Hypoxic pulmonary vasoconstriction: role of ion channels

2005 ◽  
Vol 98 (1) ◽  
pp. 415-420 ◽  
Author(s):  
Joseph R. H. Mauban ◽  
Carmelle V. Remillard ◽  
Jason X.-J. Yuan
Keyword(s):  
Ion Channels ◽  
Structural Changes ◽  
Chronic Hypoxia ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Acute Hypoxia ◽  
Pulmonary Vasculature ◽  
Cellular Mechanisms ◽  
Pulmonary Vasoconstriction ◽  
Intracellular Ca ◽  
Medial Hypertrophy

Acute hypoxia induces pulmonary vasoconstriction and chronic hypoxia causes structural changes of the pulmonary vasculature including arterial medial hypertrophy. Electro- and pharmacomechanical mechanisms are involved in regulating pulmonary vasomotor tone, whereas intracellular Ca2+ serves as an important signal in regulating contraction and proliferation of pulmonary artery smooth muscle cells. Herein, we provide a basic overview of the cellular mechanisms involved in the development of hypoxic pulmonary vasoconstriction. Our discussion focuses on the roles of ion channels permeable to K+ and Ca2+, membrane potential, and cytoplasmic Ca2+ in the development of acute hypoxic pulmonary vasoconstriction and chronic hypoxia-mediated pulmonary vascular remodeling.

Inhibition of hypoxic pulmonary vasoconstriction by antagonists of store-operated Ca2+ and nonselective cation channels

2005 ◽  
Vol 289 (1) ◽  
pp. L5-L13 ◽  
Author(s):  
Letitia Weigand ◽  
Joshua Foxson ◽  
Jian Wang ◽  
Larissa A. Shimoda ◽  
J. T. Sylvester
Keyword(s):  
Hypoxic Pulmonary Vasoconstriction ◽  
Acute Hypoxia ◽  
Pulmonary Arteries ◽  
Cation Channels ◽  
Pulmonary Vasoconstriction ◽  
Nonselective Cation Channels ◽  
Pressor Responses ◽  
Intracellular Ca ◽  
Pulmonary Arterial

Previous studies indicated that acute hypoxia increased intracellular Ca2+ concentration ([Ca2+]i), Ca2+ influx, and capacitative Ca2+ entry (CCE) through store-operated Ca2+ channels (SOCC) in smooth muscle cells from distal pulmonary arteries (PASMC), which are thought to be a major locus of hypoxic pulmonary vasoconstriction (HPV). Moreover, these effects were blocked by Ca2+-free conditions and antagonists of SOCC and nonselective cation channels (NSCC). To test the hypothesis that in vivo HPV requires CCE, we measured the effects of SOCC/NSCC antagonists (SKF-96365, NiCl2, and LaCl3) on pulmonary arterial pressor responses to 2% O2 and high-KCl concentrations in isolated rat lungs. At concentrations that blocked CCE and [Ca2+]i responses to hypoxia in PASMC, SKF-96365 and NiCl2 prevented and reversed HPV but did not alter pressor responses to KCl. At 10 μM, LaCl3 had similar effects, but higher concentrations (30 and 100 μM) caused vasoconstriction during normoxia and potentiated HPV, indicating actions other than SOCC blockade. Ca2+-free perfusate and the voltage-operated Ca2+ channel (VOCC) antagonist nifedipine were potent inhibitors of pressor responses to both hypoxia and KCl. We conclude that HPV required influx of Ca2+ through both SOCC and VOCC. This dual requirement and virtual abolition of HPV by either SOCC or VOCC antagonists suggests that neither channel provided enough Ca2+ on its own to trigger PASMC contraction and/or that during hypoxia, SOCC-dependent depolarization caused secondary activation of VOCC.

scholarly journals Role of ASIC1 in the development of chronic hypoxia-induced pulmonary hypertension

2014 ◽  
Vol 306 (1) ◽  
pp. H41-H52 ◽  
Author(s):  
Carlos H. Nitta ◽  
David A. Osmond ◽  
Lindsay M. Herbert ◽  
Britta F. Beasley ◽  
Thomas C. Resta ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Chronic Hypoxia ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Acute Hypoxia ◽  
Pulmonary Arteries ◽  
Systolic Pressure ◽  
Arterial Remodeling ◽  
Ventricular Systolic Pressure ◽  
Intracellular Ca

