IGF-1 (1007 ± 28 ng/mL for WKY v 953 ± 26 ng/mL for SHR). Aortic VSMC from SHR displayed enhanced proliferation in comparison with WKY (P < .05). Underlying this enhanced proliferation was altered SHR VSMC sensitivity to the antiproliferative NO donor 2,2"[Hydroxynitrosohydrazono] bis-ethanimine (DETA-NO) (ID₅₀: 270 ± 20 mmol/L for SHR; 150 ± 11 mmol/L for WKY; P < .05). Basal cyclic guanosine monophosphate (cGMP) secretion from SHR VSMC was 65-fold greater than that seen from WKY (P < .001). In response to DETA-NO, cGMP secretion from SHR VSMC increased modestly (1.5-fold; P < .01), whereas treatment of WKY VSMC resulted in a 26-fold (P < .001) increase in cGMP. The SHR VSMC did not respond to exogenous IGF-1, whereas WKY VSMC exhibited a dose dependent increase in proliferation with IGF-1 (10⁻¹⁰ to 10⁻⁷ mol/L). These data suggest that VSMC hyperplasia in early hypertension is not reflected by imbalances in plasma IGF-1 or NO. Rather, altered SHR VSMC sensitivity to NO is likely responsible in part for the observed hyperproliferation seen in early stages of hypertension.     

Effect of Insulin on Norepinephrine Overflow at Peripheral Sympathetic Nerve Endings in Young Spontaneously Hypertensive Rats

To determine how the effect of insulin is related to the development of salt-induced hypertension, and whether a hyporesponse to insulin exists in the peripheral sympathetic nerves of a hypertensive model rat, we measured norepinephrine overflow from the periarterial nerve of isolated mesenteric arteries exposed to insulin in spontaneously hypertensive rats (SHR) as well as Wistar-Kyoto rats (WKY) fed diets that were high and low in salt. Salt loading (diet containing 8% salt for 4 weeks) accelerated the development of hypertension in young, spontaneously hypertensive rats (SHR) (157 ± 5 mm Hg υ 198 ± 4 mm Hg, P < .01) but did not affect the blood pressure of Wistar-Kyoto rats (WKY) (102 ± 7 mm Hg υ 104 ± 6 mm Hg, P = NS). Basal norepinephrine overflow did not differ in the SHR and WKY rats, but the overflow of norepinephrine after periarterial electrical stimulation (8 Hz 1 min.) was significantly greater in SHR (0.806 ± 0.079 ng/g) than in WKY (0.723 ± 0.022 ng/g P < .01). Although insulin reduced the norepinephrine overflow by periarterial nerve stimulation in both WKY and SHR, the decrease with insulin was significantly greater in the SHR than in WKY (−18.4% ± 4.0% υ −32.0% ± 4.6%, P < .05). The inhibitory effect of insulin on norepinephrine overflow was reduced by salt loading in SHR (−8.8% ± 4.0%, P < .05), but not in WKY (−32.5% ± 4.7%, P = NS). Cocaine and ouabain completely blocked the effect of insulin in all four groups. In contrast to insulin, direct stimulation of Na⁺-K⁺ ATPase with a high-potassium buffer (12 mmol/L) reduced NE overflow to the same extent among the four groups. These findings show that SHR have a blunted response to the suppression by insulin of norepinephrine overflow. Salt loading reduced the insulin response at peripheral sympathetic nerves of young SHR, but did not affect that of age-matched WKY. Thus, hyporeactivity to insulin may play a role in the development of salt-induced hypertension in young SHR, possibly through a reduced suppression of norepinephrine overflow from sympathetic nerve endings. Am J Hypertens 1996;9:1119–1125     

Prolonged QT Interval Is Associated with Blood Pressure Rather Than Left Ventricular Mass in Spontaneously Hypertensive Rats

