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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 Hypertension exists dysfunction of vascular endothelial dysfunction, abnormal expression of nitric oxide synthase (NOS) may be involved in the process of hypertensive vascular disease. Objective To investigate the effects of benazepril and candesartan on endothelium-dependent vasodilation and NOS expression in spontaneously hypertensive rats (SHRs). Methods SHR at 12 weeks of age was randomly divided into 4 groups (n = 9): hypertension group (SHR group, normal saline), Benazepril group [Ben group, 10 mg / (kg · d) [Group Can, 4 mg / (kg · d)] and combination group [Com group, benazepril 5 mg / (kg · d) + candesartan 2 mg / (kg · d) . Nine WKY rats served as control group and received the same amount of normal saline. The tail arterial pressure was measured every two weeks. After 12 weeks, the pathological structure of the thoracic aorta was observed and the arterial vascular tone was measured. The expression of intima-induced NOS (iNOS) and endothelial NOS (eNOS) was detected by immunohistochemistry . Results Benazepril and candesartan can improve the aortic vascular structure of SHR. Compared with SHR group, the sensitivity of endothelium-dependent dilatation of rats in treatment group was significantly increased, while that in Com group was lower than that of Can group (P <0.05). The contractile responses of thoracic aortas induced by acetylcholine in SHR group pretreated with NOS inhibitor L-NAME were significantly stronger than those in WKY and treated groups (P <0.01) , There was no difference between the two groups. The contractile responses induced by norepinephrine (NE) were significantly decreased in the treatment group compared with those in the SHR group and those in the Com group at the lower NE concentration were better than those in the Can group and Ben group (P < 0.05). The expression of iNOS and eNOS in SHR group was lower than that in WKY group and administration group (P <0.01). The expression of iNOS in Can group was lower than that in Com group (P <0.05). Conclusions Endothelium-dependent systolic and diastolic dysfunction and the abnormal expressions of iNOS and eNOS may be involved in the pathogenesis and development of hypertension. Benazapril and candesartan can decrease the aortic endothelium-dependent systolic and diastolic function And structure, and up-regulate the expression of iNOS and eNOS, and the synergistic effect of the two in combination.