Chronic hypoxia (CH) associated with respiratory disease results in elevated pulmonary vascular intracellular Ca2+ concentration, which elicits enhanced vasoconstriction and promotes vascular arterial remodeling and thus has important implications in the development of pulmonary hypertension (PH). Store-operated Ca2+ entry (SOCE) contributes to this elevated intracellular Ca2+ concentration and has also been linked to acute hypoxic pulmonary vasoconstriction (HPV). Since our laboratory has recently demonstrated an important role for acid-sensing ion channel 1 (ASIC1) in mediating SOCE, we hypothesized that ASIC1 contributes to both HPV and the development of CH-induced PH. To test this hypothesis, we examined responses to acute hypoxia in isolated lungs and assessed the effects of CH on indexes of PH, arterial remodeling, and vasoconstrictor reactivity in wild-type (ASIC1+/+) and ASIC1 knockout (ASIC1−/−) mice. Restoration of ASIC1 expression in pulmonary arterial smooth muscle cells from ASIC1−/− mice rescued SOCE, confirming the requirement for ASIC1 in this response. HPV responses were blunted in lungs from ASIC1−/− mice. Both SOCE and receptor-mediated Ca2+ entry, along with agonist-dependent vasoconstrictor responses, were diminished in small pulmonary arteries from control ASIC−/− mice compared with ASIC+/+ mice. The effects of CH to augment receptor-mediated vasoconstrictor and SOCE responses in vessels from ASIC1+/+ mice were not observed after CH in ASIC1−/− mice. In addition, ASIC1−/− mice exhibited diminished right ventricular systolic pressure, right ventricular hypertrophy, and arterial remodeling in response to CH compared with ASIC1+/+ mice. Taken together, these data demonstrate an important role for ASIC1 in both HPV and the development of CH-induced PH.

scholarly journals Bypassing mitochondrial complex III using alternative oxidase inhibits acute pulmonary oxygen sensing

2020 ◽  
Vol 6 (16) ◽  
pp. eaba0694 ◽  
Author(s):  
Natascha Sommer ◽  
Nasim Alebrahimdehkordi ◽  
Oleg Pak ◽  
Fenja Knoepp ◽  
Ievgen Strielkov ◽  
...  
Keyword(s):  
Alternative Oxidase ◽  
Chronic Hypoxia ◽  
Electron Flux ◽  
Oxygen Sensing ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Acute Hypoxia ◽  
Hypoxia Inducible Factor ◽  
Initial Step ◽  
Complex Iii ◽  
Pulmonary Vasculature

Mitochondria play an important role in sensing both acute and chronic hypoxia in the pulmonary vasculature, but their primary oxygen-sensing mechanism and contribution to stabilization of the hypoxia-inducible factor (HIF) remains elusive. Alteration of the mitochondrial electron flux and increased superoxide release from complex III has been proposed as an essential trigger for hypoxic pulmonary vasoconstriction (HPV). We used mice expressing a tunicate alternative oxidase, AOX, which maintains electron flux when respiratory complexes III and/or IV are inhibited. Respiratory restoration by AOX prevented acute HPV and hypoxic responses of pulmonary arterial smooth muscle cells (PASMC), acute hypoxia-induced redox changes of NADH and cytochrome c, and superoxide production. In contrast, AOX did not affect the development of chronic hypoxia-induced pulmonary hypertension and HIF-1α stabilization. These results indicate that distal inhibition of the mitochondrial electron transport chain in PASMC is an essential initial step for acute but not chronic oxygen sensing.

Abstract 2616: Role of the Soluble Epoxide Hydrolase in Hypoxic Pulmonary Vasoconstriction and Pulmonary Vascular Remodeling

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Benjamin Keserü ◽  
Beate Fisslthaler ◽  
Ingrid Fleming
Keyword(s):  
Vascular Remodeling ◽  
Epoxide Hydrolase ◽  
Chronic Hypoxia ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Soluble Epoxide Hydrolase ◽  
Pulmonary Vasculature ◽  
Resistance Arteries ◽  
Pulmonary Vascular Remodeling ◽  
Pulmonary Vasoconstriction

