自发性高血压大鼠中枢血管紧张素Ⅱ的变化对中枢肾上腺素和去甲肾上腺素含量的影响

自发性高血压大鼠中枢肾上腺能递质含量异常,然其原因仍不清楚。本工作发现:12周龄易卒中型自发性高血压大鼠(SHRSP)脑桥,下丘脑后部、尾核中去甲肾上腺素(NE)含量及延髓、下丘脑前部,下丘脑后部中肾上腺素(E)含量均高于同龄 Wista Kyoto 大鼠(WKY),SHRSP 中枢 AⅡ含量亦明显高于同龄 WKY;向8周龄 SHRSP 和 WKY 侧脑室慢性灌注巯甲丙脯氨酸,不仅降低动脉血压及各脑区AⅡ含量,亦使中枢 NE 及 E 水平下降,但巯甲丙脯氨酸对 SHRSP 的影响远较对 WKY 明显。结果提示:SHRSP 中枢肾上腺能递质含量增加可能与 SHRSP 中枢 AⅡ量含量升高以及 SHRSP 中枢 AⅡ对中枢肾上腺能递质的促释放调节机制明显易化有关。     

高血压大鼠主动脉条血管反应性的变化

血管对加压物质反应性的增高是高血压发病机制中的一个重要方面,但其机制迄今尚未完全阐明。近年来关于血管组织内肾素-血管紧张素系统在高血压发生中的作用受到广泛注意,然而有关实验报道还不多。本实验对高血压大鼠主动脉组织中去甲肾上腺素(NE)与血管紧张素Ⅱ(AⅡ)的含量及其对此两种物质的反应性进行了研究,以探讨高血压发病的血管机制。     

自发性高血压大鼠中枢去甲肾上腺素与血管紧张素Ⅱ的含量及相互关系

用荧光分光与放射免疫法,分别测定自发性高血压大鼠(SHR)与正常血压 WKY:大鼠脑内不同部位的去甲肾上腺素(NE)与血管紧张素Ⅱ(AⅠ)的含量。用尾筒法测量清醒大鼠尾动脉压。结果发现第8周龄 SHR 的血压及延脑、脑桥、下丘脑与尾核 NE 与 A Ⅱ含量和同龄WKY 相比,无明显差异。第12周龄以后,SHR 的血压逐渐升高,至20周龄时不再升高,维持在接近16周龄时的水平。可是 WKY 的血压无明显变化。在血压升高的早期与后期SHR 延脑、脑桥、下丘脑及尾核内 AⅡ含量显著高于 WKY,但 NE 的含量变化却不同,在早期与 WKY 有明显差异,而在高血压的后期无明显差异。提示在 SHR 高血压的早期 NE与 A Ⅱ均起作用,而在后期只 A Ⅱ起作用。向 SHR 侧脑室分别注射 Captopril 与6-OHDA,均引起血压下降,延脑与下丘脑内 AⅡ与 NE 含量均下降,两者表现同向关系。SHR 脑内AⅡ与 NE 这种同向变化在高血压的发生中可能起重要作用。     

