Xiao Daliao, Zhu Ronghui, Zhang Lubo
Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA.
Int J Med Sci. 2014 Jun 20;11(9):886-92. doi: 10.7150/ijms.9338. eCollection 2014.
The present study tested the hypothesis that gestational hypoxia up-regulates protein kinase C (PKC) and inhibits calcium-activated potassium channels (KCa)-mediated relaxations of uterine arteries in pregnancy.
Uterine arteries were isolated from nonpregnant (NPUA) and pregnant (PUA) (~140 day gestation) sheep maintained at either sea level or high altitude (3,820 m for 110 days, PaO2: 60 mmHg). Contractions of uterine arteries were determined.
In normoxic PUA, selective inhibition of large-conductance KCa (BK) channels significantly enhanced PKC activator phorbol 12, 13-dibutyrate (PDBu)-induced contractions. This effect was abrogated by chronic hypoxia in gestation. Unlike BK channels, inhibition of small-conductance KCa (SK) channels had no significant effect on PDBu-mediated contractions. In normoxic PUA, activation of both BK with NS1619 or SK with NS309 produced concentration-dependent relaxations, which were not altered by the addition of PDBu. However, in uterine arteries treated with chronic hypoxia (10.5% O2 for 48 h), both NS1619- and NS309-induced relaxations were significantly attenuated by PDBu. In NPUAs, inhibition of BK channels significantly enhanced PDBu-induced contractions in both normoxic and hypoxic animals.
The results suggest that in the normoxic condition BK inhibits PKC activity and uterine vascular contractility, which is selectively attenuated by chronic hypoxia during gestation. In addition, hypoxia induces PKC-mediated inhibition of BK and SK activities and relaxations of uterine arteries in pregnancy.
本研究验证了以下假设，即孕期缺氧会上调蛋白激酶C（PKC）并抑制钙激活钾通道（KCa）介导的孕期子宫动脉舒张。
从处于海平面或高海拔（3820米，110天，动脉血氧分压：60 mmHg）的未孕（NPUA）和孕羊（PUA，~140天孕期）中分离出子宫动脉。测定子宫动脉的收缩情况。
在常氧PUA中，选择性抑制大电导KCa（BK）通道可显著增强PKC激活剂佛波醇12,13 - 二丁酸酯（PDBu）诱导的收缩。孕期慢性缺氧可消除这种作用。与BK通道不同，抑制小电导KCa（SK）通道对PDBu介导的收缩无显著影响。在常氧PUA中，用NS1619激活BK或用NS309激活SK均可产生浓度依赖性舒张，添加PDBu不会改变这种舒张。然而，在用慢性缺氧（10.5%氧气，48小时）处理的子宫动脉中，PDBu可显著减弱NS1619和NS309诱导的舒张。在NPUA中，抑制BK通道可显著增强常氧和缺氧动物中PDBu诱导的收缩。
结果表明，在常氧条件下，BK抑制PKC活性和子宫血管收缩性，孕期慢性缺氧可选择性减弱这种作用。此外，缺氧可诱导PKC介导的BK和SK活性抑制以及孕期子宫动脉舒张。