The soluble epoxide hydrolase (sEH), which is expressed in pulmonary artery smooth muscle cells, metabolizes cytochrome P450 (CYP) epoxygenase-derived epoxyeicosatrienoic acids (EETs) to their less active diols. Preliminary findings indicate a role of the sEH on hypoxic pulmonary vasoconstriction (HPV) and a vasoconstrictor role of EETs in the pulmonary vasculature. Here we assessed the influence of hypoxia on the expression of the sEH, acute HPV and pulmonary vascular remodeling. In lungs from wild-type mice (WT), exposure to hypoxia (FiO 2 = 0.1) for 21 days decreased the expression of the sEH by 70% (RT-PCR), and increased the number of partially and fully muscularised resistance arteries (by 3-fold). In isolated lungs, pre-exposure to chronic hypoxia significantly increased baseline perfusion pressures (1.3-fold) and potentiated the acute HPV (1.5-fold). While an sEH inhibitor (1-adamantyl-3-cyclohexylurea; ACU) potentiated acute HPV in lungs from mice maintained in normoxic conditions, it had no effect on HPV in lungs from mice exposed to hypoxia. The EET antagonist, 14,15-EEZE, abolished the sEH inhibitor-dependent increase in acute HPV in normoxic lungs. Under normoxic conditions the muscularization of small pulmonary arteries was greater in lungs from sEH −/− mice than in lungs from WT mice and chronic hypoxia further increased the number of fully and partially muscularized arteries in these animals. sEH −/− mice also displayed an enhanced acute HPV (1.5-fold), compared to that observed in WT mice and chronic exposure to hypoxia did not further potentiate acute HPV. Taken together, these data indicate that the sEH is involved in hypoxia-induced pulmonary vascular remodeling and hypoxic pulmonary vasoconstriction.

Abstract 658: Suppressed Hypoxic Pulmonary Vasoconstriction in Malonyl-CoA-Decarboxylase Knock-Out Mice

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Gopinath Sutendra ◽  
Sebastien Bonnet ◽  
Alois Haromy ◽  
Gary Lopaschuk ◽  
Jason Dyck ◽  
...  
Keyword(s):  
Confocal Microscopy ◽  
Exercise Tolerance ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Acute Hypoxia ◽  
Metabolic Enzyme ◽  
Acid Oxidation ◽  
Wild Mice ◽  
Pulmonary Vasoconstriction ◽  
Malonyl Coa ◽  
Intracellular Ca

Background : Hypoxic pulmonary vasoconstriction (HPV) is intrinsic to the pulmonary artery smooth muscle cells (PASMC). A recently proposed mechanism for HPV suggests that hypoxia is sensed within the mitochondria, altering the production of activated oxygen species (AOS) in response to changes in PO 2 . Decreased AOS (like H 2 O 2 ) inhibit Kv channels, depolarize PASMC, increase influx of Ca ++ , causing PASMC contraction. Malonyl-CoA-Decarboxylase (MCD) is a metabolic enzyme, that when inhibited suppresses the mitochondrial-based fatty acid oxidation, promoting glucose oxidation. We have shown that knockout mice lacking MCD (KO-MCD) are resistant to chronic-hypoxia-induced pulmonary hypertension (CH-PHT) but they have a normal phenotype in normoxia. We hypothesized that KO-MCD mice have suppressed HPV. Methods and Results : We compared KO-MCD to wild mice (W-MCD) using PASMC patch clamping, intracellular Ca ++ (fura-2), mitochondrial membrane potential (ΔΨm, using TMRM and confocal microscopy), mitochondrial AOS production (mitosox and confocal microscopy) and isolated intact resistance PA rings; we also studied exercise tolerance (distance covered in a treadmill) during normoxia and acute hypoxia (n =7–10 mice/group for all studies). As expected, in W-MCD mice acute hypoxia inhibited K + current (Ik), increased intracellular Ca ++ and mitochondrial ΔΨm, decreased mitochondrial AOS production, increased PA tone and decreased exercise tolerance (due to the rapid increase in PA pressure and decrease in cardiac output). In contrast, KO-MCD showed an impressive lack of response to acute hypoxia in all the parameters studied (table ). Conclusions : Our data show that acute hypoxia is not sensed in W-MCD mice and might offer at least a partial explanation for the resistance to CH-PHT in these mice. They also offer a novel insight into the metabolic basis of pulmonary vascular reactivity and HPV.

scholarly journals Endothelin B receptor deficiency potentiates ET-1 and hypoxic pulmonary vasoconstriction

2001 ◽  
Vol 280 (5) ◽  
pp. L1040-L1048 ◽  
Author(s):  
D. Dunbar Ivy ◽  
Ivan F. McMurtry ◽  
Masashi Yanagisawa ◽  
Cheryl E. Gariepy ◽  
Timothy D. Le Cras ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Vascular Tone ◽  
Radioligand Binding ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Acute Hypoxia ◽  
Physiological Role ◽  
Pulmonary Vasculature ◽  
Rat Lung ◽  
Pulmonary Vasoconstriction ◽  
Stimulation Of