丹参酮结合有氧运动对高血压大鼠血管功能的影响及作用机制分析

摘要 目的：分析丹参酮ⅡA（TIIA）结合有氧运动（AE）对高血压大鼠血管功能的影响及作用机制。方法：选择30只自发性高血压大鼠（SHR）,随机分为模型组、TⅡA组、TⅡA+AE组,每组10只,另选取10只健康大鼠作为对照组。TⅡA组大鼠给予20 mg/kg的TⅡA,TⅡA+AE组在此基础上进行中等强度的有氧运动,模型组和健康对照组大鼠均灌胃给予等体积的生理盐水溶液。观察各组大鼠收缩压（SBP）和舒张压（DBP）的变化,HE染色观察胸主动脉组织形态学变化,测定血管舒缩功能,检测血清血管紧张素Ⅱ（AngⅡ）、内皮素-1（ET-1）和一氧化氮（NO）的表达水平,测定胸主动脉中腺苷酸活化蛋白激酶（AMPK）、核因子E2相关因子（Nrf2）、血红素加氧酶1（HO-1）、醌氧化还原酶1（NQO-1）蛋白的相对表达。结果：TⅡA组和TⅡA+AE组大鼠的SBP和DBP均低于同期的模型组大鼠;TⅡA+AE组大鼠的SBP和DBP在第8周时均低于同期TⅡA组大鼠（P<0.05）;与模型组相比,在1×10^-7、1×10^-6和1×10^-5mol/L的PE浓度下TⅡA组和TⅡA+AE组大鼠胸主动脉血管环的收缩率均降低,且TⅡA+AE组大鼠低于同浓度下的TⅡA组（P<0.05）;在1×10^-8、1×10^-7和1×10^-6的Ach浓度下TⅡA组和TⅡA+AE组大鼠胸主动脉血管环的舒张率高于模型组,且ⅡA+AE组大鼠高于同浓度下的TⅡA组（P<0.05）;TⅡA组和TⅡA+AE组大鼠血清AngⅡ和ET-1的表达水平低于模型组、NO的表达水平高于模型组（P<0.05）;与TⅡA组相比,TⅡA+AE组大鼠血清AngⅡ和ET-1的表达水平较低、NO的表达水平较高（P<0.05）;TⅡA组和TⅡA+AE组大鼠胸主动脉中AMPK、Nrf2、HO-1、和NQO-1蛋白的相对表达显于模型组,且TⅡA+AE组高于TⅡA组（P<0.05）。结论：TⅡA联合有氧运动可降低SHR的血压,改善血管舒缩功能和内皮功能,其机制可能与AMPK/Nrf2信号通路有关。     

妊娠早期人胎盘绒毛血管紧张素的研究

用生化提取、放射免疫测定及离体培养技术研究了妊娠早期人胎盘绒毛血管紧张素的含量与 变化,观察了血管紧张素Ⅱ对早孕胎盘人绒毛膜促性腺激素（ｈＣＧ）分泌的影响,并用ＡＢＣ法探 讨了血管紧张素Ⅱ的免疫组织化学定位。结果表明：妊娠６～１０周的人胎盘绒毛组织均检测到血管 紧张素,其含量随妊娠周龄增加而升高;离体培养的６～９周人胎盘绒毛亦能分泌血管紧张素,培 液中血管紧张素的水平与妊娠周龄呈平行关系;然而妊娠６～１０周母血中血管紧张素的含量无明 显变化。免疫组织化学结果指出早孕胎盘绒毛有ＡⅡ免疫阳性反应物质．免疫阳性物主要分布在合 体滋养层细胞内;在离体培养条件下,血管紧张素Ⅱ能刺激离体培养的人胎盘绒毛ｈＣＧ的分泌,其 受体阻断剂 ［Ｓａｒ１Ｉｉｅ８］ ＡｎｇⅡ（１０－８～１１－７ｍｏｌ／Ｌ）对 ｈＣＧ分泌无影响,当 ［Ｓａｒ１　Ｉｉｅ８］ ＡｎｇⅡ浓度 达１０－６ｍｏｌ／Ｌ时,绒毛ｈＣＧ分泌量显著降低。     

肾素—血管紧张素系统——应激激素反应系统

各种急性与慢性庆激时,循环血中及脑、心血管、肾上腺等组织中血管紧张素Ⅱ（ＡⅡ）显著增多;人剧烈运动后血浆ＡⅡ与皮质醇一样均剧烈增加,在慢性应激性高血压动物循环及组织中,ＡⅡ含量持续地增高。还发现高浓度ＡⅡ对肾上腺糖皮质激素的分泌有直接的刺激作用,而组织ＡⅡ含量增多又受肾上腺素能β受体的激发。根据近年来的系列工作,并结合文献,我们认为ＡⅡ是一种重要的应激激素;肾素－血管紧张素系统是一个应激激素反应系     

