补肾降压理论及补肾降压方对自发性高血压大鼠miR-1调控心室肥厚ERK通路的影响
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摘要
文献与理论研究
高血压是心脑血管事件的重要危险因素。现代医学在降压治疗上取得长足进步,但血压达标率仍不满意。中医药在平稳降压的同时还具有多环节保护机制,但对主要终点事件的证据有待加强。
高血压病属“眩晕”范畴,从肝论治已成为现今临床治疗的‘专家共识”。但通过对历代文献的系统梳理,发现与古代的“眩晕’相比,无论在内涵、病机还是治疗上,高血压与之均存在较大差异。由于在理论认识上存在不足,临床治疗上存在错位,导致中医药降压疗效不理想。这就是照搬古代肝风理论治疗高血压病收效欠佳的根源所在。因此,对本病病机特征的认识,切莫先入为主囿于阴虚阳亢,而应忠实于临床实际,突破既往从肝论治的理论局限,重新探索其证治规律。
现代临床对高血压疾病的早期诊断、降压西药的早期干预以及不断优化与广泛运用,使升高的血压被迅速控制,直接改变了高血压病的自然进程,使其中医学病机演变规律已经发生了很大变化。进一步研究发现,肾虚是现今临床治疗高血压病面临的新问题。形成肾虚证的原因主要与年老导致的生理性肾虚,大病久病及肾导致的病理性肾虚,降压西药的不良反应,以及降压西药的治疗作用密切相关。因此,肾虚是现今高血压病病机关键,而补肾降压则为其重要治疗策略。
“补肾降压方”是基于补肾降压的治则治法而形成的治疗高血压病的经验方。前期文献及临床研究显示,本方在改善高血压病患者肾虚证的同时,还能平稳降压。围绕“稳定血压”及“保护靶器官”这两大目标,本实验旨在探讨中药对血压、心率、左心室肥厚的影响及其调控机制,为补肾降压这一新策略提供实验依据。
实验研究
目的：观察补肾降压方对自发性高血压大鼠(spontaneous hypertensive rat, SHR)血压、心率及心室肥厚的影响,并探讨其对microRNA-1调控SHR心室肥厚ERK信号通路的影响。
方法：以12周龄WKY大鼠为对照,将12周龄SHR大鼠随机分为SHR空白组、补肾大剂量组、补肾中剂量组、补肾小剂量组、卡托普利组,连续灌胃8周,每2周采用套尾法测定SHR清醒状态下尾动脉收缩压、心率。在22周龄时处死动物,观察心肌组织病理学切片,计算左心室质量指数,Rea-1time PCR检测心肌BDNF, Ras, ERK1/2, c-fox mRNA的表达,Western blot检测心肌BDNF, Ras, ERK1/2, c-fox的蛋白表达,qRT-PCR检测大鼠左心室心肌组织miRNA-1表达。
结果：(1)血压：卡托普利组及补肾大、中、小剂量组分别与SHR空白组相比较,血压均有不同程度的降低,差异有统计学性意义(P<0.05)。其中卡托普利组降压幅度明显,与补肾中、小剂量组相比差异有统计学性意义(P<0.05),而与补肾大剂量组比较则无差异(P=0.257)。
(2)心率：与SHR空白组相比较,补肾大剂量组心率下降幅度明显,差异有统计学性意义(P<0.01),而其余各组心率下降不显著。与卡托普利组相比,补肾大剂量组心率下降明显,差异有统计学性意义(P<0.05),而其余各组心率下降不显著。
(3)左心室心肌质量指数：与WKY组相比,SHR空白组、卡托普利组及补肾降压方大、中、小剂量组均显著升高,差异具有显著统一学意义(P<0.01)；与SHR空白组相比,WKY组出现显著性差异,具有显著统计学意义(P<0.01),而卡托普利组及补肾降压方大剂量组也显示有差异,具有统计学意义(P<0.05)；与卡托普利组相比,WKY组显著降低,差异具有显著的统计学意义(P<0.01),而SHR空白组显著增加,差异具有统计学意义(P<0.05)。
(4) BDNF, Ras, ERK1/2及c-fox mRNA:①在BDNF mRNA表达方面,与WKY组比较,SHR空白组、卡托普利组以及补肾大、中、小剂量组心脏BDNF mRNA含量均有显著升高(P<0.01)；与SHR空白组比较,WKY组、卡托普利组与补肾大剂量组心脏BDNF mRNA含量均有显著降低(P<0.01),补肾中剂量组含量也降低,差异有统计学意义(P<0.05),补肾小剂量未见显著性差异(P>0.05)；与卡托普利组比较,WKY组、SHR空白组及补肾中、小剂量BDNF mRNA含量显著升高,差异具有显著统计学意义(P<0.01),补肾大剂量组含量也升高,差异具有统计学意义(P<0.05)。
②在Ras mRNA表达方面,与WKY组比较,SHR空白组以及补肾小剂量组心脏Ras mRNA含量均有显著升高(P<0.01),补肾大、中剂量组升高(P<0.05),而卡托普利组未见显著性差异(P>0.05)；与SHR空白组比较,WKY组、卡托普利组与补肾大、中剂量组心脏Ras mRNA含量均有显著降低(P<0.01),补肾小剂量组含量无统计学意义(P>0.05)；与卡托普利组比较,SHR空白组及补肾小剂量Ras mRNA含量显著升高,差异具有显著统计学意义(P<0.01), WKY组、补肾大、中剂量组含量也升高,但差异无统计学意义。
③在ERK1/2mRNA表达方面,与WKY组比较,SHR空白组以及补肾小剂量组心脏ERK1/2mRNA含量均有显著升高(P<0.01),补肾大、中剂量组升高(P<0.05),而卡托普利组未见显著性差异(P>0.05)；与SHR空白组比较,WKY组、卡托普利组与补肾大、中剂量组心脏ERK1/2mRNA含量均有显著降低(P<0.01),补肾小剂量组含量无统计学意义(P>0.05)；与卡托普利组比较,SHR空白组及补肾小剂量ERK1/2mRNA含量显著升高,差异具有显著统计学意义(P<0.01),WKY组、补肾大、中剂量组含量也升高,但差异无统计学意义(P>0.05)。
