Aging impairs the protective effect of magnesium supplementation on hypertension in spontaneously hypertensive rats.

Preeclampsia is a hypertensive disorder that is unique to pregnancy. Magnesium (Mg2+) supplementation is a potential new therapy to ameliorate development of hypertension. The aim of this work was to compare the effects of Mg2+ supplementation on systolic blood pressure (SBP) in young and aged rats. Spontaneously hypertensive rats (SHR) were divided into young (6-week-old male, n = 10) and old (16-week-old male, n = 10) groups. Each group of rats comprised two subgroups made of a control subgroup fed with normal rat chow (0.2% Mg2+, n = 5) and a high Mg2+ subgroup nourished with a Mg2+ rich diet (0.8% Mg2+, n = 5). Age-matched Wistar-Kyoto rats (WKY) were also allocated into two groups. SBP was assessed weekly for 12 weeks indirectly by the tail-cuff method. SBP increased progressively in SHR-young rats after 7 weeks. This increase was greater in the control subgroup compared to high Mg2+ subgroup at 7 weeks (p < 0.05). No difference in the SBP was registered between old SHR subgroups. Mg2+ supplementation does not exert antihypertensive effects in the WKY rats. In conclusion, Mg2+ supplementation may provide beneficial effect in the developmental phase of hypertension but not in established hypertension.     

雷公藤甲素对感染性休克大鼠脑的保护作用

目的探讨雷公藤甲素对感染性休克大鼠的脑保护作用及其可能机制。方法将SPF级SD大鼠50只,体重200-250 g,随机均分为假手术组(Sham组)、感染性休克组(LPS组)、雷公藤甲素组(TR组)、PI3K抑制剂组(LY294002组)、雷公藤甲素联合PI3K抑制剂组(TR+LY294002组)。尾静脉注射5 mg/kg脂多糖(LPS)制备大鼠感染性休克模型,TR组于造模前腹腔注射TR 200μg/kg,分别于感染性休克发生后12 h处死大鼠。HE染色观察大鼠脑组织病理变化;检测脑组织中NO、ROS、SOD及MDA水平;TUNEL法检测大鼠脑内细胞凋亡;实时PCR法检测各组大鼠脑组织中Bax、Bcl-2及Caspase-3 mRNA表达水平;Western blot法检测大鼠PI3K/Akt信号通路相关蛋白PI3K、Akt及p-Akt表达情况。结果 LPS组大鼠脑组织损伤严重,脑组织中SOD水平降低,ROS、NO及MDA水平升高。TR可以抑制LPS引发的大脑损伤及神经细胞凋亡,与LPS组相比,TR组大鼠脑组织中SOD, PI3K、p-Akt蛋白的表达水平升高,ROS、NO/MDA及Bax/Bcl-2 mRNA比率及Caspase-3 mRNA表达水平降低。但是,给予PI3K抑制剂后,TR的抗凋亡作用被抑制。结论 TR对感染性休克大鼠的脑保护作用与激活PI3K/Akt信号通路相关。     

Cardiovascular end-organ damage in Ren-2 transgenic rats compared to spontaneously hypertensive rats

 To compare hypertensive end-organ damage in two genetic forms of hypertension we assessed cardiovascular function in two rat strains of genetic hypertension: transgenic rats overexpressing the mouse Ren-2 gene [(TGR(mREN2)27]) and blood pressure matched spontaneously hypertensive rats (SHR). Despite similarly elevated blood pressure, systolic dp/dt (mmHg/s) was more impaired in transgenic rats (3099±446) than in SHR (3571±272) and normals (4342±119; P<0.05). Left ventricular weight (mg/g body weight) increased more in the transgenic rats (40±3) than in SHR (31±2) and normals (26±2). Endothelium-dependent relaxation was significantly decreased only in the transgenic rats. This study shows significantly more cardiac and endothelial dysfunction in transgenic, hypertensive TGR (mREN2)27 than in age and blood pressure matched SHR. This supports the hypothesis that chronic activation of the renin-angiotensin system significantly contributes to hypertensive end-organ damage. Received: 25 November 1996 / Accepted: 18 January 1997     

Protein kinase C activity in brain tissue of spontaneously hypertensive rats

Central Research Laboratory, Ministry of Health of the USSR, Moscow. Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 108, No. 7, pp. 42–44, July, 1989.     

