血管紧张素受体阻滞剂对自发性高血压大鼠肾脏血管紧张素转换酶2表达的影响

目的:研究自发性高血压大鼠肾脏血管紧张素转换酶2(ACE2)蛋白表达水平及血管紧张素ⅡⅠ型受体阻滞剂厄贝沙坦对ACE2表达的影响,以了解高血压的病理改变,探讨血管紧张素受体阻滞剂治疗高血压又一可能机制。方法:20只14周龄雄性自发性高血压大鼠随机分为自发性高血压大鼠(SHR)组(n=10)和厄贝沙坦组(n=10)。厄贝沙坦组每只大鼠以厄贝沙坦50mg·kg-1·d-1灌胃,给药时间12周。同时取14周龄雄性京都种Wistar大鼠为正常对照(WKY)组(n=10)。利用免疫组化和逆转录聚合酶链反应检测各组大鼠肾脏ACE2表达。结果:与WKY组比较,SHR组ACE2表达显著减少(0.72±0.11vs1.11±0.15);与SHR组比较,厄贝沙坦组经12周治疗后,ACE2表达明显提高(1.03±0.13vs0.72±0.11)。结论:高血压大鼠肾脏ACE2表达减少,血管紧张素ⅡⅠ型受体阻滞剂对高血压大鼠肾脏ACE2的表达有上调作用。此作用可能是血管紧张素受体阻滞除阻滞血管紧张素受体以外的另一间接调节肾素-血管紧张素系统的途径。     

Effects of uninephrectomy on renal structural properties in spontaneously hypertensive rats

1. To investigate effects of a reduction in nephron numbers on renal structural properties in hypertension, either unilateral nephrectomy (UNX) or sham operation (SO) was performed at 5 weeks of age in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats (n = 9 for each operation for each strain). 2. At 10-12 weeks of age, flow-pressure (F-P) and pressure-glomerular filtration rate (P-GFR) relationships were determined for maximally vasodilated, perfused kidneys. Kidneys were then perfusion fixed for histological analysis. 3. In the SO groups, the slope of F-P (minimal renal vascular resistance, reflecting overall luminal dimensions of pre- and post-glomerular vasculature) was greater in SHR than in WKY rats. The threshold pressure for beginning filtration at P-GFR (preglomerular to post-glomerular vascular resistance ratio) was higher in SHR than in WKY rats, but the slope of P-GFR (glomerular filtration capacity) did not differ between the two strains. These results suggest that vascular narrowing occurred, especially in the preglomerular resistance vessels in the kidneys of SHR, although glomerular filtration capacity was normal. 4. In UNX animals, the following results were obtained: (i) the slope of F-P was not affected in either strain; (ii) the pressure for beginning filtration at P-GFR was unchanged in WKY rats, but was decreased in SHR; (iii) the slope of P-GFR increased in WKY rats, but a compensatory adaptive increase was missing in SHR; and (iv) histologically, small increases in the luminal cross-sectional area of interlobular arteries and glomerular tuft area were observed in both strains. However, the increase in vascular lumen was more pronounced in SHR, whereas glomerular enlargement was greater in WKY rats. 5. These results suggested that UNX attenuates vascular narrowing of the preglomerular resistance vessels and glomerular structural adaptations to UNX (i.e. increased filtering capacity and glomerular enlargement) are impaired in SHR.     

Cardiovascular status following combined angiotensin-converting enzyme and AT1 receptor inhibition in conscious spontaneously hypertensive rats