Endothelin (ET)-1 contributes to the regulation of pulmonary vascular tone by stimulation of the ETA and ETB receptors. Although activation of the ETA receptor causes vasoconstriction, stimulation of the ETB receptors can elicit either vasodilation or vasoconstriction. To examine the physiological role of the ETB receptor in the pulmonary circulation, we studied a genetic rat model of ETB receptor deficiency [transgenic( sl/ sl)]. We hypothesized that deficiency of the ETB receptor would predispose the transgenic( sl/ sl) rat lung circulation to enhanced pulmonary vasoconstriction. We found that the lungs of transgenic( sl/ sl) rats are ETBdeficient because they lack ETB mRNA in the pulmonary vasculature, have minimal ETB receptors as determined with an ET-1 radioligand binding assay, and lack ET-1-mediated pulmonary vasodilation. The transgenic( sl/ sl) rats have higher basal pulmonary arterial pressure and vasopressor responses to brief hypoxia or ET-1 infusion. Plasma ET-1 levels are elevated and endothelial nitric oxide synthase protein content and nitric oxide production are diminished in the transgenic( sl/ sl) rat lung. These findings suggest that the ETB receptor plays a major physiological role in modulating resting pulmonary vascular tone and reactivity to acute hypoxia. We speculate that impaired ETB receptor activity can contribute to the pathogenesis of pulmonary hypertension.

Hypoxic pulmonary vasoconstriction in reptiles: a comparative study of four species with different lung structures and pulmonary blood pressures

2005 ◽  
Vol 289 (5) ◽  
pp. R1280-R1288 ◽  
Author(s):  
Nini Skovgaard ◽  
Augusto S. Abe ◽  
Denis V. Andrade ◽  
Tobias Wang
Keyword(s):  
Blood Flow ◽  
Pulmonary Blood Flow ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Acute Hypoxia ◽  
Blood Perfusion ◽  
Pulmonary Vasculature ◽  
Vascular Conductance ◽  
Blood Flows ◽  
Pulmonary Vasoconstriction ◽  
Local Ventilation

Low O2 levels in the lungs of birds and mammals cause constriction of the pulmonary vasculature that elevates resistance to pulmonary blood flow and increases pulmonary blood pressure. This hypoxic pulmonary vasoconstriction (HPV) diverts pulmonary blood flow from poorly ventilated and hypoxic areas of the lung to more well-ventilated parts and is considered important for the local matching of ventilation to blood perfusion. In the present study, the effects of acute hypoxia on pulmonary and systemic blood flows and pressures were measured in four species of anesthetized reptiles with diverse lung structures and heart morphologies: varanid lizards ( Varanus exanthematicus), caimans ( Caiman latirostris), rattlesnakes ( Crotalus durissus), and tegu lizards ( Tupinambis merianae). As previously shown in turtles, hypoxia causes a reversible constriction of the pulmonary vasculature in varanids and caimans, decreasing pulmonary vascular conductance by 37 and 31%, respectively. These three species possess complex multicameral lungs, and it is likely that HPV would aid to secure ventilation-perfusion homogeneity. There was no HPV in rattlesnakes, which have structurally simple lungs where local ventilation-perfusion inhomogeneities are less likely to occur. However, tegu lizards, which also have simple unicameral lungs, did exhibit HPV, decreasing pulmonary vascular conductance by 32%, albeit at a lower threshold than varanids and caimans (6.2 kPa oxygen in inspired air vs. 8.2 and 13.9 kPa, respectively). Although these observations suggest that HPV is more pronounced in species with complex lungs and functionally divided hearts, it is also clear that other components are involved.

Oxygen-dependent signaling in pulmonary vascular smooth muscle

2002 ◽  
Vol 283 (4) ◽  
pp. L671-L677 ◽  
Author(s):  
Usha Raj ◽  
Larissa Shimoda
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Chronic Hypoxia ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Acute Hypoxia ◽  
Pulmonary Vasculature ◽  
Oxygen Oxygen ◽  
Smooth Muscle Function ◽  
Dependent Protein ◽  
Acute Increase

