螺内酯、厄贝沙坦单用或联用对肾血管性高血压大鼠心肌纤维化的影响及其机制  

Combined Spironolactone and Irbesartan Inhibits Myocardial Fibrosis in Renovascular Hypertensive Rats

作　　者：赵喜[1] 徐济良[1] 吴锋[1] 孟国梁[1] 乔进[1] 薛华[1] 

机构地区：[1]南通大学医学院药理学教研室,江苏南通226001

出　　处：《中华高血压杂志》2009年第8期700-705,共6页Chinese Journal of Hypertension

摘　　要：背景国外研究发现醛固酮能诱导血清和糖皮质激素诱导的蛋白激酶(SGK)+/+大鼠、结缔组织生长因子(CTGF)的表达和心肌纤维化,但在SGK-/-大鼠中醛固酮诱导的心肌纤维化过程完全被阻断,说明SGK1是醛固酮诱导心肌纤维化的必需条件。螺内酯与厄贝沙坦能否抑制心肌组织SGK1的表达,尚不清楚。目的观察螺内酯和厄贝沙坦单用或联合应用对肾血管性高血压大鼠(RHR)心肌纤维化的疗效,观察心肌SGK1、CTGF表达的变化,探讨螺内酯、厄贝沙坦抑制心肌纤维化的可能机制。方法采用两肾一夹法在SD大鼠中建立肾血管性高血压大鼠模型。随机分为5组:假手术组(n=8)、肾性高血压组(RHR组,n=8)、螺内酯组[20mg/(kg·d),n=8]、厄贝沙坦组[50mg/(kg·d),n=8]及联合用药组[联用组,螺内酯20mg/(kg·d)+厄贝沙坦50mg/(kg·d),n=8],每两周测定尾动脉收缩压。连续给药8周后测定左室心肌羟脯氨酸含量、心肌血管周围胶原面积(PVCA)/管腔面积、心肌胶原容积分数(CVF)等。放免法检测血浆及心肌中醛固酮水平,Western Blot法测定心肌中SGK1和CTGF蛋白的表达。结果RHR血压显著升高,心肌羟脯氨酸含量、PVCA/管腔面积、CVF及心肌组织中SGK1、CTGF蛋白表达明显增加,药物治疗8周后螺内酯组收缩压稍降低,但差异无统计学意义(P>0.05),厄贝沙坦组与联用组收缩压显著降低(P<0.01);各治疗组心肌羟脯氨酸含量、PVCA/管腔面积、CVF及心肌组织中SGK1、CTGF的蛋白表达均降低,其中联用组效果优于单用药组(P<0.01或P<0.05),且心肌及血浆中醛固酮的含量降低。结论螺内酯和厄贝沙坦联合应用改善肾血管性高血压大鼠心肌纤维化的作用明显优于单用药组,可能与调节醛固酮水平、减少心肌组织中SGK1和CTGF蛋白表达有关。Background Studies have shown aldosterone could induce cardiac fibrosis and upregulate protein expression of connective tissue growth factor （CTGF） only in serum and glucocorticoid-regulated protein kinase （SGK）^＋/＋ but not in SGK / mice, indicating that SGK1 plays a decisive role in aldosterone-induced cardiac fibro- sis. It remains elusive whether spironolactone and irbesartan can inhibit the expression of SGK1. Objective To investigate the effects of spironolactone and irbesartan on the myocardial fibrosis and its mechanisms. Methods Thirty-two hypertensive Sprague Dawley（SD） rats induced by two kidney, one -clip （2K1C） method were randomized to receive following approaches： placebo group （n =8）, spironolactone group[Spi, 20 mg/（kg · d）, n=8], irbesartan group [Irb, 50 mg/[kg· d）, n=8] and combination group [Com, Spi 20 mg/（kg · d）＋Irb 50 mg/[kg · d）, n=8]. Age matched SD underwent sham operation （n=8） as control. Eight weeks after operation, the hydroxyproline content of left ventricle myocardium, perivascular collagen area/luminal area ratio（PVCA/LA）, collagen volume fraction（CVF） were measured. Plasma and myocardial aldoslerone were detected by radioimmunoassay, and expressions of SGK1, CTGF were measured by Western biol. Results The arterial pressure, the hydroxyproline content of myocardium, PVCA/LA, CVF and the expressions of SGK1, CTGF were increased in rats of RHR. After 8 weeks＇ treatment, spironolactone didn＇t decrease SBP, but irbesartan and combination treatment markedly decreased SBP（P〈0.01 ）. Besides the hydroxyproline content of myocardium, decreases in PVCA/ LA. CVF and the expressions of SGK1. CTGF were shown bv all treatments. However. the effect by combined treatment was much better than that of monotherapy （P〈0.01 or P〈0.05）. Combination treatment furthermore decreased the levels of aldosterone in plasma and myocardium. Conclusion The combined treatment of spironolactone and irbesartan was better than the monotherapy

关 键 词：螺内酯 厄贝沙坦 肾血管性高血压大鼠 心肌纤维化 醛固酮 血清和糖皮质激素诱导 的蛋白激酶1 结缔组织生长因子 

分 类 号：R544.1[医药卫生—心血管疾病]