1. Combined treatment of spontaneously hypertensive rats (SHR) with AT1 receptor antagonists and angiotensin-converting enzyme (ACE) inhibitors has been shown to reduce mean arterial pressure (MAP) more than monotherapy with either agent. The aims of the present study were to investigate the effects of chronic dual renin-angiotensin system (RAS) inhibition using non-hypotensive doses of the AT1 receptor antagonist candesartan cilexetil and the ACE inhibitor perindopril on cardiovascular function and structure. 2. Adult male SHR, aged 15 weeks, were divided into four groups: (i) candesartan cilexetil (0.5 mg/kg per day in drinking water); (ii) perindopril (0.3 mg/kg per day in drinking water); (iii) combined treatment (dual RAS inhibition); or (iv) the appropriate vehicle (0.1% ethanol/0.1% polyethylene glycol/1.5 mmol/l sodium bicarbonate dissolved in water for candesartan cilexetil; distilled water for perindopril). Systolic blood pressure was measured weekly using the tail-cuff method and urinary microalbuminuria was measured fortnightly. 3. After 4 weeks, rats were instrumented for intravenous drug administration and measurement of MAP. At this time, the cardiovascular effects of angiotensin (Ang) I and AngII (5-20 ng) and sodium nitroprusside (SNP) and acetylcholine (ACh; 1-5 micro g) were assessed. In addition, left ventricular : bodyweight and media : lumen ratios were determined as indices of cardiac and vascular hypertrophy, respectively. 4. Candesartan cilexetil and perindopril alone had minimal effect on MAP when measured both directly and indirectly, whereas direct MAP was significantly decreased in the combined treatment group (131 +/- 6 mmHg; P < 0.05) compared with the vehicle group (156 +/- 9 mmHg). Pressor responses to AngI were significantly decreased in all groups compared with the vehicle-treated group and pressor responses to AngII were significantly decreased in the candesartan cilexetil-treated (P < 0.01) and combined treatment groups (P < 0.01) compared with the vehicle-treated group. Depressor responses to ACh and SNP were not significantly affected by any of the antihypertensive therapies compared with vehicle-treated SHR. 5. Vascular hypertrophy was significantly decreased in the candesartan cilexetil and combined groups compared with the vehicle-treated group, whereas cardiac hypertrophy was reduced, with the rank order of effect being: dual RAS inhibition > perindopril > candesartan cilexetil. Urinary albumin tended to decrease with dual RAS inhibition, but was not significantly affected by this short-term treatment. 6. These results demonstrate the efficacy of low-dose dual RAS inhibition as an antihypertensive modality, at least in SHR, not only in reducing arterial pressure, but also in improving cardiovascular structure.     

阿托伐他汀对高血压大鼠肾脏血管紧张素转换酶2表达的影响

目的:观察阿托伐他汀对两肾一夹(2K1C)高血压大鼠肾脏血管紧张素转换酶2(ACE2)表达的影响,探讨阿托伐他汀降血压作用可能的新的作用机制。方法:40只雄性Wistar大鼠随机分为5组(每组8只):假手术组、高血压组、缬沙坦组(20 mg·kg-1·d-1)、阿托伐他汀组(10 mg·kg-1·d-1)和阿托伐他汀组(30 mg·kg-1·d-1)。鼠尾容积法测定术前、术后1周及药物干预后4、8周的SBP变化。8周后,免疫组化法检测肾脏ACE2蛋白表达,放射免疫分析法测定心肌组织血管紧张素Ⅱ(AngⅡ)水平,RT-PCR法检测肾脏组织ACE2 mRNA表达。结果:高剂量阿托伐他汀组SBP较高血压组降低显著(P<0.01);高剂量阿托伐他汀组较高血压组降低心肌组织AngⅡ浓度显著(P<0.01);RT-PCR显示缬沙坦组和低、高剂量阿托伐他汀组肾脏组织ACE2 mRNA的表达较高血压组不同程度增高(P<0.05)。结论:2K1C高血压大鼠肾脏组织ACE2蛋白、ACE2 mRNA表达降低。阿托伐他汀在降低高血压大鼠SBP的同时,降低心肌组织AngⅡ浓度,增加肾脏组织ACE2蛋白、ACE2 mRNA表达。     

盐酸埃他卡林对自发性高血压大鼠肾组织KATP通道基因表达的影响

目的:从分子生物学水平探讨盐酸埃他卡林(iptakalimhydrohloride,Ipt)对自发性高血压大鼠(spontaneouslyhypertensiverats,SHR)肾组织KATP亚型表达的影响。方法:SHR于第12周龄进入实验,实验设Ipt1、3和9mg·kg-1·d-13个剂量组,盐酸苯那普利(benazepril)3mg·kg-1·d-1治疗组及SHR空白对照组,另设同周龄同种属正常血压大鼠(wistarKyotorat,WKY)为正常对照组,灌胃给药每天1次,连续12周,观察盐酸埃他卡林对血压和肾组织KATP亚型表达的影响。结果:SHR肾组织SUR2、Kir6.1、Kir1.1mRNA表达较WKY大鼠明显升高,盐酸埃他卡林1、3、9mg·kg-1·d-13个剂量组治疗后均可明显降低血压同时下调肾脏高表达的Kir6.1、Kir1.1mRNA水平,而对SUR2表达无明显影响。结论:盐酸埃他卡林对SHR降压治疗对肾脏的保护作用可能与其影响Kir6.1、Kir1.1基因表达有关。     

