间歇低氧对大鼠内皮素及其受体基因表达的影响

Effects of intermittent hypoxia on the expression of endothelin and its receptor in rats

目的观察慢性间歇低氧诱发大鼠高血压发病过程中内皮素(ET)及其受体的动态变化,探讨慢性间歇低氧诱发高血压的发病机制.方法将Wistar大鼠(n=72)随机均分为间歇低氧组(IH组)、实验对照组(SC组)和空白对照组(UC组).IH组大鼠循环给予氮气和压缩空气(每一循环60 s,使舱内最低氧浓度达4%～6%,然后恢复至21%,8 h/d),SC组大鼠循环给予压缩空气,UC组大鼠不给予任何处理.观察第7、21、42天时各组大鼠的血压、血浆ET-1水平及不同组织ET-1和内皮素A型受体(ETAR)mRNA的表达.结果第42天时IH组大鼠平均动脉压(MAP)较实验前升高约8 mmHg(P＜0.01),而两对照组大鼠MAP无显著变化.IH组大鼠血浆ET-1水平随间歇低氧时间的延长逐渐升高,从第7天[(157±35)ng/L]开始显著高于SC组[(123±29)ng/L]和UC组[(119±28)ng/L]水平(P＜0.05),并且与MAP呈正相关(r=0.605,P=0.002);其心脏和肾皮质ET-1 mRNA的表达随间歇低氧时间的延长也逐渐增加,从第21天开始显著高于两对照组水平(P＜0.05);其主动脉、心脏和肾皮质ETAR mRNA的表达与两对照组比较,差异无显著性(P＞0.05).SC组与UC组比较,各项观察指标差异均无显著性(P＞0.05).结论慢性间歇低氧可导致ET-1表达增加,使血循环ET-1水平升高,而对ETAR的表达没有影响,提示ET-1的过度表达可能是慢性间歇低氧诱发高血压的重要原因之一.

Objective To observe the changes of endothelin-1 （ET-1） and endothelin receptor type A （ETAR） during the development of hypertension induced by chronic intermittent hypoxia （CIHO） in rats, and to investigate the mechanism of CIHO-induced hypertension. Methods Seventy-two male Wister rats were divided into three groups： intermittent hypoxia group （IH）, sham control group （SC） and unhandled control group （UC） . Infusion of nitrogen for 30 seconds was followed by infusion of compressed air for 30 seconds into the exposure chambers. When ambient oxygen concentration reached the nadir of 4 % ～ 6 %, it was returned to 21%. IH rats were subjected to such intermittent hypoxia every 60 s for 8 h/d during the diurnal sleep period; SC rats were similarly handled but received compressed air instead of nitrogen ; whilst UC rats remained unhandled. Mean arterial pressure （MAP）, the levels of ET-1 in plasma and the expression of ET-I and ETAR mRNA in tissue were assessed at 7, 21 and 42 days after experiment. Results IH rats showed a 8 mmHg increase in MAP （ P 〈0.01） at 42 days, and no significant changes of MAP were found in the two control groups. Plasma ET-1 level in IH rats increased gradually over time, and began to increase significantly at 7 days [ （157 ± 35） ng/L] in In and （123 ± 29） ng/L in SC and UC rats [ （119 ± 28） ng/L] （both P 〈0.05）. Plasma ET- 1 levels in IH rats showed positive correlation with MAP （ r = 0.605, P = 0.002）. The levels of ET-1 mRNA in the heart and renal cortex in IH rats began to increase significantly at 21 days compared with that in the two controls （ P 〈 0.05）.The levels of ETA R mRNA in the heart, renal cortex and aorta in IH mrs showed no differences compared with that in the two controls （ P 〉 0.05 ）. All indexes were not different between SC and UC rats at any time points （ P 〉 0.05 ）. Conclusions CIHO can cause increase in the expression of ET-1 mRNA and the levels of circulating ET-1 increase, and has no effects on ETAR mRNA expression, which suggests that ET-1 overexpression may be responsible for the pathogenesis of CIHO-indueed hypertension.