The pulmonary circulation constricts in response to acute hypoxia, which is reversible on reexposure to oxygen. On exposure to chronic hypoxia, in addition to vasoconstriction, the pulmonary vasculature undergoes remodeling, resulting in a sustained increase in pulmonary vascular resistance that is not immediately reversible. Hypoxic pulmonary vasoconstriction is physiological in the fetus, and there are many mechanisms by which the pulmonary vasculature relaxes at birth, principal among which is the acute increase in oxygen. Oxygen-induced signaling mechanisms, which result in pulmonary vascular relaxation at birth, and the mechanisms by which chronic hypoxia results in pulmonary vascular remodeling in the fetus and adult, are being investigated. Here, the roles of cGMP-dependent protein kinase in oxygen-mediated signaling in fetal pulmonary vascular smooth muscle and the effects of chronic hypoxia on ion channel activity and smooth muscle function such as contraction, growth, and gene expression were discussed.

scholarly journals Effects of carbon monoxide-releasing molecules on pulmonary vasoreactivity in isolated perfused lungs

2016 ◽  
Vol 120 (2) ◽  
pp. 271-281 ◽  
Author(s):  
Oleg Pak ◽  
Adel G. Bakr ◽  
Mareike Gierhardt ◽  
Julia Albus ◽  
Ievgen Strielkov ◽  
...  
Keyword(s):  
Carbon Monoxide ◽  
Vascular Tone ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Acute Hypoxia ◽  
Pulmonary Vasculature ◽  
High Concentration ◽  
Continuous Increase ◽  
Pulmonary Vasoconstriction ◽  
Isolated Lungs ◽  
Co Gas

In addition to its renowned poisonous effects, carbon monoxide (CO) is being recognized for its beneficial actions on inflammatory and vasoregulatory pathways, particularly when applied at low concentrations via CO-releasing molecules (CO-RMs). In the lung, CO gas and CO-RMs are suggested to decrease pulmonary vascular tone and hypoxic pulmonary vasoconstriction (HPV). However, the direct effect of CO-RMs on the pulmonary vasoreactivity in isolated lungs has not yet been investigated. We assessed the effect of CORM-2 and CORM-3 on the pulmonary vasculature during normoxia and acute hypoxia (1% oxygen for 10 min) in isolated ventilated and perfused mouse lungs. The effects were compared with those of inhaled CO gas (10%). The interaction of CORM-2 or CO with cytochrome P-450 (CYP) was measured simultaneously by tissue spectrophotometry. Inhaled CO decreased HPV and vasoconstriction induced by the thromboxane mimetic U-46619 but did not alter KCl-induced vasoconstriction. In contrast, concentrations of CORM-2 and CORM-3 used to elicit beneficial effects on the systemic circulation did not affect pulmonary vascular tone. High concentration of CO-RMs or long-term application induced a continuous increase in normoxic pressure. Inhaled CO showed spectral alterations correlating with the inhibition of CYP. In contrast, during application of CORM-2 spectrophotometric signs of interaction with CYP could not be detected. Application of CO-RMs in therapeutic doses in isolated lungs neither decreases pulmonary vascular tone and HPV nor does it induce spectral alterations that are characteristic of CO-inhibited CYP. High doses, however, may cause pulmonary vasoconstriction.

Vascular adaptations to hypoxia: molecular and cellular mechanisms regulating vascular tone

2007 ◽  
Vol 43 ◽  
pp. 105-120 ◽  
Author(s):  
Michael L. Paffett ◽  
Benjimen R. Walker
Keyword(s):  
Vascular Tone ◽  
Cellular Proliferation ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Hypoxia Inducible Factor ◽  
Systemic Circulation ◽  
Cellular Mechanisms ◽  
Hypoxia Inducible Factor 1 ◽  
Pulmonary Vasoconstriction ◽  
Adaptive Mechanisms ◽  
Adaptive Processes

Several molecular and cellular adaptive mechanisms to hypoxia exist within the vasculature. Many of these processes involve oxygen sensing which is transduced into mediators of vasoconstriction in the pulmonary circulation and vasodilation in the systemic circulation. A variety of oxygen-responsive pathways, such as HIF (hypoxia-inducible factor)-1 and HOs (haem oxygenases), contribute to the overall adaptive process during hypoxia and are currently an area of intense research. Generation of ROS (reactive oxygen species) may also differentially regulate vascular tone in these circulations. Potential candidates underlying the divergent responses between the systemic and pulmonary circulations may include Nox (NADPH oxidase)-derived ROS and mitochondrial-derived ROS. In addition to alterations in ROS production governing vascular tone in the hypoxic setting, other vascular adaptations are likely to be involved. HPV (hypoxic pulmonary vasoconstriction) and CH (chronic hypoxia)-induced alterations in cellular proliferation, ionic conductances and changes in the contractile apparatus sensitivity to calcium, all occur as adaptive processes within the vasculature.

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