QT interval is prolonged in hypertensive individuals, although the factors responsible for this increase are not completely understood. We questioned whether enhanced left ventricular mass (LVM) or increased systemic blood pressure represents the principal factor determining QT prolongation in the period of development of hypertension and left ventricular hypertrophy (LVH) in spontaneously hypertensive rats (SHR). In 12-and 20-week-old SHR (SHR12 and SHR20) and age-matched normotensive Wistar-Kyoto rats (WKY12 and WKY20), arterial systolic blood pressure (sBP) was measured using tail-cuff technique. Orthogonal Frank ECG was registered in anaesthetized animals in vivo, and bipolar ECG was measured in spontaneously beating isolated hearts in vitro. Progressive increase of sBP and LVM resulted in significant QT prolongation in SHR20 as compared to WKY12, WKY20, and also to SHR12 in vivo (WKY12: 82?±?9 ms, WKY20: 81?±?9 ms, SHR12: 88?±?15 and SHR20: 100?±?10, respectively; p?<?0.05) but not in isolated hearts (WKY20: 196?±?39 ms and SHR20: 220?±?55, respectively; NS). In whole animals, QT duration was positively related to sBP (r?=?0.6842; p?<?0.001) but not to LVM (r?=?0.1632, NS) in SHR20. The results suggest that QT prolongation in SHR developing hypertension and LVH depends on blood pressure rather than increase in LVM. In this period, myocardial hypertrophy is probably the predisposition for QT prolongation, but the significant change manifests only in the presence of elevated systemic factors.     

Anti-hypertensive and renoprotective effects of berberine in spontaneously hypertensive rats

Abstract

Objectives: We aimed to investigate the effects of berberine on renin–angiotensin system (RAS) and pro-inflammatory cytokines, as well as its effects on blood pressure and renal damage in spontaneously hypertensive rats. Methods: Berberine was administrated to spontaneously hypertensive rats (SHR rats) between 3 and 20 weeks of age. Blood pressure was monitored in 3-, 6-, 9-, 12-, 16- and 20-week-old SHR rats and age-matched Wistar Kyoto rats (WKY rats). Besides, we measured levels of angiotensin II, aldosterone and pre-inflammatory cytokines (IL-6, IL-17, IL-23) in serum and kidney, as well as levels of collagen III and collagen IV in kidney and urinary markers of renal injury (osteopontin, kidney-injury-molecule (KIM-1) and albumin) in 3-, 6-, 9-, 12-, 16- and 20-week-old SHR rats and WKY rats. Glomerulosclerosis was also assessed with hematoxylin and eosin staining. Results: SHR rats developed hypertension at the age of 6 weeks and had increased levels of angiotensin II, aldosterone, IL-6, IL-17, IL-23, collagen III, collagen IV, osteopontin, KIM-1 and albumin, as well as more severe glomerulosclerosis, compared to the aged-matched WKY rats. Berberine delayed the onset and attenuated the severity of hypertension, as well as partially inhibited the increases of the above substances in SHR rats. Conclusion: Berberine could delay the onset and attenuate the severity of hypertension, as well as ameliorate hypertension-induced renal damage in SHR rats. Furthermore, berberine could inhibit the activities of RAS and pre-inflammatory cytokines IL-6, IL-17 and IL-23, which are involved in the pathophysiology of hypertension.     

Effects of olmesartan and enalapril at low or high doses on cardiac, renal and vascular interstitial matrix in spontaneously hypertensive rats

We have evaluated the effects of different doses of an angiotensin-converting enzyme (ACE) inhibitor, enalapril (ENA) and of an angiotensin II type 1 receptor blocker olmesartan (OLM), on extracellular matrix of the heart, kidney, aorta and mesenteric artery of spontaneously hypertensive rats (SHR). Forty SHR and eight Wistar-Kyoto controls (WKY) were included in the study. Eight SHR were treated with high-dose OLM 15 mg/kg per day, eight with high-dose ENA 25 mg/kg per day, eight with low-dose OLM 1 mg/kg per day and eight with low-dose ENA (2 mg/kg per day). Eight SHR and eight WKY were kept untreated as controls. Treatment was from age 4 to 12 weeks. Systolic blood pressure (SBP) was measured non-invasively every week. The left ventricular weight to body weight (RLVM) was measured, and the cardiac, aortic and glomerular interstitial collagen content was evaluated using Sirius red staining and image analysis. Mesenteric small arteries were dissected and mounted on a micromyograph, and the media:lumen ratio (M/L) was calculated. Collagen subtypes were evaluated by polarized light microscopy. The SHR treated with high-dose OLM or ENA showed a normalization of SBP. The RLVM was significantly increased in untreated SHR compared with untreated WKY, whereas significantly lower values were observed in the groups of SHR treated with high-dose OLM or ENA. A significant increase in cardiac and glomerular collagen content was observed in untreated SHR. Both high- or low-dose OLM and ENA normalized collagen content in the heart and the kidney. Both high-dose OLM and high-dose ENA normalized M/L ratio; however, OLM proved to be more effective than ENA in normalizing collagen pattern. In fact, aortic collagen content was normalized by both high-dose and low-dose OLM, but only by high-dose ENA. In conclusion, both OLM and ENA were significantly and equally effective in the prevention of cardiac and renal damage in SHR, whereas OLM was more effective than ENA in terms of effects on vascular extracellular matrix.     

