Effect Of Valsartan And VSTEt On Blood Pressure And Cardiovascular Remodeling And The Underlying Mechanisms

BACKGROUNDHypertension is a common disease that impacts human health. It may cause tissue injury such as heart, kidney, brain and artery. Cardiovascular remodeling is the most important adaptation response. Cardiac remodeling includes cardiomyocyte hypertrophy, apoptosis and myocardial fibrosis, which may cause cardiac functional decompensation and ultimately results in heart failure. Vascular remodeling is structure and function alteration responsible for environment change, and is always related to a series of biological changes such as proliferation, hypertrophy, apoptosis, migration and production of extracellular matrix of vascular cells, and acts as an important pathology that aggravates hypertension. Valsartan, an angiotensionâ…¡type 1 receptor blocker (ARB), is one of the first-line antihypertensive drugs. It inhibits cardiovascular remodeling besides decreasing blood pressure. However, valsartan has very poor bioavailability (25%) and the individual variation is large.Thus, it is very important to elevate the absorbance in intestinal. We use valsartan as substrate and synthesised a seris of compounds, and selected VSTGEt for it is more active than others. The absorbance of VSTGEt in intestinal is 6 times higher than VST. In this study, we will compare the Effects of VST and VSTGEt on blood pressure and cardiovascular remodeling.It is well known that valsartan blocks angiotensionâ…¡type1 receptor and decreases blood pressure. It has been well established that angiotension II stimulates angiotensionâ…¡type 1 receptor on presynaptic membrane, and inhibits the release of calcitonin gene-related peptide (CGRP). CGRP, the neurotransmitter of capsaicin sensitive sensory nerves, possesses complex cardiovascular actions such potent vasodilator effect and inhibiting vascular remodeling. In the present study, we therefore compared the effects of valsartan and VSTGEt on blood pressure and cardiovascular remodeling, and explored the effects of valsartan and VSTGEt on the synthesis and release of CGRP.METHODSFifty sixteen-week male spontaneously hypertensive rats (SHR) were divided randomly into 6 groups:SHR group (n=6); solvent group (0.5% CMC-Na,2 ml/day, n=6); SHR and valsartan groups (10 or 30 mg/kg/day, n=9); SHR and VSTGEt groups (10 or 30 mg/kg/day, n=10). Sex-and age-matched normotensive Wistar rats (n=8) were treated with water by gavages as normal control. And rats were weighed weekly for adjusting drug dose. Blood pressure was measured per week by noninvasive blood pressure monitoring. Rats had a cardiac ultrasonography at 26-week-old, and then were sacrificed to isolate hearts, thoracic aorta, mesenteric artery and dorsal root ganglion. HE and Masson staining were used to see hypertrophy and fibrosis in heart and artery. The mRNA expression of Collagen I and collagen III in heart and CGRP in dorsal root ganglion were measured by real-time PCR. The expression of CGRP in superior mesenteric artery was examined by immunohistochemistry. CGRP concentration in plasma was determined by radioimmunoassay.RESULTSAfter administered drug for eight weeks, SHR showed a significant decrease in blood pressure and cardiovascular remodeling:(1) VST and VSTGEt significantly lowered blood pressure in a dose-dependent tendency, but the two drugs had no significant difference. (2) VST and VSTGEt significantly decreased IVS and LWPT in a dose-dependent tendency, but there was no significant difference between the two drugs. (3) VST and VSTGEt significantly reduced left ventricular weight in a dose-dependent tendency, but the results didn't show significant difference between the two drugs. (4) VST and VSTGEt significantly inhibited cadiomyocyte hypertrophy, decreased cardiac inflammation reaction and inhibited hypertrophy in thoracic aorta and superior mesenteric artery in a dose-dependent tendency, but the effects of the two drug had also no significant difference. (5) VST and VSTGEt alleviated cardiac interstitial fibrosis and vascular fibrosis in a dose-dependent tendency and there was no significance between the two drugs. (6) VST and VSTGEt notably increased plasma CGRP concentration, CGRP mRNA expression in dorsal root ganglion and CGRP protein in superior mesenteric artery in a dose-dependent tendency, but no significant difference was seen between the two drugs.CONCLUSIONVST and VSTGEt can decrease blood pressure and improve cardiovascular remodeling markedly, which may be related to stimulation of synthesis and release of CGRP.