Effect of cross-fostering on renal anti-oxidant/oxidant status and development of hypertension in spontaneously hypertensive rats

1. The hypotensive effect of cross-fostering in spontaneously hypertensive rats (SHR) is thought to involve adjustments in renal function. However, its association with renal anti-oxidant/oxidant balance during cross-fostering is not known. 2. The present study examined the effect of cross-fostering and in-fostering of 1-day-old offspring between SHR and Wistar-Kyoto (WKY) dams on renal anti-oxidant/oxidant status and systolic blood pressure (SBP). Renal anti-oxidant/oxidant status and SBP were determined in the offspring from 4-16 weeks of age. 3. Cross-fostered SHR had significantly lower SBP than in-fostered SHR at 6, 8 and 12 weeks, but not at 16 weeks (127 ± 1 vs 144 ± 2, 138 ± 1 vs 160 ± 1, 174 ± 2 vs 184 ± 2 and 199 ± 2 vs 194 ± 3 mmHg at 6, 8, 12 and 16 weeks, respectively). No differences in SBP were evident between cross-fostered and in-fostered WKY rats. There were no significant differences in levels of thiobarbituric acid-reactive substances (TBARS), protein carbonyl and total anti-oxidant status (TAS) or superoxide dismutase, catalase, glutathione peroxidase (GPx), glutathione S-transferase and glutathione reductase activity between cross-fostered and in-fostered SHR or WKY offspring. However, compared with WKY rats, catalase activity was higher at 6 and 16 weeks, TAS was higher at 16 weeks and GPx activity and TBARS were lower at 16 weeks in SHR. 4. It appears that cross-fostering of SHR offspring to WKY dams during the early postnatal period causes a transient delay in the rise in blood pressure in SHR and that this does not involve the renal anti-oxidant/oxidant system.     

银杏内酯B对自发性高血压大鼠左室肥厚及心肌纤维化的影响

目的:观察银杏内酯B对自发性高血压大鼠模型左室肥厚心肌纤维化的影响。方法:选择12周龄雄性SHR大鼠(二级)40只,随机分成4组,每组10只,分别为银杏内酯B大剂量组(YH,120 mg.kg-1.d-1)、银杏内酯B小剂量组(YL,60mg.kg-1.d-1)、氯沙坦组(LOS,30 mg.kg-1.d-1)和SHR大鼠模型对照组(SHR),以及周龄、性别相匹配的Wistar Kyoto(WKY)大鼠10只作为空白对照。每日灌胃给药一次,对照组给等量CMCNa溶液。治疗12周后尾袖法测定动脉血压,称量后处死。计算左室质量与体质量比(LVM/BW)。天狼星红染色,计算机图像分析计算心肌胶原容积分数。结果:给药后,YH、YL组大鼠SBP均明显低于SHR组(P<0.01),YH、YL2组组间比较无显著性差异;YH组大鼠给药前后SBP比较有显著差异(P<0.01),给药后明显低于给药前,而YL组给药前后比较无统计学意义。YH、YL组大鼠心肌胶原纤维含量均明显低于SHR组(P<0.01),YH、YL2组间比较无显著性差异。结论:银杏内酯B可以抑制SHR大鼠的心肌纤维化,改善高血压所致的心肌重塑。     

Salt and water intake and sodium and potassium excretion in spontaneously hypertensive rats

1. Total fluid and saline intakes were greater in spontaneously hypertensive rats (SHR) than in normotensive rats (NTR). 2. Total fluid and saline intake were significantly elevated in prehypertensive SHR, 5 weeks old, compared with age-matched NTR, and the intakes fell with age in both strains but remained considerably greater in SHR. 3. In SHR, in which the blood pressure was maintained at normotensive levels by treatment with hydralazine, the saline and fluid intakes remained elevated above those of NTR. 4. SHR and NTR fed low sodium diet with water alone to drink have similar excretion rates of sodium, suggesting that their ability to conserve sodium was normal. 5. Measurement of sodium excretion after three different levels of sodium loading, on normal or low sodium diets, also failed to demonstrate an abnormality of renal function in SHR. 6. These results demonstrate that the fluid and saline intakes of SHR are elevated compared with NTR and this difference is independent of the hypertension in SHR and is not secondary to enhanced renal sodium loss.     

