Precursors and inhibitors of hydrogen sulfide synthesis affect acute hypoxic pulmonary vasoconstriction in the intact lung

2012 ◽  
Vol 112 (3) ◽  
pp. 411-418 ◽  
Author(s):  
Jane A. Madden ◽  
Susan B. Ahlf ◽  
Mark W. Dantuma ◽  
Kenneth R. Olson ◽  
David L. Roerig
Keyword(s):  
Hydrogen Sulfide ◽  
Arterial Pressure ◽  
Lung Tissue ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Acute Hypoxia ◽  
Pulmonary Arteries ◽  
Tissue Homogenate ◽  
Rat Lung ◽  
Western Blots ◽  
Pulmonary Vasoconstriction

The effects of hydrogen sulfide (H2S) and acute hypoxia are similar in isolated pulmonary arteries from various species. However, the involvement of H2S in hypoxic pulmonary vasoconstriction (HPV) has not been studied in the intact lung. The present study used an intact, isolated, perfused rat lung preparation to examine whether adding compounds essential to H2S synthesis or to its inhibition would result in a corresponding increase or decrease in the magnitude of HPV. Western blots performed in lung tissue identified the presence of the H2S-synthesizing enzymes, cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfur transferase (3-MST), but not cystathionine β-synthase (CBS). Adding three H2S synthesis precursors, cysteine and oxidized or reduced glutathione, to the perfusate significantly increased peak arterial pressure during hypoxia compared with control ( P < 0.05). Adding α-ketoglutarate to enhance the 3-MST enzyme pathway also resulted in an increase ( P < 0.05). Both aspartate, which inhibits the 3-MST synthesis pathway, and propargylglycine (PPG), which inhibits the CSE pathway, significantly reduced the increases in arterial pressure during hypoxia. Diethylmaleate (DEM), which conjugates sulfhydryls, also reduced the peak hypoxic arterial pressure at concentrations >2 mM. Finally, H2S concentrations as measured with a specially designed polarographic electrode decreased markedly in lung tissue homogenate and in small pulmonary arteries when air was added to the hypoxic environment of the measurement chamber. The results of this study provide evidence that the rate of H2S synthesis plays a role in the magnitude of acute HPV in the isolated perfused rat lung.

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.

Hypoxic pulmonary vasoconstriction is modified byP-450 metabolites

2000 ◽  
Vol 279 (4) ◽  
pp. H1526-H1533 ◽  
Author(s):  
Daling Zhu ◽  
Eric K. Birks ◽  
Christopher A. Dawson ◽  
Monica Patel ◽  
John R. Falck ◽  
...  
Keyword(s):  
Lung Tissue ◽  
Vascular Tone ◽  
Perfusion Pressure ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Pulmonary Arteries ◽  
Rabbit Lung ◽  
Hypoxic Conditions ◽  
Pulmonary Vasoconstriction ◽  
Arterial Relaxation ◽  
Cytochrome P 450

20-Hydroxyeicosatetraenoic acid (20-HETE) is a cytochrome P-450 4A (CYP4A) metabolite of arachidonic acid (AA) in human and rabbit lung microsomes and is a dilator of isolated human pulmonary arteries (PA). However, little is known regarding the contribution of P-450 metabolites to pulmonary vascular tone. We examined 1) the effect of two mechanistically distinct ω- and ω1-hydroxylase inhibitors on perfusion pressures in isolated rabbit lungs ventilated with normoxic or hypoxic gases, 2) changes in rabbit PA ring tone elicited by 20-HETE or ω- and ω1-hydroxylase inhibitors, and 3) expression of CYP4A protein in lung tissue. A modest increase in perfusion pressure (55 ± 11% above normoxic conditions) was observed in isolated perfused lungs during ventilation with hypoxic gas (Fi O2 = 0.05). Inhibitors of 20-HETE synthesis, 17-oxydecanoic acid (17-ODYA) or N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS), increased baseline perfusion pressure above that of vehicle and amplified hypoxia-induced increases in perfusion pressures by 92 ± 11% and 105 ± 11% over baseline pressures, respectively. 20-HETE relaxed phenylephrine (PE)-constricted PA rings. Treatment with 17-ODYA enhanced PE-induced contraction of PA rings, consistent with inhibition of a product that promotes arterial relaxation, whereas 6-(20-propargyloxyphenyl)hexanoic acid (PPOH), an epoxygenase inhibitor, blunted contraction to PE. Conversion of AA into 20-HETE was blocked by 17-ODYA, DDMS, and hypoxia. CYP4A immunospecific protein confirms expression of CYP4A in male rabbit lung tissue. Our data suggest that endogenously produced 20-HETE could modify rabbit pulmonary vascular tone, particularly under hypoxic conditions.