自发性高血压大鼠心脏中ACE,AT1R,ACE2和MasR表达变化的研究

目的：通过观察血管紧张素转化酶（ACE）和血管紧张素转化酶2（ACE2）在Wistar-京都种大鼠（WKY）和自发性高血压（SHR）大鼠心脏组织中表达的差异,探讨ACE与ACE2在自发性高血压大鼠高血压形成中的作用。方法：自由饲喂14周龄WKY和SHR雄性大鼠一周后,用BSN-II多通道无创测压系统测定大鼠收缩压（SBP）、舒张压（DBP）、心率（HR）并称重;放免法测定血浆中血管血管紧张素Ⅱ（AngII）含量;Real-time PCR测定心脏组织中ACE,ATI受体（ATIR）,ACE2和Mas受体（MasR）mRNA的表达水平;Western blot法检测心脏组织中ACE2的蛋白表达。结果：SHR大鼠SBP和DBP均显著高于WKY大鼠（P〈0.01）;两组大鼠心率和体重无显著差异（P〉0.05）;SHR大鼠血浆中AngII含量显著升高（P〈0.05）;与WKY大鼠相比,SHR大鼠心脏中ACE mRNA表达均显著升高（P〈0.05）,ACE2的mRNA和蛋白表达水平均显著下降（P〈0.05）;心脏组织中AT1R和MasR的mRNA表达没有显著性变化（P〉0.05）。结论：ACE与ACE2表达失调是SHR大鼠高血压形成的主要原因之一,其机理可能与局部组织RAS系统ACE-AngII-AT1R通路过度活跃,ACE2-Ang（1-7）-MasR通路相对不足有关。     

急性压力超负荷后心肌cAMP与肾素血管紧张素系统活化的关系

为阐明急性压力超负荷后心肌细胞内ｃＡＭＰ浓度升高和心肌肾素血管紧张素系统活化之间是否存在内在因果联系,用腹主动脉缩窄的方法建立急性压力超负荷大鼠模型。发现在术后１ｈ心肌组织中血管紧张素转换酶（ＡＣＥ）ｍＲＮＡ及蛋白表达均显著增加,ＡＣＥ活性及血管紧张素Ⅱ（ＡｎｇⅡ）含量也明显升高,并在高水平。同时,心肌组织ｃＡＭＰ含量于术后０．５ｈ明显增加,术后５ｄ时达峰值,术后３０ｄ降至正常。在心肌细胞培养的基     

压力超负荷大鼠心肌内分泌因子活化及相互作用

目的：探讨压力超负荷是否诱导心肌内分泌活化及相互间的作用。方法：用放免法及比色法检测腹主动脉缩窄高血压大鼠心肌组织中血管紧张素Ⅱ、内皮素和一氧化氮含量的变化,并观察卡普托利对它们的作用。结果：腹主动脉缩窄大鼠动脉血压逐渐升高,术后４ ｈ 即显著升高;术后３０ ｍｉｎ 心肌组织中血管紧张素Ⅱ含量显著升高,此后并保持在高水平;心肌内皮素含量于术后２４ ｈ 开始并持续显著升高;心肌中一氧化氮含量却于术后１０ ｍｉｎ 迅速显著降低并持续受抑。小剂量卡普托利对大鼠血压无明显影响,但可完全抑制心肌中血管紧张素Ⅱ的升高,而且使内皮素活化滞后、一氧化氮含量降低减轻。结论：压力超负荷可诱导心肌血管紧张素Ⅱ、内皮素含量升高及一氧化氮含量降低,而心肌血管紧张素Ⅱ可加速内皮素活化、加重一氧化氮含量降低     

血管紧张素转换酶2-血管紧张素1-7-Mas轴对血管作用的研究进展

血管紧张素转换酶2（ACE2）和Mas受体的发现使人们对肾素-血管紧张素（RAS）有了更全面的认识。ACE2可水解血管紧张素Ⅰ和血管紧张素Ⅱ直接或间接生成血管紧张素1-7（Ang 1-7）,并与高血压的形成密切相关。Ang 1-7主要通过Mas受体引起血管舒张、抑制细胞增殖。ACE2-Ang1-7-Mas轴的发现为RAS的研究、高血压等心血管疾病的防治和新药开发提供了新的思路和方向。     

Feeding blueberry diets inhibits angiotensin II-converting enzyme (ACE) activity in spontaneously hypertensive stroke-prone rats