合生元益生菌治疗自发性高血压相关机制的代谢组学研究

目的 应用代谢组学相关技术,从表观水平探索合生元制剂通过调节肠道菌群达到降压效应的可能作用机制。方法 将14只自发性高血压大鼠随机分为2组,模型组和治疗组各7只,另取7只Wistar Kyoto大鼠作为对照组,采用超高效液相色谱-四级杆飞行时间串联质谱（UHPLC-Q-TOF/MS）技术对对照组、原发性高血压模型组和合生元制剂治疗组的大鼠模型回肠段进行代谢组学分析,筛选合生元制剂治疗自发性高血压的潜在生物学标志物。结果 通过对代谢组学的分析,确定了对照组与模型组之间具有显著差异的27种代谢物。在这些代谢物中,与模型组相比,治疗组中溶血磷脂酰乙醇胺（LysoPE）和磷脂酰胆碱（PC）可以显著被重新调节。结论 合生元制剂可以通过改变肠道微生物群的结构,调节LysoPE和PC相关信号通路,进而改善自发性高血压状态;代谢组学有助于从分子水平理解自发性高血压发病机制及合生元制剂的降压机制。     

缬沙坦对自发性高血压大鼠血管结构和舒缩功能的影响

目的观察缬沙坦对自发性高血压大鼠(SHR)的血压、血管功能和结构的影响.方法30只12 wk龄雄性SHR,随机分成3组,每组10只缬沙坦大剂量组(30 mg*kg-1*d-1);缬沙坦小剂量组(10 mg*kg-1*d-1); SHR模型对照组,另设同龄雄性正常血压WKY大鼠作为正常对照组(n=10).用无创法测定尾动脉收缩压及心率,至给药 4 wk 处死.测定胸主动脉、肠系膜动脉分支第三级血管壁(中膜)/腔面积比,并采用平衡记录仪记录离体的动脉环对血管活性药物去甲肾上腺素(NE)和硝普钠反应的敏感性.结果与模型组相比,大、小剂量缬沙坦均能降低SHR血压,肠系膜动脉壁肥厚明显改善(P＜0.01);大剂量明显减少主动脉腔壁比(P＜0.01),小剂量缬沙坦也可减少腔壁比,但无统计学意义;大、小剂量均能使胸主动脉及肠系膜动脉对硝普钠的舒张敏感性增加 (P<0.05),对NE收缩的敏感性降低(P<0.05).结论缬沙坦能改善SHR的非内皮依赖性血管舒张功能,使SHR血管对循环〗活性物质的异常反应改善,并抑制SHR的血管壁变厚.     

Effect of chronic treatment with trandolapril or enalapril on brain ACE activity in spontaneously hypertensive rats

The aim of the present study was to determine whether the new ACE inhibitor trandolapril was able to inhibit brain ACE activity in spontaneously hypertensive rats (SHRs). Therefore, we have measured ex vivo ACE activity in discrete brain areas of SHRs after a 2-week oral treatment with trandolapril (0.001, 0.01, 0.1 and 1 mg/kg/day). The effects of trandolapril were compared to those of enalapril (10 mg/kg/day), used as a reference compound. Enalapril induced a decrease in ACE activity in brain areas not protected by the blood brain barrier (subfornical organ and median eminence) and in cerebral cortex. Conversely, trandolapril at a dose of 0.01 mg/kg/day and above induced a dose-dependent inhibition of ACE activity in all brain areas assayed, including the supraoptic and paraventricular hypothalamic nuclei, septum, amygdala, hippocampus, cerebellar and cerebral cortex, nucleus of the tractus solitary and caudate nucleus. The inhibition was roughly similar in all brain areas studied. These data suggest that after chronic oral administration in SHRs, trandolapril or its metabolite, in contrast to enalapril or enalaprilat, was able to reach all brain areas of SHRs, including those protected by the blood brain barrier.     