④在c-fox mRNA表达方面,与WKY组比较,SHR空白组、卡托普利组以及补肾大、中、小剂量组心脏c-fox mRNA含量均有显著升高(P<0.01)；与SHR空白组比较,WKY组、卡托普利组与补肾大、中、小剂量组心脏c-fox mRNA含量均有显著降低(P<0.01)；与卡托普利组比较,WKY组、SHR空白组及补肾大、中、小剂量c-fox mRNA含量显著升高,差异具有显著统计学意义(P<0.01)。
(5)mirRNA-1:与WKY组比较,卡托普利组未见统计学意义(P>0.05),而SHR空白组及补肾大、中、小剂量组均显著降低,差异具有统计学意义(P<0.05)；与SHR空白组比较,WKY组、卡托普利组与补肾大、中、小剂量组心脏mirRNA-1表达均显著升高,差异具有统计学意义(P<0.05)；与卡托普利组比较,WKY组与补肾大剂量差异未见统计学意义(P>0.05),而SHR空白组及补肾中、小剂量组均显著降低,差异具有统计学意义(P<0.05)。
结论：(1)补肾降压方能够在SHR模型上稳定血压,减慢心率；(2)补肾降压方能在一定程度上逆转心室肥厚；(3)高血压心室肥厚可能与下调micro RNA-1水平进而促使ERK信号通路及其关键靶标过表达有关；(4)补肾降压方逆转高血压心室肥厚的作用机制可能与上调microRNA-1水平进而抑制ERK信号通路及其关键靶标过表达有关；(5)补肾降压方各剂量组之间呈现出一定的剂量依赖性,且大剂量时降压,减慢心率,逆转心室肥厚,上调microRNA-1水平,及抑制ERK信号通路作用明显。
Theoretical Research
Hypertension, which directly threatens quality of life, is a major contributor to cardiovascular and cerebrovascular events. Over the past two decades, domestic and foreign scholars have agreed upon various standards in the treatment of hypertension, and considerable progress has been made in the field of antihypertensive drugs. Oral antihypertensive drugs represent a milestone in hypertension therapy. However, the blood pressure (BP) standard for patients with hypertension is far from satisfactory. The study of Chinese herbal formulas for treating hypertension has received much research attention. These studies seek to integrate traditional and Western medicine in China. Currently, Chinese herbal formulas are known to have an outstanding advantage with regard to bodily regulation. Research shows that Chinese herbal medicine (CHM) has multi-protected mechanisms such as smoothly controlling the blood pressure, reducing blood pressure variability, protecting target organs, reversing left ventricular remodeling, regulating renin-angiotensin-aldosterone system, reversing risk factors of hypertension, regulating metabolism of glucose and lipid, enhancing the insulin sensitivity, regulating vasoactive substances, improving endothelial function, inhibiting vascular smooth muscle cell proliferation, blocking calcium channels, improving life quality and clinical symptoms, and reversing uncontrollable factors of blood pressure. However, the effect of CHM on the primary endpoints is still unclear. The benefits of CHM for hypertension need to be confirmed in the future with randomized controlled trials (RCTs) of more persuasive primary endpoints and high-quality SRs.