Olmesartan restores the protective effect of remote ischemic perconditioning against myocardial ischemia/reperfusion injury in spontaneously hypertensive rats

OBJECTIVES:Remote ischemic perconditioning is the newest technique used to lessen ischemia/reperfusion injury. However, its effect in hypertensive animals has not been investigated. This study aimed to examine the effect of remote ischemic perconditioning in spontaneously hypertensive rats and determine whether chronic treatment with Olmesartan could influence the effect of remote ischemic perconditioning.METHODS:Sixty rats were randomly divided into six groups: vehicle-sham, vehicle-ischemia/reperfusion injury, vehicle-remote ischemic perconditioning, olmesartan-sham, olmesartan-ischemia/reperfusion and olmesartan-remote ischemic perconditioning. The left ventricular mass index, creatine kinase concentration, infarct size, arrhythmia scores, HIF–1α mRNA expression, miR-21 expression and miR-210 expression were measured.RESULTS:Olmesartan significantly reduced the left ventricular mass index, decreased the creatine kinase concentration, limited the infarct size and reduced the arrhythmia score. The infarct size, creatine kinase concentration and arrhythmia score during reperfusion were similar for the vehicle-ischemia/reperfusion group and vehicle-remote ischemic perconditioning group. However, these values were significantly decreased in the olmesartan-remote ischemic perconditioning group compared to the olmesartan-ischemia/reperfusion injury group. HIF–1α, miR-21 and miR-210 expression were markedly down-regulated in the Olmesartan-sham group compared to the vehicle-sham group and significantly up-regulated in the olmesartan-remote ischemic perconditioning group compared to the olmesartan-ischemia/reperfusion injury group.CONCLUSION:The results indicate that ¹ the protective effect of remote ischemic perconditioning is lost in vehicle-treated rats and that chronic treatment with Olmesartan restores the protective effect of remote ischemic perconditioning; ² chronic treatment with Olmesartan down-regulates HIF–1α, miR-21 and miR-210 expression and reduces hypertrophy, thereby limiting ischemia/reperfusion injury; and ³ recovery of the protective effect of remote ischemic perconditioning is related to the up-regulation of HIF–1α, miR-21 and miR-210 expression.     

Vascular changes in the brain of spontaneously hypertensive rats: hyaline and fibrinoid degeneration.

The arterial changes designated as "hyalinosis" in the vessels of spontaneously hypertensive rats were studied using light- and electron-microscopy. Such changes were classified into three types, hyaline, fibrinoid and atypical fibrinoid degeneration. Hyaline material consisted mainly of excessive lamellar thickening of the basement membrane synthesised by endothelial and smooth muscle cells and associated with cellular debris and electron-dense particles. Acid mucopolysaccharides were found to be one of the components of the hyaline material. The nature of fibrinoid material was primarily fibrin derived from polymerised fibrinogen which has permeated through the injured endothelial cell layer. Atypical fibrinoid material consisted of granular and fibrillar substances derived from blood plasma. In some cases, all three changes were encountered in the same artery.     

Vascularization of fetal neocortical grafts implanted in brain infarcts in spontaneously hypertensive rats.

The vascularization of neural grafts in ischemic brain was studied in spontaneously hypertensive rats grafted with a suspension of fetal neocortical tissue into the infarcted area five to six days after ligation of the middle cerebral artery. The brain vasculature was examined by scanning electron microscopy of corrosion vascular casts and the cortical microvasculature was stereologically quantified in light microscopy three months after the occlusion. Patent anastomoses were present between the middle cerebral artery distal to occlusion and the proximal part, as well as to the anterior and posterior cerebral arteries, in both grafted and non-grafted rats. A vascular plexus covering the infarct cavities and the grafts contained leptomeningeal vessels intermingled with a thin capillary network which is not normally found on the brain surface. The graft vessels were derived from this vascular plexus. The regular pattern of arterioles and venules penetrating from the cortical surface in normal neocortex was absent in the grafts but the capillary morphology was similar in both types of tissue. The grafts had a lower capillary density than normal tissue and lacked the laminar distribution of capillaries characteristic of normal neocortex. The results demonstrate the plasticity of the vascular system where remodeling of the vascular tree after an ischemic insult provides suitable conditions for the vascularization of neocortical grafts.     

Renal medullary effects of transient prehypertensive treatment in young spontaneously hypertensive rats