Effects of exercise training on nitric oxide synthase in the kidney of spontaneously hypertensive rats

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艾力沙坦钾单次给药对自发性高血压大鼠血压的影响

目的本实验通过观察艾力沙坦钾（allisartan potassium,ALS3K）对自发性高血压大鼠（spontaneously hypertensirerats,SHR）单次给药前后血压变化的情况,研究艾力沙坦钾对SHR的降压作用及量效关系。方法SHR随机分为7个组,每组9只。SHR麻醉状态下行股动脉插管并造胃瘘管,恢复1d后,动物在清醒自由活动状态下,由计算机连续记录每搏收缩压（systolicblood pressure,SBP）,舒张压（diastolic blood pressure,DBP）和心动间期（heart period,HP）。记录给药前1h内血压和心动间期作为给药前基础值。然后每组SHR经胃瘘管分别给予0．5％的羧甲基纤维素钠（sodium carboxymathyl cellulose,CMC-Na）、艾力沙坦酯（allisartan,ALS-3）2．5mg／kg、氯沙坦钾（losartan potassium,Los）2．5mg／kg和受试药品ALS3K各1．0、2．5、5．0、10mg／kg;给药后连续记录6hSBP、DBP和HP的变化。结果ALS3K在2．5mg／kg剂量开始明显降压,与给药前比较,SBP和DBP分别下降15、16mmHg（P〈0．01）;ALS3K5．0和10mg／kg降压效果与2．5mg／kg相近;各剂量对HP没有明显的影响。ALS-3以及Los在2．5mg／kg给药剂量下无明显的降压作用。结论ALS3K单次给药能平稳持久地降低SHR的血压,在一定剂量范围内有较好的量效关系。经过结构改造,ALS3K可以通过更低的给药剂量而获得比ALS-3更好的降压疗效。     

Effects of preweaning doxazosin treatment on adult pressure in the spontaneously hypertensive rat

1. The neonatal/preweaning period appears to represent a critical period of involvement of the sympathetic nervous system in the development of hypertension in spontaneously hypertensive rats (SHR). 2. We tested whether alpha1-adrenoceptor-mediated effects during the preweaning period are involved in the development of hypertension in the adult SHR. 3. Male SHR were treated with the alpha1-adrenoceptor antagonist doxazosin (10 mg/kg per day, s.c.) from postnatal day 1 to 21 inclusive. Direct conscious blood pressure and heart rate were measured via the caudal artery at 12 weeks of age. 4. Preweaning treatment with doxazosin had no significant effect on mean arterial blood pressure or heart rate in male SHR at 12 weeks of age. 5. These findings do not support the involvement of alpha1-adrenoceptor-mediated effects during the preweaning period in the development of hypertension in adult SHR.     

Blockade of tachykinin NK3 receptor reverses hypertension through a dopaminergic mechanism in the ventral tegmental area of spontaneously hypertensive rats

BACKGROUND AND PURPOSE

Intracerebroventricularly injected tachykinin NK₃ receptor (R) antagonists normalize mean arterial blood pressure (MAP) in spontaneously hypertensive rats (SHR). This study was pursued to define the role played by NK₃R located on dopamine neurones of the ventral tegmental area (VTA) in the regulation of MAP in SHR.

EXPERIMENTAL APPROACH

SHR (16 weeks) were implanted permanently with i.c.v. and/or VTA guide cannulae. Experiments were conducted 24 h after catheterization of the abdominal aorta to measure MAP and heart rate (HR) in freely behaving rats. Cardiovascular responses to i.c.v. or VTA-injected NK₃R agonist (senktide) and antagonists (SB222200 and R-820) were measured before and after systemic administration of selective antagonists for D₁R ({"type":"entrez-protein","attrs":{"text":"SCH23390","term_id":"1052733334","term_text":"SCH23390"}}SCH23390), D₂R (raclopride) or non-selective D₂R (haloperidol), and after destruction of the VTA with ibotenic acid.

KEY RESULTS

I.c.v. or VTA-injected SB222200 and R-820 (500 pmol) evoked anti-hypertension, which was blocked by raclopride. Senktide (10, 25, 65 and 100 pmol) elicited greater increases of MAP and HR when injected in the VTA, and the cardiovascular response was blocked by R-820, {"type":"entrez-protein","attrs":{"text":"SCH23390","term_id":"1052733334","term_text":"SCH23390"}}SCH23390 and haloperidol. VTA-injected SB222200 prevented the pressor response to i.c.v. senktide, and vice versa, i.c.v. senktide prevented the anti-hypertension to VTA SB222200. Destruction of the VTA prevented the pressor response to i.c.v. senktide and the anti-hypertension to i.c.v. R-820.

CONCLUSIONS AND IMPLICATIONS

The NK₃R in the VTA is implicated in the maintenance of hypertension by increasing midbrain dopaminergic transmission in SHR. Hence, this receptor may represent a therapeutic target in the treatment of hypertension.     

