Long-Term High Altitude Hypoxia influences Pulmonary Arterial L-type Calcium Channel mediated Ca2+ signals and Contraction in Fetal and Adult Sheep (original) (raw)
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AJP: Lung Cellular and Molecular Physiology, 2012
Ca2+ sparks are fundamental Ca2+ signaling events arising from ryanodine receptor (RyR) activation, events that relate to contractile and dilatory events in the pulmonary vasculature. Recent studies demonstrate that long-term hypoxia (LTH) can affect pulmonary arterial reactivity in fetal, newborn, and adult animals. Because RyRs are important to pulmonary vascular reactivity and reactivity changes with ontogeny and LTH we tested the hypothesis that RyR-generated Ca2+ signals are more active before birth and that LTH suppresses these responses. We examined these hypotheses by performing confocal imaging of myocytes in living arteries and by performing wire myography studies. Pulmonary arteries (PA) were isolated from fetal, newborn, or adult sheep that lived at low altitude or from those that were acclimatized to 3,801 m for > 100 days. Confocal imaging demonstrated preservation of the distance between the sarcoplasmic reticulum, nucleus, and plasma membrane in PA myocytes. Matur...
American Journal of Physiology-Lung Cellular and Molecular Physiology, 2008
Inhibition of voltage-gated, L-type Ca2+ (CaL) channels by clinical calcium channel blockers provides symptomatic improvement to some pediatric patients with pulmonary arterial hypertension (PAH). The present study investigated whether abnormalities of vascular CaL channels contribute to the pathogenesis of neonatal PAH using a newborn piglet model of hypoxia-induced PAH. Neonatal piglets exposed to chronic hypoxia (CH) developed PAH by 21 days, which was evident as a 2.1-fold increase in pulmonary vascular resistance in vivo compared with piglets raised in normoxia (N). Transpulmonary pressures (ΔPtp) in the corresponding isolated perfused lungs were 20.5 ± 2.1 mmHg (CH) and 11.6 ± 0.8 mmHg (N). Nifedipine reduced the elevated ΔPtp in isolated lungs of CH piglets by 6.4 ± 1.3 mmHg but only reduced ΔPtp in lungs of N piglets by 1.9 ± 0.2 mmHg. Small pulmonary arteries from CH piglets also demonstrated accentuated Ca2+-dependent contraction, and Ca2+ channel current was 3.94-fold hig...
Reproductive Sciences, 2011
Antenatal maternal long-term hypoxia (LTH) can alter serotonin (5-HT) and calcium (Ca 2þ ) signaling in fetal pulmonary arteries (PAs) and is associated with persistent pulmonary hypertension of the newborn (PPHN). In humans, the antenatal maternal hypoxia can be secondary to smoking, anemia, and chronic obstructive pulmonary disorders. However, the mechanisms of antenatal maternal hypoxia-related PPHN are unresolved. Because both LTH and 5-HT are associated with PPHN, we tested the hypothesis that antenatal maternal LTH can increase 5-HT-mediated PA contraction and associated extracellular Ca 2þ influx through L-type Ca 2þ channels (Ca L ), nonselective cation channels (NSCCs), and reverse-mode sodium-calcium exchanger (NCX) in the near-term fetus. We performed wire myography and confocal-Ca 2þ imaging approaches on fetal lamb PA (*140 days of gestation) from normoxic ewes or those acclimatized to high-altitude LTH (3801 m) for *110 days. Long-term hypoxia reduced the potency but not the efficacy of 5-HT-induced PA contraction. Ketanserin (100 nmol/L), a 5-HT 2A antagonist, shifted 5-HT potency irrespective of LTH, while GR-55562 (1 mmol/L), a 5-HT 1B/D inhibitor, antagonized 5-HT-induced contraction in normoxic fetuses only. Various inhibitors for Ca L , NSCC, and reverse-mode NCX were used in contraction studies. Contraction was reliant on extracellular Ca 2þ regardless of maternal hypoxia, NSCC was more important to contraction than Ca L , and reverse-mode NCX had little or no role in contraction. Long-term hypoxia also attenuated the effects of 2-APB and flufenamic acid and reduced Ca 2þ responses observed by imaging studies. Overall, LTH reduced 5HT 1B/D function and increased NSCC-related Ca 2þ -dependent contraction in ovine fetuses, which may compromise pulmonary vascular function in the newborn. Reproductive Sciences 18(10) 948-962 ª The Author(s) 2011 Reprints and permission: sagepub.com/journalsPermissions.nav
Pulmonary Circulation, 2012
Membrane depolarization is critical to pulmonary arterial (PA) contraction. Both L-type Ca 2+ channels (Ca L ) and Rho-kinase are important signaling components of this process and mitochondrial and non-mitochondrial generated superoxides can be part of the signaling process. Maturation and long-term hypoxia (LTH) each can modify depolarization-dependent contraction and the role of superoxides. By the use of wire myography, we tested the hypothesis that maturation and LTH increase pulmonary arterial reactivity to high-K + -induced membrane depolarization through enhancements in the importance of Ca L and Rho-kinase-dependent pathways. The data show that maturation, but not LTH, increases contraction to 125 mM KCl (high-K + ) without altering the EC 50 . High-K + -dependent contraction was inhibited to a similar extent in fetal and adult PA by multiple Ca L blockers, including 10 μM diltiazem, 10 μM verapamil, and 10 μM nifedipine. Postnatal maturation increased the role for 10 μM nifedipine-sensitive Ca L , and decreased that for 10 μM Y-27632-sensitive Rho-kinase. In all groups, the combination of nifedipine and Y-27632 effectively inhibited high-K + contraction. Tempol (3 mM) but not 100 μM apocynin slightly reduced contraction in arteries from fetal hypoxic and adult normoxic and hypoxic sheep, indicating a limited role for non-mitochondrial derived superoxide to high-K + -induced contraction. Western immunoblot for alpha smooth muscle actin indicated small increases in relative abundance in the adult. The data suggest that while Ca L therapies more effectively vasodilate PA in adults and rho-kinase therapies are more effective in newborns, combination therapies would provide greater efficacy in both young and mature patients regardless of normoxic or hypoxic conditions.