According to TCM theory, hypertension belongs to the category of vertigo. Therefore, TCM principles, which have been used to treat vertigo in clinical practice for centuries, have been applied to the treatment of hypertension by physicians in China. Consequently, it is widely accepted that hypertension should be treated based on the theory of liver-wind until now. However, due to the different understandings between vertigo and hypertension, it can't be neglected that some new problems have arisen in treating hypertension. Previous treatment experience can't solve these problems perfectly. Both specific differences between them and new understandings about the etiology, pathogenesis, diagnosis and treatment of hypertension are needed to be explored.
It is worth noting that, the natural process of hypertension is changed directly because of constantly optimizing and widely using antihypertensive drugs, which results in the change of evolution law in traditional Chinese medicine pathology correspondingly. It is found out that kidney deficiency is the key pathology of hypertension nowadays. It is highly related to the following4reasons:physiological kidney deficiency due to the aged, pathological kidney deficiency due to chronic disease, the adverse effects of antihypertensive drugs, and the therapeutic function of antihypertensive drugs. Consequently, tonifying the kidney is an important therapeutic strategy for the treatment of hypertension.
Bu shen jiang ya decoction (BSJYD) is a clinical experience prescription based on the therapeutic principle of tonifying kidney. Early literature researches and clinical studies have shown that BSJYD could contribute to lowering blood pressure and clinical symptoms in hypertensive patients with kidney deficiency syndrome. Therefore, aiming the two main objectives in the treatment of hypertension including stabilizing blood pressure and protecting target organs, this experimental study was designed to investigate the effect BSJYD on blood pressure and ventricular hypertrophy and its potential mechanisms.
Experimental Study
Objective:To investigate the effect of BSJYD on blood pressure, heart rate, and ventricular hypertrophy in SHR, and the effect of BSJYD on microRNA-1that regulating ERK signaling pathway in LVH with SHR.
Method:60male SHRs of12weeks old were randomly and equally divided into5groups:the untreated control group (SHR-C), BSJYD high dose group (SHR-Bh), BSJYD middle dose group (SHR-Bm), BSJYD low dose group (SHR-B1), and the positive control group (SHR-Ca), and they were treated respectively with distilled water, high dose BSJYD, middle dose BSJYD, low dose BSJYD, and captoprilby dissolving in equalvolume ofwater administrated via gavage for8weeks. Besides,12age matched Wistar-Kyoto (WKY) rats treated with distilled water were allocated in a normal control group. Blood pressure and heart rate were measured every2weeks. Rats were managed at22weeks. Myocardialpathology and left ventricular mass index (LVMI) were observed, and their mRNAexpressions of BDNF, Ras, ERK1/2, and c-fox were determined by Real-tmie PCR. the expressions of BDNF, Ras, ERK1/2, and c-fox were also determined by western blot (WB). miRNA-1was also measured by qRT-PCR.
Results:(1) blood pressure:as compared with SHR-C, blood pressure in SHR-Bh, SHR-Bm, SHR-B1, and SHR-Ca were significantly lowered (P<0.05). As compared with SHR-Ca, SHR-Bm and SHR-B1were significantly elevated (P<0.05), while there is no significantly difference in SHR-Bh (P=0.257). Among them, blood pressure was decreased most significantly in SHR-Ca and SHR-Bh.
(2) heart rate:as compared with SHR-C, heart rate in SHR-Bh were significantly lowered (P<0.01), while heart rate in SHR-Bm, SHR-B1, and SHR-Ca were not significantly lowered. As compared with SHR-Ca, SHR-Bh were significantly lowered (P<0.05), while there is no significantly difference in the other groups (P>0.05).