Feeding flavonoid-rich blueberries to spontaneously hypertensive stroke-prone rats (SHRSP) lowers blood pressure. To determine whether this is due to inhibition of angiotensin-converting enzyme (ACE) activity, as seen with other flavanoid-rich foods, we fed blueberries to SHRSP and normotensive rats and analyzed ACE activity in blood and tissues. After 2 weeks on a control diet, the hypertensive rats showed 56% higher levels of ACE activity in blood as compared with the normotensive rats (p < 0.05). Feeding a 3% blueberry diet for 2 weeks lowered ACE activity in the SHRSP (p < 0.05) but not the normotensive rats. ACE activity in plasma of SHRSP was no longer elevated at weeks 4 and 6, but blueberry feeding inhibited ACE in SHRSP after 6 weeks. Blueberry diets had no effect on ACE activity in lung, testis, kidney, or aorta. Our results suggest that dietary blueberries may be effective in managing early stages of hypertension, partially due to an inhibition of soluble ACE activity.     

Muscarinic cholinoceptors and choline acetyltransferase activity in the hypothalamus of spontaneously hypertensive rats

To study the role of central cholinergic mechanisms in hypertension, we have determined muscarinic receptors using [³H](-)quinuclidinyl benzilate (QNB) and choline acetyltransferase (ChAT) activity in the brain regions of spontaneously hypertensive rats (SHR), stroke-prone SHR (SHRSP) and renal hypertensive rats. The number of muscarinic receptors was significantly (33–38%) elevated in the hypothalamus of SHR and SHRSP at the ages of 16 and 24 weeks compared to that of Wistar-Kyoto rats (WKY). An increased density of muscarinic receptors was consistently observed in the prehypertensive (5 weeks) and developmental (10 weeks) stages of hypertension. In contrast, in the hypothalamus of rats with renal hypertension there was no muscarinic receptor alteration. The receptor alteration in the SHRSP hypothalamus was not abolished by a chronic hypotensive treatment which prevented the development of hypertension, suggesting that an enhancement of the muscarinic receptors in spontaneous hypertension does not occur secondarily to the elevation of blood pressure. The hypothalamus of SHR and SHRSP at the ages of 5 and 24 weeks showed significantly less activity of ChAT. These data demonstrate that there is a specific increase in muscarinic receptors and a decrease in cholinergic activity in the hypothalamus of SHR and SHRSP. Thus, the present study suggests an important role for hypothalamic cholinergic receptors in the pathogenesis of spontaneous hypertension.     

正常大鼠植入高血压大鼠肾脏后 动脉血压的变化

本实验对12周龄的自发性高血压大鼠(spontaneously hypertensive rat,SHR)及其对照组Wistar Kyoto (WKY)大鼠进行了肾脏移植的研究, 并观察受肾移植大鼠动脉血压的变化以及免疫抑制剂对动脉血压的影响。 用尾套法对接受同窝另一同胞WKY大鼠肾脏移植且存活5周的6只WKY大鼠(A组)及接受SHR肾脏移植且存活5周的6只WKY大鼠(B组)的尾动脉收缩压进行检测, 移植前A、 B两组受肾移植大鼠的尾动脉收缩压分别为18.0±0.93 和18.3±0.68 kPa,无统计学显著差异(P>0.05); 移植后3、 4、 5周时, B组大鼠的尾动脉收缩压显著高于A组大鼠, 移植后5周时, A, B两组大鼠的收缩压分别为19.0±0.71 和23.0±0.69 kPa (P<0.001); 所用剂量的免疫抑制剂CsA对双侧肾脏完整以及右侧肾脏切除的SHR、 WKY大鼠的动脉血压无显著影响。 以上结果表明, SHR的肾脏在高血压的形成中可能起重要作用。     

Primary dysfunction in aggregation and secretion of SHRSP platelets: not secondary to the circulation of "exhausted" platelets

The thrombin-induced secretion of [14C]-serotonin and adenine nucleotides from stroke-prone spontaneously hypertensive rats (SHRSP) platelets was markedly reduced with the development of hypertension accompanying hypo-aggregability compared with that from age-matched Wistar Kyoto rats (WKY) platelets. Calcium Ionophore A23187-induced secretion and aggregation were also attenuated in SHRSP platelets. Additionally, an enhancement of platelet secretion as well as aggregation by extracellular Ca2+ was less in SHRSP platelets than in WKY platelets. The platelet contents of adenine nucleotides and serotonin were not different between SHRSP and WKY at 5-16 weeks of age whereas they became significantly lower in SHRSP beginning at 22 weeks. The serotonin content in SHRSP platelets at 36 weeks of age was only 55% of that in WKY platelets. It is suggested that the reduced platelet aggregation and secretion observed in SHRSP platelets at ages lower than approximately 20 weeks are not secondary phenomena to the circulation of degranulated platelets, but the primary defect of SHRSP platelets appears to be an impaired function of Ca2+.     

