苯那普利与坎地沙坦改善自发性高血压大鼠血管内皮结构及功能

The Relationship between Serum Uric Acid and the Progression of Blood Pressure in Patients with Prehypertension

背景高血压患者存在血管内皮舒缩功能失调,一氧化氮合酶(NOS)表达异常可能参与了高血压血管病变过程。目的探讨苯那普利与坎地沙坦对自发性高血压大鼠(SHR)主动脉血管内皮依赖性舒缩功能和NOS表达的影响。方法 12周龄SHR随机分为4组(n=9):高血压组(SHR组,生理盐水)、苯那普利组[Ben组,10mg/(kg·d)]、坎地沙坦组[Can组,4mg/(kg·d)]和联合用药组[Com组,苯那普利5mg/(kg·d)+坎地沙坦2mg/(kg·d)],连续灌胃给药。9只WKY大鼠作为对照组,给予等量生理盐水。每2周测定尾动脉压;12周后,观察胸主动脉病理结构,进行动脉环血管张力测定,免疫组化方法检测主动脉内膜诱导型NOS(iNOS)和内皮型NOS(eNOS)的表达。结果苯那普利与坎地沙坦均能改善SHR主动脉血管结构。用药组大鼠内皮依赖性舒张敏感性较SHR组显著增加,Com组在乙酰胆碱浓度较低时效果优于Can组(P<0.05)。NOS抑制剂左旋硝基精氨酸甲酯(l-NAME)预处理的SHR组大鼠胸主动脉对乙酰胆碱诱发的收缩反应明显强于相同处理的WKY组及用药组大鼠(P<0.01),用药组之间无差异;对重酒石酸去甲肾上腺素(NE)诱发的收缩反应,用药组较SHR组明显降低,Com组在NE浓度较低时效果优于Can组和Ben组(P<0.05)。SHR组的iNOS、eNOS表达水平低于WKY组及给药组(P<0.01),Can组的iNOS表达水平低于Com组(P<0.05)。结论内皮舒缩功能及iNOS、eNOS表达的异常可能参与了高血压血管病变的发生、发展过程;苯那普利和坎地沙坦能在降压同时不同程度地改善SHR的主动脉内皮舒缩功能及结构,并上调iNOS、eNOS的表达,两者联用具有一定的协同作用。

Background The functional disorder of vascular endothelium exists in the development of hyper- tension. The abnormal expression of nitric oxide synthase （NOS） probably participate in the development of vascu- lar lesion caused by hypertension. Objective To explore the impact of benazepril （Ben} and candesartan （Can） on the aortic endothelial dependent vasodilatation and vasoconstriction and the expression of NOS of spontaneously hy- pertensive rats （SHR） Methods SHRs were randomly divided into four groups： SHR （n：9, given normal sa- line）, Benin=9, 10 mg/（kg· d）], Can [n=9, 4 mg/{kg·d}] and Corn In=9, Ben 5 mg/（kg · d）＋Can 2 mg/（kg · d）]; normotensive rats （WKY Group, n=9） served as control. The rats were given drugs or normal saline for 12 weeks and blood pressure was measured every two weeks by tail-cuff method. On the 12th weekend, the pathological structure changes of thoracic aorta was observed, vasoconstriction response of thoracic aorta was tested, and the expression of inducible NOS（iNOS） and endothelial NOS（eNOS） in aortic intima was detected by im- munohistochemistry. Results Both benazepril and eandesartan improved the structure of thoracic aorta in SHRs. Compared with SHR, the treated groups （ben, can, corn） showed higher endothelial dependent vasodilatation. A- mong the three groups, Corn had a sensitive vasodilatation than Can in response to low-concenlration acetyleholine （Aeh） （P〈0.05）After pretreatment with/-NAME, the constriction of thoracic aorta in response to Ach in the SHR rats responded more strongly than that of rats in WKY and the treated groups （P〈0.01 ） No difference was found among the three treated groups. The constriction response induced by noradrenaline （NE） in the treated rats was significantly weaker than that in SHR. Among the three groups, Com showed a better effect of constriction than Can and Ben in response to low-concentration NE （P〈0.05）. The expression level of iNOS and eNOS in SHR was markedly lower than that of WKY and treated groups （P〈0.01）. And among the three treated groups, Can showed a weaker expression of iNOS than Com （P〈0.05）. Conelusion The abnormity of endothelial depend- ent vasoactive function and the expression of iNOS and eNOS probably participate in the development of hypertensive vascular lesion. Candesartan and benazepril showed the effect of ameliorating the aortic endothelial dependent vaso- constriction and dilatation independent of blood pressure lowering and the aortic structure in SHRs, and up-regula- ting the expression of iNOS and eNOS. Benazepril and candesartan also showed a synergistic effect in combination.