(3) LVMI:as compared with WKY, LVMI in SHR-C, SHR-Ca, SHR-Bh SHR-Bm, and SHR-B1were significantly elevated (P<0.01). As compared with SHR-C, LVMI in WKY, SHR-Ca, and SHR-Bh were significantly lowered (P<0.05). As compared with SHR-Ca, LVMI in WKY was significantly lowered (P<0.01), while LVMI in SHR-C was significantly elevated (P<0.05).
(4) BDNF, Ras, ERK1/2及c-fox mRNA:①In the mRNA expression of BDNF, as compared with WKY, BDNF in SHR-C, SHR-Ca, SHR-Bh SHR-Bm, and SHR-B1were significantly elevated (P<0.01). As compared with SHR-C, BDNF in WKY, SHR-Ca, SHR-Bh, and SHR-Bm were significantly lowered (P<0.01), while there is no differencr in SHR-B1(P>0.05). As compared with SHR-Ca, BDNF in WKY, SHR-C, SHR-Bh, SHR-Bm, and SHR-B1were significantly elevated (P<0.05).
②In the mRNA expression of Ras, as compared with WKY, Ras in SHR-C, SHR-Bh SHR-Bm, and SHR-B1were significantly elevated (P<0.05), while there is no difference in SHR-Ca (P>0.05). As compared with SHR-C, Ras in WKY, SHR-Ca, SHR-Bh, and SHR-Bm were significantly lowered (P<0.01), while there is no differencr in SHR-B1(P>0.05). As compared with SHR-Ca, Ras in SHR-C and SHR-B1were significantly elevated (P<0.01), while there were no difference in WKY, SHR-Bh, and SHR-Bm.
③In the mRNA expression of ERK1/2, as compared with WKY, ERK1/2in SHR-C, SHR-Bh SHR-Bm, and SHR-B1were significantly elevated (P<0.01), while there is no difference in SHR-Ca (P>0.05). As compared with SHR-C, ERK1/2in WKY, SHR-Ca, SHR-Bh, and SHR-Bm were significantly lowered (P<0.01), while there is no differencr in SHR-Bl (P>0.05). As compared with SHR-Ca, ERK1/2in SHR-C and SHR-Bl were significantly elevated(P<0.01), while there were no difference in WKY, SHR-Bh, and SHR-Bm (P>0.05).
④In the mRNA expression of c-fox, as compared with WKY, c-fox in SHR-C, SHR-Ca, SHR-Bh SHR-Bm, and SHR-B1were significantly elevated (P<0.01). As compared with SHR-C, c-fox in WKY, SHR-Ca, SHR-Bh, SHR-Bm, and SHR-Bl were significantly lowered (P<0.01). As compared with SHR-Ca, c-fox in WKY, SHR-C, SHR-Bh, SHR-Bm, and SHR-Bl were significantly elevated (P<0.01).
(5) mirRNA-1:as compared with WKY, mirRNA-1in SHR-C, SHR-Bh SHR-Bm, and SHR-Bl were significantly lowered (P<0.05), while there is no difference in SHR-Ca (P>0.05). As compared with SHR-C, mirRNA-1in WKY, SHR-Ca, SHR-Bh, SHR-Bm, and SHR-B1were significantly elevated (P<0.01). As compared with SHR-Ca, mirRNA-1in SHR-C, SHR-Bm, and SHR-B1were significantly lowered (P<0.05), while there were no difference in WKY and SHR-Bh
Conclusion:(1) BSJYD could control blood pressure and reduce heart rate in SHR.(2) BSJYD could reverse LVH to a certain extent.(3) Hypertensive ventricular hypertrophy maybe caused by down-regulating microRNA-1to promote the overexpression of ERK signaling pathway and its key targets.(4) Mechanism of BSJYD reversing LVH maybe related to up-regulating microRNA-1to inhibite the expression of ERK signaling pathway and its key targets.(5) A dose-dependent effection was shown between SHR-Bh, SHR-Bm, and SHR-Bl. As compared with SHR-Bm and SHR-B1, SHR-Bh has shown better effect on reducing blood pressure and heart rate, reversing LVH, up-regulating microRNA-1, and inhibiting the expression of ERK signaling pathway.
