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

Abstract

Key pointsr Chronic hypoxia has a direct effect in down-regulating the BK Ca channel β1 subunit and inhibiting the BK Ca channel activity in uterine arteries of pregnant sheep.r Oxidative stress plays a causal role in hypoxia-mediated suppression of BK Ca channel function. r The steroid hormone-induced effect on BK Ca channels is a target of hypoxia-mediated oxidative stress.r Inhibition of oxidative stress ameliorates the adverse effect of hypoxia both ex vivo and in vivo in pregnant sheep exposed to long-term high-altitude hypoxia.r Our findings provide novel evidence of a causative role of oxidative stress in hypoxia-mediated inhibition of the BK Ca channel activity in uterine arteries and new insights in understanding and alleviating pregnancy complications associated with gestational hypoxia such as pre-eclampsia and fetal growth restriction.Abstract Uterine arteries of pregnant sheep acclimatized to long-term high-altitude hypoxia were associated with a decrease in large-conductance Ca 2+ -activated K + (BK Ca ) channel activity. The present study tested the hypothesis that prolonged hypoxia has a direct effect in suppressing BK Ca channel activity by increasing oxidative stress. Uterine arteries were isolated from non-pregnant and near-term (ß142 days) pregnant sheep, and were treated ex vivo with 21.0 or 10.5% O 2 for 48 h. 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 BK Ca 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 BK Ca channel β1 subunit, which was restored in the presence of N-acetylcysteine. In addition, the N-acetylcysteine treatment significantly increased BK Ca channel β1 subunit abundance and BK Ca channel current density in uterine arteries from pregnant sheep exposed to high-altitude hypoxia (3801 m, P aO 2 : 60 mmHg) for 110 days. In uterine arteries of non-pregnant animals, hypoxia inhibited steroid hormone-induced up-regulation of BK Ca 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 BK Ca channel currents in uterine arteries. The results demonstrate a direct effect of hypoxia in inhibiting the BK Ca channel activity in uterine arteries via increased oxidative stress.

Oxidation of ion channels in the aging nervous system

“…In addition, the presence of accessory subunits may contribute to BK dependence on redox. Recently, Hu and colleagues reported that oxidative stress acts to directly decrease BK current density in sheep uterine arteries during chronic hypoxia by downregulating its β1 accessory subunit (Hu et al, 2015). Another β-subunit of BK channel, β3, brings redox-dependent gates that block ion permeation (Zeng et al, 2003).…”

Effects of Silymarin Plus® Versus Antibiotics on Improving Idiopathic Poor Conception and Pregnancy Rates of Mares.

“…For the first time, the current study explored the effect of silymarin plus ® in the uterine wash in comparing with Amikacin+ Ciprofloxacin. The current results revealed that both silymarin plus ® alone or in combination with Amikacin+ Ciprofloxacin improved mare conception and pregnancy rates .These results might be due to the powerful antioxidant capability of silymarin plus ® due to its components that represented in Silymarin, vitamin E and C, Selenium Hu et al, 2016). The association between ROS and various gynecologic and obstetric conditions related to infertility suggests a potential role for oral antioxidant supplementation.…”

“…Acetylcysteine (NAC) is the N-acetyl stable derivative of L-cysteine; a precursor of glutathione (Gayatri et al, 2010 andHu et al, 2016), which functions as an ROS scavenger through increasing intracellular glutathione formation and its thiol-disulfide exchange activity (Zafarullah et al 2003). Furthermore, NAC has anti-inflammatory and mucolytic effects (Conesa et al, 2001 andSehirli et al, 2003;Ocal et al, 2004 andGayatri et al, 2010).…”

Survival and growth of C57BL/6J mice lacking the BK channel,Kcnma1: lower adult body weight occurs together with higher body fat

“…; Rosenfeld and Roy ), and oxidative stress suppresses this BK activation (Hu et al. ). Any gene dosage effects from the (+/−) Kcnma1 dams likely would influence blood flow to all of the fetuses equally.…”

“…In contrast, fetuses adjacent to hypoperfusion mutant fetuses exhibited increased maternal blood volume in their placenta indicating an advantage for growth. Increases in blood flow to the placenta occur through opening of BK channels that dilate uterine smooth muscle cells (Rosenfeld et al 2009;Rosenfeld and Roy 2012), and oxidative stress suppresses this BK activation (Hu et al 2016). Any gene dosage effects from the (+/À)Kcnma1 dams likely would influence blood flow to all of the fetuses equally.…”