Effects And Mechanisms Of Telmisartan On Vascular Endothelial Function Of Hypertension And Artherosclerosis

Background Hypertension and atherosclerosis(AS) are two major diseases endangering the human health seriously, which are called"the fatal killers". Of the patients with the death and attack of cadio-cerebrovascular diseases, more than half are related to hypertension in our country, and AS is the major pathologic basis of cadio-cerebrovascular diseases, such as coronary artery disease, cerebral ischemic stroke, peripheral vascular disease. Vascular endothelial dysfunction(VED) and the excessive activation of renin-angiotensin-aldosterone system(RAAS) are the common pathogenesis of them. VED is associated with hypertension, which had been proven to be the central role in the genesis, development and outcome of hypertension. At the same time, VED is the initial step of AS development, existed in every part of the chain of cardio-cerebrovascular events. Thus, reverse of VED is a new important target to treat hypertension and AS.Recently, some researchers have found that hepatocyte growth factor(HGF) and its specific receptor named as mesenchymal-epithelial transition factor(Met) have the central role in protecting vascular endothelial function, increasing the expression of HGF/Met system in vasculature may be a new attractive target for reversing VED. Peroxisome proliferator activated receptorγ(PPARγ) is one of the ligand-activated nuclear transcription factors, activating PPARγcan increase the expression of HGF and protect vascular endothelial function.The excessive activation of RAAS is a classic mechanism of hypertension and AS, which alone can induce VED. AngiotensinⅡtype 1 receptor blockers(ARBs) have been used to treat hypertension and coronary artery disease, which significantly improved their outcomes.Telmisartan is a new-type ARBs, because of its unique molecular structure, it can selectively agitate PPARγand protect vascular endothelial function, which maybe independent of antihypertensive effect. However, it is unclear whether telmisartan can decrease blood HGF and increase the expression of HGF/Met in vasculature and whether telmisartan protects vascular endothelial function via directly activating HGF/Met system.In our study, we investigated the effects of compound telmisartan on vascular endothelial function and serum HGF of hypertensive patients. Then we observed the effects of telmisartan on vascular endothelial function and the expressions of HGF, Met, PPARγin the aorta of AS model rabbit. At last, we explored the effect of telmisartan on VED of rabbit thoracic aortic rings impaired by AngⅡ, and analyzed whether telmisartan protected vascular endothelial function via directly agitating HGF/Met system and/or PPARγ. We hope to find the new targets to reverse VED and treat hypertension and AS, and open a new frontier for the development of novel drugs to control them.Aim To investigate the effects of compound telmisartan on vascular endothelial function and serum HGF of hypertensive patients, and to observe the effects of telmisartan on vascular endothelial function and the expressions of HGF, Met, PPARγin the aorta of AS model rabbit, and to explore the effect of telmisartan on VED of rabbit thoracic aortic rings impaired by AngⅡand analyze whether telmisartan protected vascular endothelial function via directly agitating HGF/Met system and/or PPARγ.Methods (1) Sixty-six hypertensive patients were randomly divided into compound telmisartan group(T group) and compound losartan group(L group) and received the treatment with either drug for 8 weeks. The rates of under control of 2-, 6-, 8-week treatment were calculated as means to assess antihypertensive efficacy. Serum HGF, plasma von Willebrand factor(vWF), serum nitric oxide(NO) and plasma endothelin(ET) were measured with sandwich enzyme-linked immunoabsorbent assay(ELISA), immuno-turbidimetric assay, chemical method and radio immunoassay(RIA) before and after 8-week treatment. Twenty healthy subjects were selected as control(control group). (2) Twenty-seven Male New-Zealand white rabbits aged 4 months were randomly divided into normal group, AS model group and telmisartan group, respectively received normal diets, high fat diets and high fat diets plus telmisartan treatment(10mg/kg/d) for 12 weeks. After 12 weeks, serum lipids were detected, arterial blood pressure was detected by carotid arterial cannula, abdominal aorta endothelial function was detected by transcutaneous ultrasound method, the accumulative concentration vasodilatator responses to Ach and SNP of the rabbit isolated thoracic aortic rings were detected using the organ bath pharmacology assay, morphology of rabbit aortic intima was observed by microscope(HE staining) and transmission electron