Aim: Transient angiotensin II receptor blockade (ARB) leads to prolonged blood pressure (BP) lowering, but the underlying mechanism remains uncertain. Long‐term BP control is regulated by the medullary microcirculation with the pericyte as contractile cell. We hypothesize that the prolonged BP effect is caused by increased medullary blood flow (MBF) associated with structural alterations based on reduced medullary pericyte number. Methods: Four‐week‐old spontaneously hypertensive rats (SHR) were treated for 4 weeks with losartan (SHR‐Los: 20 mg kg^?1 day^?1), hydralazine (SHR‐Hyd: 15 mg kg^?1 day^?1), losartan and pan‐caspase inhibitor zVAD (SHR‐Los + 1 mg kg^?1 day^?1 zVAD), losartan and glycogen synthase kinase‐3β (GSK) inhibitor valproate (SHR‐Los + 10 mg kg^?1 day^?1 Val) or placebo. BP, MBF and pericyte number were determined under and after treatment (8 and 12 weeks). Apoptotic pericytes were determined with α‐actin and TUNEL double staining. Sodium concentration was determined in renal medulla and urine. Results: Antihypertensive treatment equipotently reduced BP at 8 weeks of age. After drug withdrawal (12 weeks of age) BP reduction was restricted to SHR‐Los (SHR‐Los: 153 ± 5, SHR‐Hyd: 177 ± 2, SHR: 184 ± 3 mmHg). Simultaneously, MBF was increased and pericyte number reduced, while medullary and urinary sodium concentration increased. Transient ARB in combination with zVAD or valproate resulted in more medullary pericytes and higher BP (SHR‐Los/zVAD: 164 ± 7; SHR‐Los/Val: 168 ± 6 mmHg) compared with transient ARB alone. Conclusion: After drug withdrawal, transient ARB leads to increased MBF and is associated with a reduction in medullary pericytes. This may be associated with pericyte apoptosis as anti‐apoptosis during transient ARB increases pericyte number and BP.     

Improvement of organ damage by a non-depressor dose of imidapril in diabetic spontaneously hypertensive rats

Many clinical trials have demonstrated that angiotensin converting enzyme inhibitors have protective effects on organ damage, suggesting the importance of inhibition of the renin-angiotensin system. In this study, we investigated the effects of a non-depressor dose of imidapril on organ damage induced by diabetes and hypertension. Diabetes was induced by an intravenous injection of streptozotocin (STZ, 40 mg/kg) in 15-week-old male spontaneously hypertensive rats (SHR). Imidapril (2 mg/kg/day) or vehicle was given orally for 28 days, and then the heart weight, left ventricle mass (LVM), urinary albumin excretion (UAE) and endothelial function were examined, as well as the urinary NOx level and local hepatocyte growth factor (HGF) expression. There were no significant differences between the treated groups in systolic blood pressure and plasma parameters. On the other hand, UAE was significantly suppressed in the imidapril-treated group (450+/-44 mg/day) compared to the vehicle-treated group (963+/-182 mg/day) (p<0.01). Moreover, endothelial function assessed by dilative reaction to acetylcholine as well as cardiac hypertrophy assessed by both heart/body weight ratio and LVM were significantly improved in the imidapril-treated group (p<0.05 and p<0.01, respectively). The urinary NOx concentration and local HGF expression in vessel walls were also significantly increased in the imidapril-treated group (p<0.01). A non-depressor dose of imidapril showed protective effects against organ damage in diabetic SHR, which may be partially due to the increase of HGF and NO.     

Adenylate cyclase-cyclic AMP-phosphodiesterase system in microdissected brain areas of normotensive and spontaneously hypertensive rats

The topographical distribution of the adenylate-cyclase-cyclic adenosine monophosphate-phosphodiesterase system was investigated in specific brain areas of rats, and compared with spontaneously hypertensive rats. In normotensive animals, brain cyclic adenosine monophosphate levels were quite uniform (between 7.14 and 13.04 pmol/mg protein) with highest concentrations in catecholamine-containing cell groups. In contrast, the distribution of basal adenylate cyclase and phosphodiesterase activity is not uniform. The unstimulated adenylate cyclase activity was very low in the striatum and catecholamine-containing cell groups in the medulla oblongata (A1C1-cell groups) and very high in the central gray matter and the cerebellum, where the lowest phosphodiesterase activities were measured. In spontaneously hypertensive rats, altered cyclic adenosine monophosphate levels were found in 17 of 36 brain areas investigated in comparison to those of normotensive rats. Increased concentrations were found in regions which are known to participate in the central regulation of blood pressure (nucleus of the solitary tract, A1C1 catecholaminergic cell groups in the ventrolateral medulla oblongata, locus coeruleus) and in the periaqueductal central gray matter, the hippocampus and the cingulate cortex. Lower levels were measured only in hypothalamic nuclei, especially in the paraventricular and dorsomedial nucleus. No significant differences in basal adenylate cyclase activity were found in spontaneously hypertensive rats compared with Wistar-Kyoto control rats, while phosphodiesterase activity was generally higher in spontaneously hypertensive rats, most significantly in the medulla oblongata. Present data show that characterization of the adenylate cyclase-cyclic adenosine monophosphate-phosphodiesterase system helps to localize structural and/or functional differences between the spontaneously hypertensive rat and its normotensive control rat and indicate that more than one functional system is affected in spontaneous hypertension.     

