Store-operated channels in the pulmonary circulation of high- and low-altitude neonatal lambs

Abstract

AJ, Reyes RV. Store-operated channels in the pulmonary circulation of high-and low-altitude neonatal lambs. Am J Physiol Lung Cell Mol Physiol 304: L540 -L548, 2013. First published February 15, 2013 doi:10.1152/ajplung.00024.2012.-We determined whether store-operated channels (SOC) are involved in neonatal pulmonary artery function under conditions of acute and chronic hypoxia, using newborn sheep gestated and born either at high altitude (HA, 3,600 m) or low altitude (LA, 520 m). Cardiopulmonary variables were recorded in vivo, with and without SOC blockade by 2-aminoethyldiphenylborinate (2-APB), during basal or acute hypoxic conditions. 2-APB did not have effects on basal mean pulmonary arterial pressure (mPAP), cardiac output, systemic arterial blood pressure, or systemic vascular resistance in both groups of neonates. During acute hypoxia 2-APB reduced mPAP and pulmonary vascular resistance in LA and HA, but this reduction was greater in HA. In addition, isolated pulmonary arteries mounted in a wire myograph were assessed for vascular reactivity. HA arteries showed a greater relaxation and sensitivity to SOC blockers than LA arteries. The pulmonary expression of two SOC-forming subunits, TRPC4 and STIM1, was upregulated in HA. Taken together, our results show that SOC contribute to hypoxic pulmonary vasoconstriction in newborn sheep and that SOC are upregulated by chronic hypoxia. Therefore, SOC may contribute to the development of neonatal pulmonary hypertension. We propose SOC channels could be potential targets to treat neonatal pulmonary hypertension.hypoxia; pulmonary vasoconstriction; pulmonary hypertension; 2-aminoethydiphenylborinate; pulmonary vascular reactivity PULMONARY ARTERIES HAVE AN intrinsic vasoconstrictor response to low oxygen levels when exposed to acute hypoxia. This is a reversible, rapid and physiological response, known as hypoxic pulmonary vasoconstriction (HPV), that redirects blood flow from poorly oxygenated to better oxygenated alveoli. Thus, when total lung is exposed to hypoxia, HPV results in an increase in pulmonary artery pressure (PAP) that reverses when normoxia is reestablished (31). However, exposure to chronic hypoxia produces an imbalance between vasodilator and vasoconstrictor mechanisms, and there is pulmonary vascular remodeling that includes proliferation of pulmonary artery myocytes among other cellular processes (46). The result is a pathological and persistent increase in pulmonary artery contractile tone and pulmonary arterial hypertension, which in many cases leads to right ventricular hypertrophy, right heart failure, and eventually death (13).In pulmonary artery smooth muscle cells, an increase in intracellular calcium concentration ([Ca 2ϩ ] i ) is essential for HPV, proliferation, and remodeling (13,19,20,42). This increase in [Ca 2ϩ ] i greatly depends on an influx of extracellular calcium (13, 59), which may enter the smooth muscle cell through store-operated channels (SOC) among other pathways (5,8,22,40). These are channels physiologically ...

Melatonin improves cerebrovascular function and decreases oxidative stress in chronically hypoxic lambs

“…The systemic cardiovascular variables and arterial blood gases in the vehicle group were similar to previously reported [49,51,53]. In addition, both groups of neonates have similar values in arterial blood gases, systemic arterial blood pressure, cardiac output, and systemic vascular resistance (Table S1 & Figure S1).…”

Pharmacological approaches in either intermittent or permanent hypoxia: A tale of two exposures

“…Other emerging pharmacological targets are store operated calcium channels. Drugs like 2-aminoethyldiphenylborinate (2-APB), initially described as an inhibitor of inositol trisphosphate dependent calcium channels inhibitor [76], was later described as a store-operated calcium (SOC) channels blocker, limiting the calcium flux to intracellular compartment, attenuating the vasoconstrictor tone [77,78,79]. The acute administration attenuates the pulmonary vasoconstriction in an episode of superimposed hypoxia, and this effect is more marked in HA newborn lambs, where these channels are up-regulated [79].…”

“…Drugs like 2-aminoethyldiphenylborinate (2-APB), initially described as an inhibitor of inositol trisphosphate dependent calcium channels inhibitor [76], was later described as a store-operated calcium (SOC) channels blocker, limiting the calcium flux to intracellular compartment, attenuating the vasoconstrictor tone [77,78,79]. The acute administration attenuates the pulmonary vasoconstriction in an episode of superimposed hypoxia, and this effect is more marked in HA newborn lambs, where these channels are up-regulated [79]. Adiitionally, up-regulation of SOC in pulmonary artery smooth muscle cells increases proliferation, and pharmacological blockade or knock down of these SOC forming proteins stops this proliferation [80,81,82].…”

Smooth muscle acid‐sensing ion channel 1: pathophysiological implication in hypoxic pulmonary hypertension

“…; Parrau et al . ). Interestingly, we have not observed the same correlation between enhanced ASIC1‐dependent Ca 2+ influx and ASIC1 protein expression.…”