Kidney denervation combined with elimination of adrenal-renal portal circulation prevents the development of hypertension in spontaneously hypertensive rats

1. Kidney denervation in spontaneously hypertensive rats (SHR) during the prehypertensive stage delays and attenuates the development of hypertension. The same results have been obtained after elimination of the adrenal-renal portal circulation (ARPC). The aim of the present study was to investigate the influence of concomitant kidney denervation and elimination of ARPC on hypertension in SHR. 2. Experiments were performed on 6-week-old male SHR and Wistar-Kyoto (WKY) rats. In the first group of animals (group I), the ARPC was eliminated by removing the left adrenal gland and the right kidney. In the second group of rats (group II), the right kidney and the right adrenal gland were removed and the left kidney was denervated. In the third group of rats (group III), the right adrenal gland and the left kidney were removed and the right kidney was denervated. In the fourth group of rats (group IV), the right adrenal gland and the right kidney were removed. Group IV served as the control group. Denervations were repeated every 3 weeks. Systolic blood pressure was measured indirectly. 3. Elimination of ARPC (group I) and kidney denervation (group II) delayed and attenuated hypertension to the same degree (163 +/- 5 and 157 +/- 4 mmHg, respectively). Application of the these two methods concomitantly (group III) prevented the development of hypertension (130 +/- 6 mmHg). 4. We conclude that both intact efferent sympathetic renal nerves and adrenal hormones reaching the kidney through the ARPC may be mandatory factors for the development of arterial hypertension in SHR.     

Systemic delivery of adult stem cells improves cardiac function in spontaneously hypertensive rats

1. Heart regeneration after myocardial infarction (MI) can occur after cell therapy, but the mechanisms, cell types and delivery methods responsible for this improvement are still under investigation. In the present study, we evaluated the impact of systemic delivery of bone marrow cells (BMC) and cultivated mesenchymal stem cells (MSC) on cardiac morphology, function and mortality in spontaneously hypertensive rats (SHR) submitted to coronary occlusion. 2. Female syngeneic adult SHR, submitted or not (control group; C) to MI, were treated with intravenous injection of MSC (MI + MSC) or BMC (MI + BM) from male rats and evaluated after 1, 15 and 30 days by echocardiography. Systolic blood pressure (SBP), functional capacity, histology, mortality rate and polymerase chain reaction for the Y chromosome were also analysed. 3. Myocardial infarction induced a decrease in SBP and BMC, but not MSC, prevented this decrease. An improvement in functional capacity and ejection fraction (38 +/- 4, 39 +/- 3 and 58 +/- 2% for MI, MI + MSC and MI + BM, respectively; P < 0.05), as well as a reduction of the left ventricle infarcted area, were observed in rats from the MI + BM group compared with the other three groups. Treated animals had a significantly reduced lesion tissue score. The mortality rate in the C, MI + BM, MI + MSC and MI groups was 0, 0, 16.7 and 44.4%, respectively (P < 0.05 for the MI + MSC and MI groups compared with the C and MI + BM groups). 4. The results of the present study suggest that systemic administration of BMC can improve left ventricular function, functional capacity and, consequently, reduce mortality in an animal model of MI associated with hypertension. We speculate that the cells transiently home to the myocardium, releasing paracrine factors that recruit host cells to repair the lesion.     

Brain converting enzyme inhibition: A possible mechanism for the antihypertensive action of captopril in spontaneously hypertensive rats

The effects of various doses of the converting enzyme inhibitor captopril injected into the lateral brain ventricle (i.c.v.) and intravenously (i.v.) on blood pressure (BP) and on converting enzyme activity were tested in stroke prone conscious spontaneously hypertensive rats (SHR-sp) and in normotensive Wistar Kyoto rats (WKY). Injection of 500 μg captopril i.c.v. produced a marked biphasic BP effect in SHR-sp, an initial increase followed by a long-lasting decrease. Only the initial BP increase was observed in WKY. The pressor responses to i.c.v. angiotensin I (ANG I) were completely blocked after i.c.v. captopril injection and this effect lasted for 24 h. The pressor responses to i.v. ANG I were also inhibited immediately after 500 μg captopril i.c.v. and gradually returned to control values within 5 h. Intravenous injections of 500 μg captopril almost completely inhibited the pressor responses to i.v. ANG I; they caused a moderate BP decrease in SHR-sp and had no significant BP effects in WKY. In SHR-sp, 5 μg captopril i.c.v. caused a reduction of BP with a concomitant inhibition of the pressor effects of i.c.v. ANG I. Both effects lasted about 30 min. The pressor responses to i.v. ANG I were not inhibited. In WKY, 5 μg captopril i.c.v. had no effect on BP. It is concluded that captopril can reduce BP by action on the brain without peripheral inhibition of converting enzyme. Following high doses injected i.c.v., the inhibitor leaks into the periphery but this cannot explain the marked hypotensive effect in SHR-sp.     