ACE2在高血压大鼠左心室重构中的作用及缬沙坦干预的作用

目的观察血管紧张素转换酶2(ACE2)在自发性高血压大鼠(SHR)左心室中的表达以及缬沙坦干预后对ACE2表达水平的影响。方法 24只12周龄雄性SHR随机分为SHR组、缬沙坦组,12只同龄雄性血压正常的Wistar大鼠作为正常对照组。10周后处死,测定心脏重量指数(HWI)、左心室重量指数(LVWI);酶联免疫法测定血浆中AngⅡ的浓度;碱水解法测定心肌中羟脯氨酸的含量;反转录-聚合酶链反应检测心肌中ACE2的表达。结果与正常对照组比较,SHR组LVWI、血浆中AngⅡ的浓度以及心肌羟脯氨酸的含量均增高(P<0.05),心肌组织中ACE2的表达显著降低(P<0.05);与SHR组比较,缬沙坦组LVWI、血浆中AngⅡ的浓度以及心肌羟脯氨酸的含量均降低(P<0.05),心肌组织中ACE2表达显著增高(P<0.05)。结论缬沙坦可逆转高血压左心室重构,机制可能与增加心肌中ACE2的表达有关。     

The effect of enalapril on the cardiac remodelling in ovariectomized spontaneously hypertensive rats

Angiotensin-converting enzyme inhibitors reduce the blood pressure (BP) and inhibit the generation of the angiotensin II from the inactive angiotensin I. Ten 28-week-old spontaneously hypertensive rats (SHRs) had their ovaries bilaterally removed and five rats were left intact and studied for 7 additional weeks: intact group, ovariectomized group (ovx SHRs) and ovariectomized + enalapril group (ovx + en). BP was higher in ovx SHRs and lower in treated ovx SHRs. Left ventricular (LV) mass index was greater in untreated ovx SHRs and smaller in ovx + en group. The LV cardiomyocyte (cmy) mean cross-sectional area, measured by stereology, was greater in ovx SHRs and smaller in both intact and ovx + en SHRs. Ovx significantly decreased the density of intramyocardial blood vessels (ive), but administration of enalapril was able to restore the density of the ive to that seen in intact group. The worst ive:cmy ratio was found in untreated ovx SHRs, the intact group showed a 90% greater ratio, and the treated ovx group showed a 150% greater ratio than the untreated ovx group. In conclusion, ovariectomy, in SHRs, causes cardiac hypertrophy and an unfavourable myocardial remodelling. Of the spectrum of changes seen, the major effect of enalapril appears to be mediated via an increase in the density of ive.     

Changes of imidazoline receptors in spontaneously hypertensive rats

The role of imidazoline receptors in the regulation of vascular function remains unclear. In this study, we evaluated the effect of agmatine, an imidazoline receptor agonist, on systolic blood pressure (SBP) in spontaneously hypertensive rats (SHRs) and investigated the expressions of imidazoline receptors by Western blot. The isometric tension of aortic rings isolated from male SHRs was also estimated. Agmatine decreased SBP in a dose‐dependent manner in SHRs but not in the normal group [Wistar–Kyoto (WKY) rats]. This reduction in SBP in SHRs was abolished by BU224, a selective antagonist of imidazoline I₂‐receptors. Higher expression of imidazoline receptors in SHR was observed. Moreover, agmatine‐induced relaxation in isolated aortic rings precontracted with phenylephrine or KCl. This relaxation was also abolished by BU224 but was not modified by efaroxan, an imidazoline I₁‐receptor antagonist. Agmatine‐induced relaxation was also attenuated by PNU 37883, a selective blocker of vascular ATP‐sensitive potassium (K_ATP) channels. Additionally, vasodilatation by agmatine was reduced by an inhibitor of protein kinase A (PKA). We suggest that agmatine can lower blood pressure in SHRs through activation of the peripheral imidazoline I₂‐receptor, which is expressed more highly in SHRs.     

自发性高血压大鼠主动脉结构重建

本文采用组织形态学方法和计算机图象分析,研究了４－５５周自发性高血压大鼠胸主动脉几何形态及显微结构成分的重建。结果显示：随着血压增高和年龄增长,ＳＨＲ主主显微结构成分的重均比ＷＫＹ大鼠显著,说明压力因素对血管重建起重要作用。ＳＨＲ主 动脉肥厚为研。高血压早期以血管平滑肌细胞肥大和ＶＳＭＣ面积增加为主,高血压老龄期则以胶原纤维积聚为特征。ＶＳＭＣ及细胞外基质的变化构成了ＳＨＲ主动脉重建的重要过程。