利尿剂对高血压大鼠细胞色素P450表氧化酶及血管紧张素Ⅱ1型受体基因表达的影响

Effects of thiazide diuretics on expression of cytochrome P450 epoxgenase and angiotensin Ⅱ receptor type 1 in spontaneously hypertensive rats

目的 噻嗪类利尿剂是广泛使用的降血压药物 ,然而其降血压机理仍然不完全清楚。本研究观察了氢氯噻嗪和吲哒帕胺对自发性高血压大鼠 (SHR)细胞色素P4 5 0 (CYP)表氧化酶 2C11及血管紧张素Ⅱ 1型受体 (AT1)基因表达的影响 ,以探讨其降低血压的分子机制。方法 成年雄性SHR随机分为三组 ,分别每日经胃管给予氢氯噻嗪 (10mg/kg)、吲哒帕胺 (0 6 2 5mg/kg)和等量去离子水灌胃 ,并测量血压和 2 4h尿量。 4周后 ,检测主要脏器的CYP表氧化酶 2C11和AT1表达情况及形态学变化。结果 氢氯噻嗪和吲哒帕胺用药 1周后动物血压降低 ,4周时降压幅度达到非常显著水平 ,与对照组比较P <0 0 1。同时在mRNA和蛋白质水平上调肾脏、心脏和主动脉中CYP表氧化酶 2C11和下调AT1基因表达 ;胶原染色显示 ,两种药物均能显著减少心肌胶原沉积 ,减轻高血压所致的肾脏损害。结论 噻嗪类利尿剂氢氯噻嗪和吲哒帕胺可能通过上调CYP表氧化酶及下调AT1降低血压和保护器官。

Objective To investigate the effects of hydrochlorothiazide (HCTZ) and indapamide on gene expression of cytochrome p450 (CYP) epoxgenase 2C11 and angiotensin Ⅱ receptor type 1 (AT 1) and to explore their molecular antihypertensive mechanisms. Methods Spontaneous hypertensive rats (SHR) were divided randomly into three groups and administered orally once a day with HCTZ (10 mg/kg), indapamide (0.625 mg/kg) and vehicle, respectively. Then body weight, blood pressure and 24 h urine volume were observed. All animals were sacrificed at 4 weeks after treatment. Morphological change and levels of gene expression of CYP2C11 and AT 1 were determined in major organs (heart, liver, kidneys and aorta). Results Both HCTZ and indapamide can effectively reduce blood pressure in SHRs, and also, up-regulate the gene expression of CYP 2C11 at mRNA and protein levels and down-regulate AT 1, so that attenuate damages of heart and kidneys induced by hypertension. Conclusion Thiazide diuretics can reduce elevated blood pressure and prevent organ damage through up-regulating the gene expression of CYP epoxgenase and down-regulating AT 1.