Effects And Mechanisms Of Diltiazem And Nisoldipine On The Left Ventricle Remodeling In Renal Hypertensive Rats

Objectives:Myocardial remodeling (MR) is an important factor that influences the progression of hypertension and it's complication and prognosis, it usually leads to heart failure if the remodeling couldn't be reversed efficiently and promptly. Related researches have revealed that not all the anti-hypertensive drugs could reverse MR efficiently, for example, minoxidil, the side effects including aggravating left ventricle hypertrophy and/or myocardial ischemia appeared at the same time of reducing blood pressure efficiently. So we must pay more attention to the anti-hypertensive drug's effects independent of reducing blood pressure, especially the side-effect on the heart. Now, calcium channel blockers (CCB) are widely used to treat the cardiovascular diseases including the hypertension. The related reports about the effects of CCB on MR were limited in the primary morphological research, such as the ratio left ventricle mass to body mass (mLV/mH). The field in the effects of CCB on extracellular matrix (ECM) and it's regulatory factors lack of detail research.In hypertension, left ventricle hypertrophy (LVH) and interstitial collagen net remodeling are the main changes. Interstitial collagen net remodeling plays an important role in MR, it not only affects the hardness and compliance of myocardium, but also takes part in the process of myocardial hypertrophy. Many factors are involved in the regulating of MR, including mechanical tension, neurohormone, cytokines, matrix metalloproteinases (MMPs), and it's tissue inhibitors (TIMPs), etc. Each factor has different effect on the process of MR, and different drug has different influence on these factors. In our study, the renal hypertensive rats (RHR) were established as the model, we focused on the process of MR in RHR and the changes of related neurohormone, cytokines, ECM and it's regulatory factors; then this process was interfered by two kinds of CCB with different target organ --- diltiazem (DIL) and nisoldipine (NIS), the related index and factors of MR were measured, we aimed to investigate the effects and molecular mechanisms of diltiazem and nisoldipine on the MR of RHR, provide the foundation for selecting reasonable CCB to cure hypertension in clinical practice, scan the candidate target for the design of new anti-hypertensive drug.Methods:Established RHR model by constricting renal artery with 2-kindey 2-clip operation. The model which met the requirements was selected 1 month after operation, then it was divided into four groups: the model of initial control (MIC: sampled while other groups were administered), the model of end control (MEC: 1% carboxymethylcellulose sodium(CMC-Na), 10 ml/kg), the model treated by dilitazem (MTD: DIL, 100 mg/kg), the model treated by nisoldipine (MTN: NIS, 10 mg/kg). In addition, the sham-operation (S group) and non-operation (N group) were set up as control (1% CMC-Na, 10 ml/kg). All groups were intragastricly administered q 12 h for 30 days. During administration, the systolic blood pressure (SBP) and heart rate (HR) were monitored at the scheduled time. At the endpoint of experiment, sacrificed these rats, related sample were collected and studied as follow: ① Scaled and calculated the ratio of mLV/mB; ② Paraffin section of heart, HE staining, the microstructure was studied; ③ Ultrathin section of heart and observed the changes of ultrastructure; ④ Measured regulatory factors in ciuculation by radioimmunoassay: renin-angiotensin-aldosterone (RAAS), endothelin (ET), atrial natriuretic peptide (ANP), interleukin-1 (IL-1), tumor necrosis factor (TNF); ⑤ Stained by picrosirus red, analyzed the collagen volume fraction(CVF) and the ratio type Ⅰto type Ⅲ; ⑥ Detected the fibronectin (FN), laminin (LN), MMP1, MMP2 and MMP9 by immunohistochemistry; ⑦ Measured the messenger RNA (mRNA) abundance of TIMP1 and TIMP2 by reverse transcript polymerase chain reaction (RT-PCR). Results:① Of 50 rats accepted the 2K2C operation, 37 rats met the requir...