Paper One: Effects Of Farnesyltransferase Inhibition On Blood Pressure, Lipid Profiles And Ventricular Remodeling In Spontaneously Hypertensive Rats Paper Two: Dual Effects Of Sodium Aescinate On Vascular Tension In Rat Thoracic Aorta

Background:Statins, the inhibitor of 3-hydroxy -3- methyl-glutaric acid coenzyme A reductase at the upstream of mevalonate (MVA) pathway, was reported the roles in reducing blood pressure and improving ventricular remodeling in addition of its lipid-lowering effect. Farnesyltransferase (FT), an essential enzyme at the downstream of MVA pathway, was reported to be upregulated in spontaneously hypertensive rats (SHRs) compared with Wistar-Kyoto rats (WKYs). This upregulation was accompanied with ventricular remodeling.Objective:To determine whether inhibition of FT can influence the levels of blood pressure, lipid profiles and ventricular remodeling in SHRs and explore its underlying mechanisms. Methods:Twenty male SHRs were randomly divided into two groups consisting of the normal saline group (SHR-C) and FTI-276 intervention (307?g/kg/d i.v.) group (SHR-FTI). Six male age- and weight- matched WKY rats were housed as controls (WKY). Echocardiography was performed before and after 3-week's intervention. Blood pressures were monitored by the tailcuff method every week. After 3-week's intervention of FTI-276, hemodynamic was tested by carotid artery catheteration. Whole heart weight and left heart weight were obtained and weight indexs were calculated. Collagen content and distribution were evaluated by hydroxyproline content and immunohistochemistry technique. Cardiac function was evaluated by isolated SHR heart perfusion with Langendorff apparatus. Vasomotion was measured in isolated aortic rings of SHRs. Activation of Ras in heart was determined by pull-down assay, and phosphorylated ERK1/2 was obtained by Western blot. The mRNA expression of procollagen type?/?, TGF-?1, connective tissue growth factor and bone morphogenetic protein-7 in left ventricle were detected by real-time polymerase chain reaction.Results:Three weeks intervention of FTI-276 attenuated hydroxyproline content (P<0.05), collagen deposition (P<0.01), Ras activation, ERK1/2 phosphorylation (P<0.01) and mRNA expression of procollagen type I, TGF-?1 and CTGF, and elevated mRNA expression of BMP-7 (P<0.05) in left ventricles of SHRs. FTI-276 intervention decreased the IVSd compared with SHR-C (P<0.05). The levels of blood pressure and lipid profiles, hemodynamic, mass indexes, cardiac function and vasomotion in SHRs were not significantly affected by the intervention (P>0.05).Conclusions:The present study indicated that the inhibition of FT could attenuate the development of cardiac fibrosis and improve ventricular remodeling in SHRs. The beneficial effects might be mediated through suppression of the activation of Ras and ERK1/2 phosphorylation pathway. The enhanced mRNA expression of BMP-7 with inhibition of TGF-?1 and CTGF mRNA expression might be an important mechanism. Background:Sodium aescinate (SA) is triterpene saponin derived from horse chestnut (Aesculus hippocastanum) seed. Nowadays SA has been widely used as a vasoactive drug in clinical treatment. The effects of SA for the treatment are increasing intravenous tension, improving microcirculation, attenuating the exudative inflammation response and protecting endothelial cells from hypoxia and inflammation injury.Objective:This study was designed to investigate the effects of SA on rat isolated thoracic aorta and the possible mechanisms.Methods:Isometric tension was recorded in response to drugs in organ bath.Results:The effects of SA obeyed an all-or-nothing response. SA in relatively low dose (?50?g/ml,50?100?g/ml) had an endothelium-independent contractile effect on rat aorta (P<0.01), which depended on extracellular Ca2+ influx via L-type Ca2+ channel (P<0.05). SA in relatively high dose (?100?g/m1) also induced vasoconstriction in Ca2+ -free medium (P<0.01), which independed on the activity of inositol-1,4,5-trisphosphat receptor (IP3R), ryanodine-receptor (RYR) and protein kinase C (PKC). SA in relatively high dose (?100?g/m1) dilated both endothelium-intact and endothelium-denuded aortic rings pre-contracted by Phenylephrine (PE) or KC1 (each P<0.01). SA inhibited extracellular Ca2+ influx induced by PE or KC1 (each P<0.01), and had no activation effect on K+ channels on vascular smooth muscle. The relaxant effect of SA partly depended on the activity of NO-synthase, but not on the activity of cycloxygenase.Conclusions:Taken together, this study indicated that SA had dual effects on vascular tension in rat isolated thoracic aorta.