高血压是心脑血管事件的重要危险因素。现代医学在降压治疗上取得长足进步,但血压达标率仍不满意。中医药在平稳降压的同时还具有多环节保护机制,但对主要终点事件的证据有待加强。
高血压病属“眩晕”范畴,从肝论治已成为现今临床治疗的‘专家共识”。但通过对历代文献的系统梳理,发现与古代的“眩晕’相比,无论在内涵、病机还是治疗上,高血压与之均存在较大差异。由于在理论认识上存在不足,临床治疗上存在错位,导致中医药降压疗效不理想。这就是照搬古代肝风理论治疗高血压病收效欠佳的根源所在。因此,对本病病机特征的认识,切莫先入为主囿于阴虚阳亢,而应忠实于临床实际,突破既往从肝论治的理论局限,重新探索其证治规律。
现代临床对高血压疾病的早期诊断、降压西药的早期干预以及不断优化与广泛运用,使升高的血压被迅速控制,直接改变了高血压病的自然进程,使其中医学病机演变规律已经发生了很大变化。进一步研究发现,肾虚是现今临床治疗高血压病面临的新问题。形成肾虚证的原因主要与年老导致的生理性肾虚,大病久病及肾导致的病理性肾虚,降压西药的不良反应,以及降压西药的治疗作用密切相关。因此,肾虚是现今高血压病病机关键,而补肾降压则为其重要治疗策略。
“补肾降压方”是基于补肾降压的治则治法而形成的治疗高血压病的经验方。前期文献及临床研究显示,本方在改善高血压病患者肾虚证的同时,还能平稳降压。围绕“稳定血压”及“保护靶器官”这两大目标,本实验旨在探讨中药对血压、心率、左心室肥厚的影响及其调控机制,为补肾降压这一新策略提供实验依据。
实验研究
目的：观察补肾降压方对自发性高血压大鼠(spontaneous hypertensive rat, SHR)血压、心率及心室肥厚的影响,并探讨其对microRNA-1调控SHR心室肥厚ERK信号通路的影响。
方法：以12周龄WKY大鼠为对照,将12周龄SHR大鼠随机分为SHR空白组、补肾大剂量组、补肾中剂量组、补肾小剂量组、卡托普利组,连续灌胃8周,每2周采用套尾法测定SHR清醒状态下尾动脉收缩压、心率。在22周龄时处死动物,观察心肌组织病理学切片,计算左心室质量指数,Rea-1time PCR检测心肌BDNF, Ras, ERK1/2, c-fox mRNA的表达,Western blot检测心肌BDNF, Ras, ERK1/2, c-fox的蛋白表达,qRT-PCR检测大鼠左心室心肌组织miRNA-1表达。
结果：(1)血压：卡托普利组及补肾大、中、小剂量组分别与SHR空白组相比较,血压均有不同程度的降低,差异有统计学性意义(P<0.05)。其中卡托普利组降压幅度明显,与补肾中、小剂量组相比差异有统计学性意义(P<0.05),而与补肾大剂量组比较则无差异(P=0.257)。
(2)心率：与SHR空白组相比较,补肾大剂量组心率下降幅度明显,差异有统计学性意义(P<0.01),而其余各组心率下降不显著。与卡托普利组相比,补肾大剂量组心率下降明显,差异有统计学性意义(P<0.05),而其余各组心率下降不显著。
(3)左心室心肌质量指数：与WKY组相比,SHR空白组、卡托普利组及补肾降压方大、中、小剂量组均显著升高,差异具有显著统一学意义(P<0.01)；与SHR空白组相比,WKY组出现显著性差异,具有显著统计学意义(P<0.01),而卡托普利组及补肾降压方大剂量组也显示有差异,具有统计学意义(P<0.05)；与卡托普利组相比,WKY组显著降低,差异具有显著的统计学意义(P<0.01),而SHR空白组显著增加,差异具有统计学意义(P<0.05)。
(4) BDNF, Ras, ERK1/2及c-fox mRNA:①在BDNF mRNA表达方面,与WKY组比较,SHR空白组、卡托普利组以及补肾大、中、小剂量组心脏BDNF mRNA含量均有显著升高(P<0.01)；与SHR空白组比较,WKY组、卡托普利组与补肾大剂量组心脏BDNF mRNA含量均有显著降低(P<0.01),补肾中剂量组含量也降低,差异有统计学意义(P<0.05),补肾小剂量未见显著性差异(P>0.05)；与卡托普利组比较,WKY组、SHR空白组及补肾中、小剂量BDNF mRNA含量显著升高,差异具有显著统计学意义(P<0.01),补肾大剂量组含量也升高,差异具有统计学意义(P<0.05)。
②在Ras mRNA表达方面,与WKY组比较,SHR空白组以及补肾小剂量组心脏Ras mRNA含量均有显著升高(P<0.01),补肾大、中剂量组升高(P<0.05),而卡托普利组未见显著性差异(P>0.05)；与SHR空白组比较,WKY组、卡托普利组与补肾大、中剂量组心脏Ras mRNA含量均有显著降低(P<0.01),补肾小剂量组含量无统计学意义(P>0.05)；与卡托普利组比较,SHR空白组及补肾小剂量Ras mRNA含量显著升高,差异具有显著统计学意义(P<0.01), WKY组、补肾大、中剂量组含量也升高,但差异无统计学意义。
③在ERK1/2mRNA表达方面,与WKY组比较,SHR空白组以及补肾小剂量组心脏ERK1/2mRNA含量均有显著升高(P<0.01),补肾大、中剂量组升高(P<0.05),而卡托普利组未见显著性差异(P>0.05)；与SHR空白组比较,WKY组、卡托普利组与补肾大、中剂量组心脏ERK1/2mRNA含量均有显著降低(P<0.01),补肾小剂量组含量无统计学意义(P>0.05)；与卡托普利组比较,SHR空白组及补肾小剂量ERK1/2mRNA含量显著升高,差异具有显著统计学意义(P<0.01),WKY组、补肾大、中剂量组含量也升高,但差异无统计学意义(P>0.05)。