美托洛尔对隐匿性肾功能不全的高血压患者肾小球滤过功能的影响

目的:评价β受体阻滞剂美托洛尔单独或与血管紧张素转换酶(ACE)抑制剂贝那普利联合应用对隐匿性肾功能不全的轻、中度高血压患者肾小球滤过功能的影响。方法:73例隐匿性肾功能不全的高血压患者,随机分为美托洛尔(MET)、美托洛尔+贝那普利(MET+BEN)两组,分别应用美托洛尔50～75mg/d或美托洛尔25mg/d+贝那普利5～10mg/d,疗程6个月。血压控制目标为140/90mmHg。治疗前和治疗满6个月时,检测两组患者血尿酸(SUA)血肌酐(Scr)和肾小球滤过率GFR。结果:①治疗后,MET组与MET+BEN组的血压平均水平的差别均无统计学意义(131.3±9.9/71.9±10.5,132.0±10.2/68.9±10.7mmHg,P均>0.05),血压控制达标率亦无显著差别(78.4%,77.8%,P>0.05)。②治疗后MET组血尿酸、肌酐较治疗前升高(439±62,429±57mmol/L,P<0.05;109±17,103±14μmol/L,P<0.01),肾小球滤过率轻度下降(49.9±6.9,52.9±5.8mL/min·1.73m2,P<0.01);③MET+BEN组血尿酸、血肌酐较治疗前降低(417±57,426±62mmol/L,P<0.01;98±12,105±13μmol/L,P<0.01),肾小球滤过率较治疗前升高(54.7±6.2,51.3±5.6mL/min·1.73m2,P<0.01)。④治疗6个月后,MET+BEN组血尿酸、血肌酐均低于MET组(417±57,439±62mmol/L,P<0.01;98±12,109±17μmol/L,P<0.01),肾小球滤过率高于MET组(54.7±6.2,49.9±6.9ml/min·1.73m2,P<0.01)。结论:对合并隐匿性肾功能不全的高血压患者,应避免单独应用美托洛尔,以免加重肾小球滤过功能的损害;而美托洛尔与贝那普利联合应用,可能有益于肾功能的保护。     

Differential regulations of blood pressure and perturbed metabolism by total ginsenosides and conventional antihypertensive agents in spontaneously hypertensive rats

Aim:

To investigate the regulatory effects of total ginsenosides and the conventional antihypertensive agents (captopril, amlodipine, terazosin and hydrochlorothiazide) on the blood pressure and perturbed metabolism in spontaneously hypertensive rats (SHRs) and to analyze the cause-effect relationships between high blood pressure and the metabolic disorders of hypertension.

Methods:

SHRs were administrated with total ginsenosides or the antihypertensive agents for eight weeks. Systolic blood pressure (SP) was measured every week and low-molecular-weight compounds in blood plasma were quantitatively analyzed using a nontargeted high-throughput metabolomic tool: gas chromatography/time of flight mass spectrometry (GC/TOFMS) . The metabolic patterns were evaluated using principal components analysis and potential markers of hypertension were identified.

Results:

Total ginsenosides and the antihypertensive agents differentially regulated SP and the metabolic pattern in SHRs. Total ginsenosides caused a progressive and prolonged reduction of SP and markedly normalized the perturbed metabolism with 14 of 27 (51.8%) markers of hypertension which were regulated toward normal. Total ginsenosides also reduced free fatty acids'' level toward normal levels. In contrast, captopril, amlodipine and terazosin efficiently depressed SP, but had little effect on metabolic perturbation with only 8 (29.6%), 4 (14.8%), and 4 (14.8%) markers, respectively, which were regulated.

Conclusion:

The metabolic changes persisted when the blood pressure was lowered by the conventional antihypertensive agents, suggesting that hypertension may not be the cause of the metabolic perturbation in SHRs.