High Altitude Medicine & Biology, 2011
Preservation of serotonin-mediated contractility in adult sheep pulmonary arteries following long-term high-altitude hypoxia. High Alt. Med. Biol. 12:253-264.-Long-term hypoxia (LTH) can increase serotonin (5-HT) signaling as well as extracellular calcium entry in adult rodent pulmonary arteries (PA), and 5-HT is associated with pulmonary hypertension. Because LTH, 5-HT, and calcium entry are related, we tested the hypothesis that LTH increases 5-HT-mediated PA contractility and associated calcium influx through L-type Ca 2 + channels, nonselective cation channels (NSCC), and reverse-mode sodium-Ca 2 + exchange. We performed wire myography and confocal calcium imaging on pulmonary arteries from adult ewes that lived near sea level or were maintained at high-altitude (3801 m) for *110 days. LTH did not increase the arterial medial wall thickness, nor did it affect the potency or efficacy for 5-HT-induced PA contraction. Ketanserin (100 nM), a 5-HT 2A antagonist, shifted the 5-HT potency to a far greater extent than 1 lM GR-55562, a 5-HT 1B/D inhibitor. These influences were unaffected by LTH. The rank order for reducing 5-HT
The Journal of physiology, 2012
• A prolonged reduced oxygen level in the lungs, as occurs in patients of many chronic lung diseases and in residents living at high altitude, causes pulmonary hypertension characterized by profound structural and functional changes in pulmonary vasculature. • Many of these changes are ascribed to alterations in Ca 2+ homeostasis related to cation channels of pulmonary arterial smooth muscle cells. • Here we report the increase of an anion conductance called calcium-activated chloride channel and the expression of the channel gene TMEM16A in pulmonary arterial smooth muscle cells isolated from rats exposed to 10% oxygen for 3-4 weeks. • The upregulation of the chloride channel contributes to the hyper-responsiveness of pulmonary arteries to serotonin associated with pulmonary hypertension. • These results help us to appreciate the importance of anion channels in the pathophysiology of pulmonary hypertension, and may lead to alternative strategies for the treatment of the disease.
Frontiers in Physiology
Autonomic innervation of the pulmonary vasculature triggers vasomotor contractility predominately through activation of alpha-adrenergic receptors (α-ARs) in the fetal circulation. Long-term hypoxia (LTH) modulates pulmonary vasoconstriction potentially through upregulation of α 1-AR in the vasculature. Our study aimed to elucidate the role of α-AR in phenylephrine (PE)-induced pulmonary vascular contractility, comparing the effects of LTH in the fetal and adult periods on α-AR subtypes and PE-mediated Ca 2+ responses and contractions. To address this, we performed wire myography, Ca 2+ imaging, and mRNA analysis of pulmonary arteries from ewes and fetuses exposed to LTH or normoxia. Postnatal maturation depressed PE-mediated contractile responses. α 2-AR activation contracted fetal vessels; however, this was suppressed by LTH. α 1A-and α 1B-AR subtypes contributed to arterial contractions in all groups. The α 1D-AR was also important to contractility in fetal normoxic vessels and LTH mitigated its function. Postnatal maturity increased the number of myocytes with PE-triggered Ca 2+ responses while LTH decreased the percentage of fetal myocytes reacting to PE. The difference between myocyte Ca 2+ responsiveness and vessel contractility suggests that fetal arteries are sensitized to changes in Ca 2+. The results illustrate that α-adrenergic signaling and vascular function change during development and that LTH modifies adrenergic signaling. These changes may represent components in the etiology of pulmonary vascular disease and foretell the therapeutic potential of adrenergic receptor antagonists in the treatment of pulmonary hypertension.
American Journal of Physiology-Lung Cellular and Molecular Physiology, 2016
Calcium signaling through store-operated channels (SOC) is involved in hypoxic pulmonary hypertension. We determined whether a treatment with 2-aminoethyldiphenylborinate (2-APB), a compound with SOC blocker activity, reduces pulmonary hypertension and vascular remodeling. Twelve newborn lambs exposed to perinatal chronic hypoxia were studied, six of them received a 2-APB treatment and the other six received vehicle treatment for 10 days in both cases. Throughout this period, we recorded cardiopulmonary variables and on day 11 we evaluated the response to an acute hypoxic challenge. Additionally, we assessed the vasoconstrictor and vasodilator function in isolated pulmonary arteries as well as their remodeling in lung slices. 2-APB reduced pulmonary arterial pressure between the 3rd and 10th days, cardiac output between the 4th and 8th days, and pulmonary vascular resistance at the 10th day of treatment. The pulmonary vasoconstrictor response to acute hypoxia was reduced by the end ...
AJP: Lung Cellular and Molecular Physiology, 2013
artery by upregulating Cav1.2 and Cav3.2 voltage-dependent Ca2+ channel activity in pulmonary Chronic hypoxia selectively enhances L-and T-type You might find this additional info useful... 65 articles, 40 of which you can access for free at: This article cites http://ajplung.physiology.org/content/305/2/L154.full#ref-list-1 including high resolution figures, can be found at: Updated information and services http://ajplung.physiology.org/content/305/2/L154.full can be found at: Molecular Physiology American Journal of Physiology -Lung Cellular and about Additional material and information