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.

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.

scholarly journals Pulmonary vasodilation by acetazolamide during hypoxia: impact of methyl-group substitutions and administration route in conscious, spontaneously breathing dogs

2014 ◽  
Vol 116 (7) ◽  
pp. 715-723 ◽  
Author(s):  
Philipp A. Pickerodt ◽  
Roland C. Francis ◽  
Claudia Höhne ◽  
Friederike Neubert ◽  
Stella Telalbasic ◽  
...  
Keyword(s):  
Hypoxic Pulmonary Vasoconstriction ◽  
Acute Hypoxia ◽  
Administration Routes ◽  
Pulmonary Vasodilation ◽  
Mean Pulmonary Arterial Pressure ◽  
Pulmonary Vasoconstriction ◽  
Thiadiazole Ring ◽  
Pulmonary Arterial ◽  
Isolated Lungs ◽  
Spontaneously Breathing

Acetazolamide (ACZ) prevents hypoxic pulmonary vasoconstriction (HPV) in isolated lungs, animals, and humans, but not by carbonic anhydrase (CA) inhibition. We studied administration routes in, and certain structural aspects of, ACZ critical to HPV inhibition. Analogs of ACZ during acute hypoxia were tested in unanesthetized dogs. Dogs breathed normoxic gas for 1 h (inspired O2 fraction = 0.21), followed by 10% O2 for 2 h (hypoxia) in these protocols: 1) controls; 2) ACZ intravenously (2 mg·kg−1·h−1); 3) ACZ orally (5 mg/kg, 12 and 1 h before the experiment); 4) inhaled ACZ (750 mg); 5) methazolamide (MTZ) intravenously (3 mg·kg−1·h−1); and 6) N-methyl-acetazolamide (NMA) intravenously (10 mg·kg−1·h−1). In controls, mean pulmonary arterial pressure (MPAP) increased 7 mmHg, and pulmonary vascular resistance (PVR) 224 dyn·s·cm−5 with hypoxia ( P < 0.05). With intravenous and inhaled ACZ, MPAP and PVR did not change during hypoxia. With oral ACZ, HPV was only slightly suppressed; MPAP increased 5 mmHg and PVR by 178 dyn·s·cm−5 during hypoxia. With MTZ and NMA, the MPAP rise (4 ± 2 mmHg) was reduced, and PVR did not increase during hypoxia compared with normoxia (MTZ intravenous: 81 ± 77 and 68 ± 82 dyn·s·cm−5 with NMA intravenous). Inhaled ACZ prevents HPV, but not without causing systemic CA inhibition. NMA, a compound lacking CA inhibiting effects by methylation at the sulfonamide moiety, and MTZ, a CA-inhibiting analog methylated at the thiadiazole ring, are only slightly less effective than ACZ in reducing HPV.

scholarly journals Genetic deletion of p66shc and/or cyclophilin D results in decreased pulmonary vascular tone

2020 ◽  
Author(s):  
Mareike Gierhardt ◽  
Oleg Pak ◽  
Akylbek Sydykov ◽  
Simone Kraut ◽  
Julia Schäffer ◽  
...  
Keyword(s):  
Vascular Tone ◽  
Calcium Handling ◽  
Pulmonary Vasculature ◽  
Mitochondrial Calcium ◽  
Cyclophilin D ◽  
Vascular Contractility ◽  
Pulmonary Vasoconstriction ◽  
Mptp Opening ◽  
Isolated Lungs ◽  
Deficient Mice

Abstract Aims The pulmonary vascular tone and hypoxia-induced alterations of the pulmonary vasculature may be regulated by the mitochondrial membrane permeability transition pore (mPTP) that controls mitochondrial calcium load and apoptosis. We thus investigated, if the mitochondrial proteins p66shc and cyclophilin D (CypD) that regulate mPTP opening affect the pulmonary vascular tone. Methods and results Mice deficient for p66shc (p66shc−/−), CypD (CypD−/−), or both proteins (p66shc/CypD−/−) exhibited decreased pulmonary vascular resistance (PVR) compared to wild-type mice determined in isolated lungs and in vivo. In contrast, systemic arterial pressure was only lower in CypD−/− mice. As cardiac function and pulmonary vascular remodelling did not differ between genotypes, we determined alterations of vascular contractility in isolated lungs and calcium handling in pulmonary arterial smooth muscle cells (PASMC) as underlying reason for decreased PVR. Potassium chloride (KCl)-induced pulmonary vasoconstriction and KCl-induced cytosolic calcium increase determined by Fura-2 were attenuated in all gene-deficient mice. In contrast, KCl-induced mitochondrial calcium increase determined by the genetically encoded Mito-Car-GECO and calcium retention capacity were increased only in CypD−/− and p66shc/CypD−/− mitochondria indicating that decreased mPTP opening affected KCl-induced intracellular calcium peaks in these cells. All mouse strains showed a similar pulmonary vascular response to chronic hypoxia, while acute hypoxic pulmonary vasoconstriction was decreased in gene-deficient mice indicating that CypD and p66shc regulate vascular contractility but not remodelling. Conclusions We conclude that p66shc specifically regulates the pulmonary vascular tone, while CypD also affects systemic pressure. However, only CypD acts via regulation of mPTP opening and mitochondrial calcium regulation.

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.

Contribution of endothelin to pulmonary vascular tone under normoxic and hypoxic conditions

2002 ◽  
Vol 283 (2) ◽  
pp. H568-H575 ◽  
Author(s):  
Wendy Johnson ◽  
Anju Nohria ◽  
Leslie Garrett ◽  
James C. Fang ◽  
James Igo ◽  
...  
Keyword(s):  
Cardiac Output ◽  
Vascular Resistance ◽  
Vascular Tone ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Acute Hypoxia ◽  
Hemodynamic Effects ◽  
Hypoxic Conditions ◽  
Pulmonary Vasoconstriction ◽  
Endothelin Type A Receptor ◽  
Vehicle Treated Control

The contribution of endothelin to resting pulmonary vascular tone and hypoxic pulmonary vasoconstriction in humans is unknown. We studied the hemodynamic effects of BQ-123, an endothelin type A receptor antagonist, on healthy volunteers exposed to normoxia and hypoxia. Hemodynamics were measured at room air and after 15 min of exposure to hypoxia (arterial Po 2 99.8 ± 1.8 and 49.4 ± 0.4 mmHg, respectively). Measurements were then repeated in the presence of BQ-123. BQ-123 decreased pulmonary vascular resistance (PVR) 26% and systemic vascular resistance (SVR) 21%, whereas it increased cardiac output (CO) 22% (all P < 0.05). Hypoxia raised CO 28% and PVR 95%, whereas it reduced SVR 23% (all P< 0.01). During BQ-123 infusion, hypoxia increased CO 29% and PVR 97% and decreased SVR 22% (all P < 0.01). The pulmonary vasoconstrictive response to hypoxia was similar in the absence and presence of BQ-123 [ P = not significant (NS)]. In vehicle-treated control subjects, hypoxic pulmonary vasoconstriction did not change with repeated exposure to hypoxia ( P = NS). Endothelin contributes to basal pulmonary and systemic vascular tone during normoxia, but does not mediate the additional pulmonary vasoconstriction induced by acute hypoxia.

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.

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.

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.

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