The Role of Preventing Nitric Oxide Deficiency in the Antihypertensive Effect of Adaptation to Hypoxia

Shortage of endothelial nitric oxide (NO) manifested as decreased daily urinary excretion of nitrate and nitrite as well as attenuated endothelium-dependent relaxation of conduit and resistance vessels progresses with age-related increase of blood pressure (BP) in stroke-prone spontaneously hypertensive rats (SHRSP). Simultaneous NO-dependent suppression of vascular contractions is, apparently, due to the inducible NO synthase activity in vascular smooth muscle specific for spontaneously hypertensive rat. The adaptation of rats to hypobaric hypoxia initiated at early hypertensive stage (at the age of 5–6 weeks) decelerates hypertension progress. The antihypertensive effect of the adaptation was accompanied by stimulation of endothelial NO synthesis and prevention of impaired NO-dependent response in isolated blood vessels. Nitric oxide stores were formed in the vascular wall of SHRSP and WKY rats at the same time. The obtained data indicate that the correction of endothelial NO deficiency plays a significant role in the antihypertensive effect of adaptation to hypoxia.     

自发性高血压大鼠中枢血管紧张素Ⅱ的变化对中枢肾上腺素...

The content of norepinephrine (NE) and epinephrine (E) in the brain of spontaneously hypertensive rats has proved abnormal, but the cause remained unknown. It was shown in the recent work that NE content in pons, posterior hypothalamus, nucleus caudatus and E concentration in medulla oblongata, anterior and posterior hypothalamus of 12-week old stroke-prone spontaneously hypertensive rats (SHRSP) were much higher than those of age-matched Wister-Kyoto rats (WKY). SHRSP also showed higher levels of systolic blood pressure (SBP) and brain angiotensin II (A II) than WKY. Intracerebroventricular (icv) perfusion of angiotensin-converting enzyme inhibitor captopril (20 micrograms for each time and three times for each day for four weeks) inhibited the synthesis of brain A II and reduced SBP and NE, E contents in all examined brain areas in SHRSP and WKY. However, the effects of chronically perfused captopril on SBP and brain NE, E levels in SHRSP were much more significant than in WKY. The results indicate that the modulatory effects of central renin-angiotensin system (RAS) on central adrenergic and noradrenergic system might be overactivated in SHRSP, which might partially responsible for the abnormally high levels of NE, E in some of the brain areas of SHRSP.     

Accumulation of 8-oxo-deoxyguanosine in cardiovascular tissues with the development of hypertension

Accumulation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) in DNA is associated with mutagenesis and cell death. Little attention has been given to the biological significance of 8-oxo-dG accumulation in cardiovascular tissues during the different stage of hypertension and its prevention. We thus investigated the levels and localization of both 8-oxo-dG accumulation and expression of MTH1, which hydrolyzes 8-oxo-dGTP to prevent its incorporation into DNA, in the thoracic aorta prepared from stroke-prone spontaneously hypertensive rats (SHRSP) and age-matched Wister-Kyoto rats (WKY), aged 5-32 weeks. HPLC-MS/MS analysis revealed that the levels of nuclear 8-oxo-dG in the aorta increased significantly in SHRSP, but not WKY, with aging. Immunohistochemical study revealed that both TUNEL reactivity and 8-oxo-dG immunoreactivity were increased in smooth muscle cells (SMC) and endothelial cells (EC) of the aorta with aging, and they exhibited similar distributions in serial sections. The number of 8-oxo-dG and TUNEL positive cells in EC, but not in SMC, was significantly higher in SHRSP than WKY at 32 weeks of age. In contrast, the expression levels of Mth1mRNA and MTH1 protein in the aorta were similarly decreased both in SHRSP and WKY with aging. However, the number of MTH1 expressing EC was remarkably increased in the older SHRSP compared to the younger ones or age-matched WKY. Hypertension significantly increased not only 8-oxo-dG accumulation but also the expression of MTH1 in EC of the aorta during aging. While accumulation of 8-oxo-dG in SMC of the aorta was slightly increased, the expression of MTH1 protein in SMC was rather decreased by hypertension. We thus suggest that MTH1 may protect EC in the aorta from the oxidative damage increased by hypertension.     