④在c-fox mRNA表达方面,与WKY组比较,SHR空白组、卡托普利组以及补肾大、中、小剂量组心脏c-fox mRNA含量均有显著升高(P<0.01)；与SHR空白组比较,WKY组、卡托普利组与补肾大、中、小剂量组心脏c-fox mRNA含量均有显著降低(P<0.01)；与卡托普利组比较,WKY组、SHR空白组及补肾大、中、小剂量c-fox mRNA含量显著升高,差异具有显著统计学意义(P<0.01)。
(5)mirRNA-1:与WKY组比较,卡托普利组未见统计学意义(P>0.05),而SHR空白组及补肾大、中、小剂量组均显著降低,差异具有统计学意义(P<0.05)；与SHR空白组比较,WKY组、卡托普利组与补肾大、中、小剂量组心脏mirRNA-1表达均显著升高,差异具有统计学意义(P<0.05)；与卡托普利组比较,WKY组与补肾大剂量差异未见统计学意义(P>0.05),而SHR空白组及补肾中、小剂量组均显著降低,差异具有统计学意义(P<0.05)。
结论：(1)补肾降压方能够在SHR模型上稳定血压,减慢心率；(2)补肾降压方能在一定程度上逆转心室肥厚；(3)高血压心室肥厚可能与下调micro RNA-1水平进而促使ERK信号通路及其关键靶标过表达有关；(4)补肾降压方逆转高血压心室肥厚的作用机制可能与上调microRNA-1水平进而抑制ERK信号通路及其关键靶标过表达有关；(5)补肾降压方各剂量组之间呈现出一定的剂量依赖性,且大剂量时降压,减慢心率,逆转心室肥厚,上调microRNA-1水平,及抑制ERK信号通路作用明显。
Theoretical Research
Hypertension, which directly threatens quality of life, is a major contributor to cardiovascular and cerebrovascular events. Over the past two decades, domestic and foreign scholars have agreed upon various standards in the treatment of hypertension, and considerable progress has been made in the field of antihypertensive drugs. Oral antihypertensive drugs represent a milestone in hypertension therapy. However, the blood pressure (BP) standard for patients with hypertension is far from satisfactory. The study of Chinese herbal formulas for treating hypertension has received much research attention. These studies seek to integrate traditional and Western medicine in China. Currently, Chinese herbal formulas are known to have an outstanding advantage with regard to bodily regulation. Research shows that Chinese herbal medicine (CHM) has multi-protected mechanisms such as smoothly controlling the blood pressure, reducing blood pressure variability, protecting target organs, reversing left ventricular remodeling, regulating renin-angiotensin-aldosterone system, reversing risk factors of hypertension, regulating metabolism of glucose and lipid, enhancing the insulin sensitivity, regulating vasoactive substances, improving endothelial function, inhibiting vascular smooth muscle cell proliferation, blocking calcium channels, improving life quality and clinical symptoms, and reversing uncontrollable factors of blood pressure. However, the effect of CHM on the primary endpoints is still unclear. The benefits of CHM for hypertension need to be confirmed in the future with randomized controlled trials (RCTs) of more persuasive primary endpoints and high-quality SRs.
