洛沙坦和卡维地洛对高血压大鼠心肌中细胞外信号调节激酶途径的影响

Role of losartan and carvedilol on in extracellular signal-regulated kinases in myocardium of spontaneously hypertensive rats

目的探讨血管紧张素Ⅱ受体拮抗剂洛沙坦和β-受体阻滞剂卡维地洛对自发性高血压大鼠(SHR)心肌中细胞外信号调节激酶(ERK)和丝裂原活化蛋白激酶磷酸酶(MKP-1)的影响。方法将21只雄性SHR随机分为SHR对照组、卡维地洛组、洛沙坦组组药物干预,并设WKY为对照,分别用免疫沉淀法和RT-PCR法测定大鼠心肌组织中ERK活性和MKP-1mRNA的含量。结果①给药8周后,卡维地洛组和洛沙坦组SHR的血压均较SHR对照组明显下降(P<0.01),且心肌肥厚指数也降低(P<0.05),其中洛沙坦组心肌肥厚指数降低更明显(P<0.05);②给药后,卡维地洛组和洛沙坦组SHR心肌组织中ERK活性较SHR对照组下降(P<0.01),MKP-1mRNA的表达增加(P<0.05),两组无明显差异。结论卡维地洛和洛沙坦均可通过增加MKP-1表达,降低ERK活性型的活性ERK抑制MAPK信号途径,逆转增加MKP-1表达,从而明显减轻心肌肥厚程度。

OBJECTIVE To explore the role of losartan and carvedilol on extracellular signal-regulated kinase （ERK） and mitogen-acfi- vated protein kinase phosphatase- 1 （MKP-1） in the myocardium of spontaneously hypertensive rat （SHR）,METHODS Twenty-one 14-week old SHRs were randomily divided into 3 groups, 7 rats each. One group was given with carvedilol 30 mg·kg^-1·d^-1, one group was given with losartan 10 mg·kg^-1·d^-1 for 8 weeks, while the SHR sham group and 7 Wistar Kyoto rats（WKY）as control group were routinely given with vehicle （0.5% carboxymethyl cellulose） only for equal time. Then the activity of ERK and the expression of MKP-1 mRNA in myocardium were studied by immuno-precipitation and RT-PCR, respectively. RESULTS ①After administration for 8 weeks, the blood pressure of the SHR group treated with carvediM or losartan decreased significantly （P 〈 0.01 ）. LVW/BW ratio in SHR with carvedilol or losatan treatment was lower than that in SHR sham group （carvedilol group, P 〈 0.01, losartan group, P 〈 0.05）, and the reduction in hypertrophy with losartan treatment was more than with carvedilol （ P 〈 0.05）. ②After treatment in SHR, the activity of ERK in the group with carvediM or losartan can treatment was lower than that in the SHR control （ P 〈 0.01 ）, while the expression of MKP- 1 mRNA of them was higher （ P 〈 0.05）. CONCLUSION Both carvediM and losartan can inhibit the activity of ERK, increase the expression of MKP-1 mRNA, and then relieve cardiacl hypertrophy.