Atrial natriuretic polypeptide (ANP) in the development of spontaneously hypertensive rats (SHR) and stroke-prone SHR (SHRSP)

In order to investigate the pathophysiological role of atrial natriuretic polypeptide (ANP) in genetic hypertensive rats, the atrial content and plasma concentration of ANP were measured by a sensitive radioimmunoassay (RIA) for rat ANP in 5-, 10- and 20-week-old spontaneously hypertensive rats (SHR) and stroke-prone SHR (SHRSP) and compared to age-matched Wistar Kyoto rats (WKY). Atrial content of immunoreactive ANP (ir-ANP) tended to be higher in SHR and was already significantly higher in SHRSP than in WKY at 5 weeks of age. Atrial content in the hypertensive strains became significantly higher than in WKY when hypertension developed at 10 and 20 weeks. On the other hand, plasma ir-ANP in SHR was significantly lower than in WKY at 5 weeks, however, it became significantly higher in both SHR and SHRSP than in WKY at 10 and 20 weeks. These findings suggest that ANP release may increase to compensate for the elevation of blood pressure in SHR and SHRSP and that biosynthesis of ANP may be concomitantly stimulated, resulting in an increase in atrial ANP.     

DAY-NIGHT VARIATION IN THE IN VITRO CONTRACTILITY OF AORTA AND MESENTERIC AND RENAL ARTERIES IN TRANSGENIC HYPERTENSIVE RATS*

TGR(mREN2)27 (TGR) rats develop severe hypertension and an inverted circadian blood pressure profile with peak blood pressure in the daytime rest phase. The present study investigated the in vitro responsiveness of different arteries of TGR rats during day and night. Twelve-week-old TGR rats and normotensive Sprague-Dawley (SPRD) controls, synchronized to 12h light, 12h dark (LD 12:12) (light 07:00 19:00), were killed at 09:00 (during rest) and 21:00 (during activity), and endothelium-dependent relaxation by acetylcholine and vascular contraction by angiotensin II were studied by measuring isometric force in ring segments of abdominal aorta and mesenteric and renal arteries. In SPRD rats, consistent day-night variation was found, with greater responses to angiotensin II during the daytime rest span. In TGR rats, biological time-dependent differences were found in the renal vasculature, but not in the aorta and mesenteric artery. Relaxation of SPRD rat aorta and mesenteric artery by acetylcholine was greater at 09:00, whereas in TGR rats, day-night variation was absent (mesenteric artery) or inverted (aorta). In conclusion, based on the study of two time points, daynight variation in vascular contractility of aorta and mesenteric artery is blunted in TGR rats, whereas renal artery segments showed an unchanged daynight pattern compared to SPRD controls. (Chronobiology International, 18(4), 665 681, 2001)     

Dietary fish oil administration retards the development of hypertension and influences vascular neuroeffector function in the stroke prone spontaneously hypertensive rat (SHRSP).

An influence of fish oils (rich in eicosapentaenoic acid, EPA) in modulating (a) the development of hypertension in the stroke prone spontaneously hypertensive rat (SHRSP) and (b) vascular neuroeffector mechanisms in the SHRSP was explored. Rats (SHRSP) were placed on a series of diets for a period of 13 weeks from 4 weeks of age. The fatty acid composition of the diets was derived from fish oil, olive oil, safflower oil or beef fat. After 13 weeks, rats fed diets containing fish oil (at a total dietary fat level of either 5% or 15%) had mean blood pressures approximately 20-25 mmHg lower than other SHRSP rats maintained on diets containing either olive oil, safflower oil or beef fat. The dietary schedules providing fish oil depressed the contractile responses mediated by sympathetic nerve stimulation in the mesenteric vascular bed preparation. The results suggest that the n-3 polyunsaturated fatty acids retard the development of hypertension in the SHRSP rat and modulate the contractile responses of blood vessels mediated by sympathetic nerves in the isolated perfused mesenteric vascular bed preparation.