Xiao DaLiao, Huang XiaoHui, Bae Soochan, Ducsay Charles A, Longo Lawrence D, Zhang Lubo
Center for Perinatal Biology, Dept. of Physiology and Pharmacology, Loma Linda Univ. School of Medicine, Loma Linda, CA 92350, USA.
Am J Physiol Heart Circ Physiol. 2004 Feb;286(2):H716-22. doi: 10.1152/ajpheart.00805.2003. Epub 2003 Oct 9.
We previously demonstrated that cortisol regulated alpha(1)-adrenoceptor-mediated contractions differentially in nonpregnant and pregnant uterine arteries. Given that chronic hypoxia during pregnancy has profound effects on maternal uterine artery reactivity, the present study investigated the effects of chronic hypoxia on cortisol-mediated regulation of uterine artery contractions. Pregnant (day 30) and nonpregnant ewes were divided between normoxic control and chronically hypoxic [maintained at high altitude (3,820 m), arterial Po(2): 60 mmHg for 110 days] groups. Uterine arteries were isolated and contractions measured. In hypoxic animals, cortisol (10 ng/ml for 24 h) increased norepinephrine-induced contractions in pregnant, but not in nonpregnant, uterine arteries. The 11beta-hydroxysteroid dehydrogenase inhibitor carbenoxolone did not change cortisol effects in nonpregnant uterine arteries, but abolished it in pregnant uterine arteries by increasing norepinephrine pD(2) (-log EC(50)) in control tissues. The dissociation constant of norepinephrine-alpha(1)-adrenoceptors was not changed by cortisol in nonpregnant, but decreased in pregnant uterine arteries. There were no differences in the density of glucocorticoid receptors between normoxic and hypoxic tissues. Cortisol inhibited the norepinephrine-induced increase in Ca(2+) concentrations in nonpregnant arteries, but potentiated it in pregnant arteries. In addition, cortisol attenuated phorbol 12,13-dibutyrate-induced contractions in normoxic nonpregnant and pregnant uterine arteries, but had no effect on the contractions in hypoxic arteries. The results suggest that cortisol differentially regulates alpha(1)-adrenoceptor- and PKC-mediated contractions in uterine arteries. Chronic hypoxia suppresses uterine artery sensitivity to cortisol, which may play an important role in the adaptation of uterine vascular tone and blood flow in response to chronic stress of hypoxia during pregnancy.
我们先前证明，皮质醇对非妊娠和妊娠子宫动脉中α(1)-肾上腺素受体介导的收缩具有不同的调节作用。鉴于孕期慢性缺氧对母体子宫动脉反应性有深远影响，本研究调查了慢性缺氧对皮质醇介导的子宫动脉收缩调节的影响。将妊娠（第30天）和非妊娠母羊分为常氧对照组和慢性缺氧组[维持在高海拔（3820米），动脉血氧分压：60 mmHg，持续110天]。分离子宫动脉并测量收缩情况。在缺氧动物中，皮质醇（10 ng/ml，持续24小时）增加了妊娠子宫动脉中去甲肾上腺素诱导的收缩，但对非妊娠子宫动脉没有影响。11β-羟基类固醇脱氢酶抑制剂甘草次酸在非妊娠子宫动脉中未改变皮质醇的作用，但在妊娠子宫动脉中通过增加对照组织中去甲肾上腺素的pD(2)（-log EC(50)）而消除了其作用。去甲肾上腺素-α(1)-肾上腺素受体的解离常数在非妊娠子宫动脉中未被皮质醇改变，但在妊娠子宫动脉中降低。常氧和缺氧组织之间糖皮质激素受体的密度没有差异。皮质醇抑制非妊娠动脉中去甲肾上腺素诱导的Ca(2+)浓度升高，但在妊娠动脉中增强了这种升高。此外，皮质醇减弱了常氧非妊娠和妊娠子宫动脉中佛波醇12,13-二丁酸酯诱导的收缩，但对缺氧动脉中的收缩没有影响。结果表明，皮质醇对子宫动脉中α(1)-肾上腺素受体和蛋白激酶C介导的收缩具有不同的调节作用。慢性缺氧会抑制子宫动脉对皮质醇的敏感性，这可能在孕期对慢性缺氧应激的子宫血管张力和血流适应中起重要作用。
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