Effects Of Valsartan On Ventricular Hypertrophy And Expression Of Connective Tissue Growth Factor In The Rats With Renovascular Hypertension

Background & ObjectiveHypertension is a clinical syndrome caused by complex factors of genetics and environment. It can result in progressive damage of many target organs such as brain, heart, kidney, eye and aorta and is the chief criminal of the cardiovascular and cerebrovascular diseases.Rennin-angiotensin-aldosterone system (RAAS) plays important role in the pathophysiologic process of hypertension and the related target organ damages, and in which, the angiotensin II is the key effector molecule, as a circulatory or autocrine/ paracrine hormone, mainly through the angiotensin II receptor type1(AT1) pathway, leading to a series of biological effect, such as vasoconstriction, aldosterone and vasopressin release, salt and water retention, sympathetic activation. In addition, Ang II, via AT1 receptor, directly causes cell growth, oxidation, proliferation and migration, regulates the gene expression of various bioactive substances, and activates multiple intracellular signaling cascades. AT1 receptor has become an important intervention target of current medication on cardiovascular disease, many selective antagonists such as losartan, candesartan, valsartan etc have been developed and in use clinically.valsartan,one of selective antagonists of AT1 receptor, have been used clinically, to decrease blood pressure, which can also prevent or reverse remodeling of myocardium and artery with mechanisms not well known yet. Connective tissue growth factor(CTGF) is a kind of multi- peptides which was recently discovered and have many biological effects such as embryonic growth, cells hyperplasia and wound healing. In this study, we studed effects of valsartan on ventricular hypertrophy and expression of CTGF in the rats with renovascular hypertension (RVH).Methods32 male Sprague-Dawley two-kidney one-clip (2K1C) renovascular hypertension(RVH)rats were established. Then they were randomly divided into four groups: Some RVH rats received valsartan(RT1) or no treatment for 4 weeks(RC1),other RVH rats received valsartan(RT2) or no treatment for 8 weeks(RC2). In addition, sham-operated rats without any intervention were designed as controls(SC). RT1 and RT2 were given valsartan (30mg·kg-1·d-1) for treatment for 4weeks or 8weeks respectively. RC1 and RC2 were simply given equal-volume dd-H2O for 4weeks or 8weeks. The systolic blood pressure (SBP), the left ventricular weight(LVW) and the ratio of left ventricle weight to body weight(LVW/BW) were measured at the endpoint of the study. The myocardium collagen was observed by VG dyeing. The CTGF mRNA and protein in the left ventricular myocardium were assayed by semi-quantitative RT-PCR and immunohistochemical methods.Results1. 4 weeks later, the caudal artery pressure of the 2K1C rats increased over 50mmHg compared to the values before surgery ( P<0.01).2. The SBP decreased by about 33mmHg in the RT1 group and 63mmHg in the RT2 group after 4 and 8 weeks therapy with valsartan respectively (P <0.05). However, The SBP of RC1 and RC2 rats continued to increase by about 7-11mmHg. 2) Ventricular hypertrophy appeared at the 8th week and became more significant at the 12th week after surgery ,which could be partially prevented by valsartan(P<0.01). Compared with RC1 and RC2 rats, LVW and LVW/BW of RT1 and RT2 rats relieved significantly.3. Compared with the SC group, the expression of CTGF mRNA in the left ventricular myocardium increased significantly in RC1 and RC2 groups, which decreased significantly in RT1 and RT2 groups after 4wks or 8wks treatment with Valsartan(P<0.05).Conclusion1. Valsartan can significantly decrease SBP of RVH rats, reverse ventricular hypertrophy and alleviate myocardial fibrosis.2. Increased expression of CTGF mRNA and protein in left ventricular myocardium of rats with renovascular hypertension can be partially inhibited by valsartan.3) Increase of the expression of CTGF may be involved in the process of left ventricular remodeling of renovascular hypertension rats. This may be one of the mechanisms for AT1 receptor antagonists to prevent and reverse Left ventricle remodeling.