Direct effect of chronic hypoxia in suppressing large conductance Ca2+-activated K+ channel activity in ovine uterine arteries via increasing oxidative stress

Uterine arteries of pregnant sheep acclimatized to long-term high-altitude hypoxia were associated with a decrease in large-conductance Ca2+-activated K+ (BKCa) channel activity. The present study tested the hypothesis that prolonged hypoxia has a direct effect in suppressing BKCa channel activity by increasing oxidative stress. Uterine arteries were isolated from non-pregnant and near-term (similar to 142days) pregnant sheep, and were treated ex vivo with 21.0 or 10.5% O-2 for 48h. The hypoxia treatment significantly increased the production of reactive oxygen species in uterine arteries, which was blocked by N-acetylcysteine. In uterine arteries of pregnant sheep, hypoxia significantly inhibited BKCa channel current density, decreased NS1619-induced relaxations and increased pressure-dependent tone, which were annulled by N-acetylcysteine. In accordance, hypoxia resulted in down-regulation of BKCa channel beta 1 subunit, which was restored in the presence of N-acetylcysteine. In addition, the N-acetylcysteine treatment significantly increased BKCa channel beta 1 subunit abundance and BKCa channel current density in uterine arteries from pregnant sheep exposed to high-altitude hypoxia (3801m, P-aO2: 60mmHg) for 110days. In uterine arteries of non-pregnant animals, hypoxia inhibited steroid hormone-induced up-regulation of BKCa channel current density and NS1619-mediated relaxations, which were reversed by N-acetylcysteine. Furthermore, the synthetic superoxide dismutase and catalase mimetic EUK-134 also ablated the effects of hypoxia on BKCa channel currents in uterine arteries. The results demonstrate a direct effect of hypoxia in inhibiting the BKCa channel activity in uterine arteries via increased oxidative stress.