microscope, the expressions of HGF, Met, PPARγin the rabbit aorta were detected by immunohistochemical staining and Western blot. (3) The thoracic aortas of New-Zealand white rabbits were dissected and cut into rings, and then these aortic rings were incubated in Krebs solution containing penicillin and streptomycin for 6h in a homeothermia incubator in the presence of vehicle, AngⅡ(0.01μmol/L, 0.1μmol/L, 1μmol/L), telmisartan(0.1μmol/L, 1μmol/L, 10μmol/L)+ AngⅡ(1μmol/L), SU11274 (5μmol/L)+telmisartan(10μmol/L)+AngⅡ(1μmol/L), GW9662(10μmol/L)+telmisartan (10μmol/L) + AngⅡ(1μmol/L), SU11274(5μmol/L)+ GW9662(10μmol/L)+telmisartan (10μmol/L)+AngⅡ(1μmol/L). After 6h, the accumulative concentration vasodilatator responses to Ach and SNP of the thoracic aortic rings were detected using the organ bath pharmacology assay.Results (1) After 8-week treatment SBP and DBP in two treatment groups were significally decreased(P<0.01), but the rates of under control were not different between two groups after treatment(P>0.05). The levels of serum HGF, plasma vWF, plasma ET and ET/NO ratio were higher and the levels of serum NO were lower in hypertensive patients before treatment than those in normal group(P<0.01). The levels of serum HGF, plasma vWF, plasma ET and ET/NO ratio after treatment were lower and the levels of serum NO were higher than those before treatment(P<0.01). The levels of plasma△vWF,△ET and△ET/△NO ratio were lower after treatment in T group than those after treatment in L group(P<0.01), but the levels of serum△HGF and△NO after treatment were not different between two groups(P>0.05). Spearman correlation showed that there was no significant correlation between the absolute values of blood pressure(BP) reduction and the absolute values of changes of other parameters in either group except a significant correlation of△vWF and△SBP in L group(P<0.01). (2) The AS rabbit model was replicated successfully by high fat diets of 12 weeks. Compared with normal group, vascular endothelial function in the AS model rabbits was obviously impaired(P<0.01) and the expression levels of HGF, Met, PPARγin aortas were significantly decreased(P<0.01). Compared with AS model group, telmisartan obviously improved VED, body weight and serum lipids, significantly reduced AS development and increased the expressions of HGF, Met, PPARγin aortas of AS model rabbits(P<0.01). (3) The accumulative concentration-vasodilatator responses to Ach of the phenylephrine(Phe)-contracted thoracic aortic rings significantly decreased in a dose-dependent manner by incubation with AngⅡ(0.01μmol/L, 0.1μmol/L, 1μmol/L) in vitro for 6h(P<0.01). Among them, the inhibiting effect of 1μmol/L AngⅡwas most obvious(P<0.01). The accumulative concentration-vasodilatator responses to SNP of them were not significantly impared(P>0.05). Telmisartan(0.1μmol/L, 1μmol/L, 10μmol/L) significantly reversed the impared accumulative concentration-vasodilatator responses to Ach of the Phe -contracted thoracic aortic rings by 1μmol/L AngⅡin a dose-dependent manner. Among them, the reveral effect of 10μmol/L telmisartan was most obvious(P<0.01). 5μmol/L SU11274 and 10μmol/L GW9662 both partially abolished the protective effect of 10μmol/L telmisartan on the impared accumulative concentration-vasodilatator responses to Ach of the Phe -contracted thoracic aortic rings by 1μmol/L AngⅡ(P<0.01). Compared with 10μmol/L GW9662, the effect of 5μmol/L SU11274 may be more significant(P<0.05).Conclusions (1) Compound telmisartan could effectively control BP, improve vascular endothelial function and decrease serum HGF of hypertensive patients, which was independent of antihypertensive effect. Compared with compound losartan, compound telmisartan had a significantly greater decrease in plasma vWF and ET, which indicated that it might improve vascular endothelial function better under the condition of the same lowering-BP effects. (2) In AS model rabbits, endothelium-dependented diastolic function was obviously impaired, the expression levels of HGF, Met, PPARγin aortas significantly decreased. Telmisartan obviously improved VED, serum lipids and reduced AS progression and increased the expression levels of HGF, Met, PPARγin aortas of AS model rabbits, which was independent of its antihypertensive effect. (3) AngⅡsignificantly impared the endothelium-dependent relaxation response induced by Ach of the rabbit thoracic aortic rings in a dose-dependent manner, without the effects on the endothelium-independent relaxation response induced by SNP of them. Telmisartan significantly reversed in a dose-dependent manner the endothelium-dependent relaxation response induced by Ach of the rabbit thoracic aortic rings impared by AngⅡ, its mechanisms were via directly activating HGF/Met system and PPARγ, especially was the former.