内皮素受体拮抗剂波生坦通过降低肾交感神经活性改善间歇性低氧大鼠的高血压

Bosentan ameliorates hypertension in rats exposed to chronic intermittent hypoxia through inhibiting renal sympathetic nerve activity

本文旨在观察内皮素受体拮抗剂波生坦对慢性间歇性低氧(chronic intermittent hypoxia,CIH)暴露大鼠血压和肾交感神经活性(renal sympathetic nerve activity,RSNA)的影响,探讨内皮素-1(endothelin-1,ET-1)参与CIH诱发血压升高的交感神经兴奋性机制。24只成年雄性SD大鼠随机分为常氧对照组、CIH组及波生坦组;对照组大鼠暴露于常氧环境,CIH组与波生坦组大鼠暴露于CIH环境3周,其中波生坦组在每天CIH暴露前给予波生坦灌胃(50 mg/kg)。采用BP-2000血压分析系统测定尾动脉收缩压,采用Power Lab信号采集系统记录RSNA以及对苯肾上腺素的压力感受性反射敏感性,采用ELISA法测定大鼠血清中ET-1和去甲肾上腺素(norepinephrine,NE)的含量。结果显示:大鼠血压随CIH暴露时间延长而逐渐升高,在第7、14和21天与对照组相比均具有统计学差异;CIH暴露显著增强大鼠的RSNA,抑制压力感受性反射的敏感性;此外,CIH大鼠血压与血清中ET-1水平呈正相关(r=0.833,P=0.01)。波生坦干预明显降低CIH暴露大鼠的收缩压和RSNA,提高压力感受性反射敏感性,降低血清NE水平。上述结果提示,ET-1参与了CIH诱发血压升高的过程,而波生坦通过降低RSNA改善了CIH诱导的高血压。

The purpose of this study is to investigate the effect of the oral endothelin antagonist Bosentan on blood pressure and renal sympathetic nerve activity （RSNA） in rats exposed to chronic intermittent hypoxia （CIH）, and to explore the sympathoexcitation mechanism of endothelin-1 （ET-1） in CIH-induced hypertension. Twenty-four male SD rats were randomly divided into normoxia, CIH and Bosentan groups. Rats in the normoxia group were exposed to normoxic environment, and rats in CIH or Bosentan group were exposed to intermittent hypoxia for 3 weeks. Bosentan was given at 50 mg/kg by intragastric administration before intermittent hypoxia exposure in Bosentan group. Systolic blood pressure （SBP） was measured by BP-2000, and the change of RSNA to sodium nitroprusside （SNP） or phenylephrine （PE） was recorded by PowerLab signal acquisition system. Serums of all rats were collected and the contents of ET-1 and norepinephrine （NE） were measured by ELISA. Results showed that blood pressure was gradually increased following CIH exposure compared with the normoxia group during the 3 weeks （P 〈 0.01, P 〈 0.01, P 〈 0.001）. The basal RSNA wasincreased and baroreflex sensitivity was decreased in rats exposed to CIH. Furthermore, the blood pressure was positively correlated with the level of ET-I in serum in rats exposed to CIH （r = 0.833, P = 0.01）. Bosentan administration significantly decreased SBP and basal RSNA, increased the baroreflex sensitivity, and decreased serum NE level in rats exposed to CIH. These results suggest that ET-1 is related with blood pressure elevation in rats exposed to CIH, and Bosentan reverses C1H-induced hypertension by decreasing RSNA.