According to TCM theory, hypertension belongs to the category of vertigo. Therefore, TCM principles, which have been used to treat vertigo in clinical practice for centuries, have been applied to the treatment of hypertension by physicians in China. Consequently, it is widely accepted that hypertension should be treated based on the theory of liver-wind until now. However, due to the different understandings between vertigo and hypertension, it can't be neglected that some new problems have arisen in treating hypertension. Previous treatment experience can't solve these problems perfectly. Both specific differences between them and new understandings about the etiology, pathogenesis, diagnosis and treatment of hypertension are needed to be explored.
It is worth noting that, the natural process of hypertension is changed directly because of constantly optimizing and widely using antihypertensive drugs, which results in the change of evolution law in traditional Chinese medicine pathology correspondingly. It is found out that kidney deficiency is the key pathology of hypertension nowadays. It is highly related to the following4reasons:physiological kidney deficiency due to the aged, pathological kidney deficiency due to chronic disease, the adverse effects of antihypertensive drugs, and the therapeutic function of antihypertensive drugs. Consequently, tonifying the kidney is an important therapeutic strategy for the treatment of hypertension.
Bu shen jiang ya decoction (BSJYD) is a clinical experience prescription based on the therapeutic principle of tonifying kidney. Early literature researches and clinical studies have shown that BSJYD could contribute to lowering blood pressure and clinical symptoms in hypertensive patients with kidney deficiency syndrome. Therefore, aiming the two main objectives in the treatment of hypertension including stabilizing blood pressure and protecting target organs, this experimental study was designed to investigate the effect BSJYD on blood pressure and ventricular hypertrophy and its potential mechanisms.
Experimental Study
Objective:To investigate the effect of BSJYD on blood pressure, heart rate, and ventricular hypertrophy in SHR, and the effect of BSJYD on microRNA-1that regulating ERK signaling pathway in LVH with SHR.
Method:60male SHRs of12weeks old were randomly and equally divided into5groups:the untreated control group (SHR-C), BSJYD high dose group (SHR-Bh), BSJYD middle dose group (SHR-Bm), BSJYD low dose group (SHR-B1), and the positive control group (SHR-Ca), and they were treated respectively with distilled water, high dose BSJYD, middle dose BSJYD, low dose BSJYD, and captoprilby dissolving in equalvolume ofwater administrated via gavage for8weeks. Besides,12age matched Wistar-Kyoto (WKY) rats treated with distilled water were allocated in a normal control group. Blood pressure and heart rate were measured every2weeks. Rats were managed at22weeks. Myocardialpathology and left ventricular mass index (LVMI) were observed, and their mRNAexpressions of BDNF, Ras, ERK1/2, and c-fox were determined by Real-tmie PCR. the expressions of BDNF, Ras, ERK1/2, and c-fox were also determined by western blot (WB). miRNA-1was also measured by qRT-PCR.
Results:(1) blood pressure:as compared with SHR-C, blood pressure in SHR-Bh, SHR-Bm, SHR-B1, and SHR-Ca were significantly lowered (P<0.05). As compared with SHR-Ca, SHR-Bm and SHR-B1were significantly elevated (P<0.05), while there is no significantly difference in SHR-Bh (P=0.257). Among them, blood pressure was decreased most significantly in SHR-Ca and SHR-Bh.
(2) heart rate:as compared with SHR-C, heart rate in SHR-Bh were significantly lowered (P<0.01), while heart rate in SHR-Bm, SHR-B1, and SHR-Ca were not significantly lowered. As compared with SHR-Ca, SHR-Bh were significantly lowered (P<0.05), while there is no significantly difference in the other groups (P>0.05).