Effects of losartan and enalapril at different doses on cardiac and renal interstitial matrix in spontaneously hypertensive rats

We have evaluated the effects of an ACE inhibitor, enalapril (ENA) and of an angiotensin II receptor blocker, losartan (LOS), administered either at hypotensive or non-hypotensive dosage, on the cardiac and renal structure of spontaneously hypertensive rats (SHR). Forty-eight rats were included in the study: eight SHR were treated with low-dose (ld, 1 mg/kg/day) ENA; eight with low-dose (ld, 0.5 mg/kg/day) LOS; eight with high-dose (hd, 25 mg/kg/day) ENA; eight with high-dose (hd, 15 mg/kg/day) LOS; while eight Wistar-Kyoto (WKY) and eight SHR were kept untreated (unt). Treatment was given from the 4th to the 12th week of age. Systolic blood pressure (SBP) was measured non-invasively every week. The left ventricular weight to body weight (RLVM) and the left + right kidney weight (RKW) to body weight was measured, and the cardiac and glomerular interstitial collagen content was evaluated using sirius red staining and image analysis. In addition, cardiac metalloproteinases activity (43 kDa MMP, MMP-2, and MMP-9) was evaluated by zymography. A significant reduction in RLVM was observed in SHR given ENA hd or LOS hd. Cardiac collagen was significantly reduced in SHR ENA hd and SHR LOS hd as well as in SHR LOS ld, but not in SHR ENA ld. The 43 kDa MMP collagenase activity was greater in WKY unt compared with SHR unt, being normalized only in SHR ENA hd. The gelatinase activity of MMP-9 showed a trend similar to 43 kDa MMP, but differences between SHR and WKY unt were only of borderline statistical significance. No difference among groups was observed in MMP-2 activity. No significant differences in RKW was observed between groups. However, the collagen content in the glomerular perivascular space was significantly reduced in all treated groups, including those given ld, compared with SHR unt. In conclusion, LOS and ENA showed a similar preventive effect on the increase of RLVM in SHR, but, at least in part, different effects on the extracellular matrix in different organs, being cardiac collagen less sensitive to low dose (ld) ACE inhibition.     

The effects of single and combined application of ramipril and losartan on renal structure and function in hypertensive rats

The objective of the present study was to investigate the effects of single and combined administration of ramipril and losartan on renal structure and function in spontaneously hypertensive rats (SHRs). Thirty-two 9-week-old SHRs and eight Wistar-Kyoto (WKY) rats were randomly divided into five groups: the WKY control group, the SHR control group, the SHR-ramipril group, the SHR-losartan group, and the SHR-combined mediation group. The rat body weight, SBP, heart rate, and urinary albumin excretion rate (UAER) were measured. (1) The SBP was reduced to the normal level in all groups of rats except for the SHR control group. Combined administration of ramipril and losartan can be reduced to the normal level earlier than single (P < 0.01). (2) The SHR-ramipril group and the SHR-losartan group still experienced a higher UAER than that in the WKY control group (P < 0.01). (3) The renal mass/BW ratio was decreased in the SHR-ramipril group, SHR-losartan group, and SHR-combined medication group compared to that in the SHR control group (P < 0.01). (4) Compared with the SHR control group, the SHR-ramipril group, the SHR-losartan group, and the SHR-combined medication group had a lower percentage of the IOD of glomerular collagen relative to the glomerular area (P < 0.01). (5) The reduction in tubulointerstitial injury score was more significant in the SHR-combined medication group than in the SHR-ramipril group and the SHR-losartan group (P < 0.01). The combination of ramipril and losartan is superior to either single drug in reducing the UAER, resisting glomerular collagen deposition, and protecting renal tubular structure.