(3) LVMI:as compared with WKY, LVMI in SHR-C, SHR-Ca, SHR-Bh SHR-Bm, and SHR-B1were significantly elevated (P<0.01). As compared with SHR-C, LVMI in WKY, SHR-Ca, and SHR-Bh were significantly lowered (P<0.05). As compared with SHR-Ca, LVMI in WKY was significantly lowered (P<0.01), while LVMI in SHR-C was significantly elevated (P<0.05).
(4) BDNF, Ras, ERK1/2及c-fox mRNA:①In the mRNA expression of BDNF, as compared with WKY, BDNF in SHR-C, SHR-Ca, SHR-Bh SHR-Bm, and SHR-B1were significantly elevated (P<0.01). As compared with SHR-C, BDNF in WKY, SHR-Ca, SHR-Bh, and SHR-Bm were significantly lowered (P<0.01), while there is no differencr in SHR-B1(P>0.05). As compared with SHR-Ca, BDNF in WKY, SHR-C, SHR-Bh, SHR-Bm, and SHR-B1were significantly elevated (P<0.05).
②In the mRNA expression of Ras, as compared with WKY, Ras in SHR-C, SHR-Bh SHR-Bm, and SHR-B1were significantly elevated (P<0.05), while there is no difference in SHR-Ca (P>0.05). As compared with SHR-C, Ras in WKY, SHR-Ca, SHR-Bh, and SHR-Bm were significantly lowered (P<0.01), while there is no differencr in SHR-B1(P>0.05). As compared with SHR-Ca, Ras in SHR-C and SHR-B1were significantly elevated (P<0.01), while there were no difference in WKY, SHR-Bh, and SHR-Bm.
③In the mRNA expression of ERK1/2, as compared with WKY, ERK1/2in SHR-C, SHR-Bh SHR-Bm, and SHR-B1were significantly elevated (P<0.01), while there is no difference in SHR-Ca (P>0.05). As compared with SHR-C, ERK1/2in WKY, SHR-Ca, SHR-Bh, and SHR-Bm were significantly lowered (P<0.01), while there is no differencr in SHR-Bl (P>0.05). As compared with SHR-Ca, ERK1/2in SHR-C and SHR-Bl were significantly elevated(P<0.01), while there were no difference in WKY, SHR-Bh, and SHR-Bm (P>0.05).
④In the mRNA expression of c-fox, as compared with WKY, c-fox in SHR-C, SHR-Ca, SHR-Bh SHR-Bm, and SHR-B1were significantly elevated (P<0.01). As compared with SHR-C, c-fox in WKY, SHR-Ca, SHR-Bh, SHR-Bm, and SHR-Bl were significantly lowered (P<0.01). As compared with SHR-Ca, c-fox in WKY, SHR-C, SHR-Bh, SHR-Bm, and SHR-Bl were significantly elevated (P<0.01).
(5) mirRNA-1:as compared with WKY, mirRNA-1in SHR-C, SHR-Bh SHR-Bm, and SHR-Bl were significantly lowered (P<0.05), while there is no difference in SHR-Ca (P>0.05). As compared with SHR-C, mirRNA-1in WKY, SHR-Ca, SHR-Bh, SHR-Bm, and SHR-B1were significantly elevated (P<0.01). As compared with SHR-Ca, mirRNA-1in SHR-C, SHR-Bm, and SHR-B1were significantly lowered (P<0.05), while there were no difference in WKY and SHR-Bh
Conclusion:(1) BSJYD could control blood pressure and reduce heart rate in SHR.(2) BSJYD could reverse LVH to a certain extent.(3) Hypertensive ventricular hypertrophy maybe caused by down-regulating microRNA-1to promote the overexpression of ERK signaling pathway and its key targets.(4) Mechanism of BSJYD reversing LVH maybe related to up-regulating microRNA-1to inhibite the expression of ERK signaling pathway and its key targets.(5) A dose-dependent effection was shown between SHR-Bh, SHR-Bm, and SHR-Bl. As compared with SHR-Bm and SHR-B1, SHR-Bh has shown better effect on reducing blood pressure and heart rate, reversing LVH, up-regulating microRNA-1, and inhibiting the expression of ERK signaling pathway.
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