Acetazolamide prevents hypoxic pulmonary vasoconstriction in conscious dogs

2004 ◽  
Vol 97 (2) ◽  
pp. 515-521 ◽  
Author(s):  
Claudia Höhne ◽  
Martin O. Krebs ◽  
Manuela Seiferheld ◽  
Willehad Boemke ◽  
Gabriele Kaczmarczyk ◽  
...  
Keyword(s):  
Arterial Pressure ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Pulmonary Arterial Pressure ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Acute Hypoxia ◽  
Conscious Dogs ◽  
Mean Pulmonary Arterial Pressure ◽  
Pulmonary Vasoconstriction ◽  
Pulmonary Arterial

Acute hypoxia increases pulmonary arterial pressure and vascular resistance. Previous studies in isolated smooth muscle and perfused lungs have shown that carbonic anhydrase (CA) inhibition reduces the speed and magnitude of hypoxic pulmonary vasoconstriction (HPV). We studied whether CA inhibition by acetazolamide (Acz) is able to prevent HPV in the unanesthetized animal. Ten chronically tracheotomized, conscious dogs were investigated in three protocols. In all protocols, the dogs breathed 21% O2 for the first hour and then 8 or 10% O2 for the next 4 h spontaneously via a ventilator circuit. The protocols were as follows: protocol 1: controls given no Acz, inspired O2 fraction (FiO2) = 0.10; protocol 2: Acz infused intravenously (250-mg bolus, followed by 167 μg·kg−1·min−1 continuously), FiO2 = 0.10; protocol 3: Acz given as above, but with FiO2 reduced to 0.08 to match the arterial Po2 (PaO2) observed during hypoxia in controls. PaO2 was 37 Torr during hypoxia in controls, mean pulmonary arterial pressure increased from 17 ± 1 to 23 ± 1 mmHg, and pulmonary vascular resistance increased from 464 ± 26 to 679 ± 40 dyn·s−1·cm−5 ( P < 0.05). In both Acz groups, mean pulmonary arterial pressure was 15 ± 1 mmHg, and pulmonary vascular resistance ranged between 420 and 440 dyn·s−1·cm−5. These values did not change during hypoxia. In dogs given Acz at 10% O2, the arterial PaO2 was 50 Torr owing to hyperventilation, whereas in those breathing 8% O2 the PaO2 was 37 Torr, equivalent to controls. In conclusion, Acz prevents HPV in conscious spontaneously breathing dogs. The effect is not due to Acz-induced hyperventilation and higher alveolar Po2, nor to changes in plasma endothelin-1, angiotensin-II, or potassium, and HPV suppression occurs despite the systemic acidosis with CA inhibition.

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 Roles for Nox4 in the contractile response of bovine pulmonary arteries to hypoxia

2010 ◽  
Vol 298 (6) ◽  
pp. H1879-H1888 ◽  
Author(s):  
Mansoor Ahmad ◽  
Melissa R. Kelly ◽  
Xiangmin Zhao ◽  
Sharath Kandhi ◽  
Michael S. Wolin
Keyword(s):  
Transforming Growth Factor ◽  
Contractile Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Acute Hypoxia ◽  
Pulmonary Arteries ◽  
Prolonged Treatment ◽  
Superoxide Generation ◽  
Contractile Mechanism ◽  
Pulmonary Vasoconstriction ◽  
Tgf Β1

Hypoxia appears to promote contraction [hypoxic pulmonary vasoconstriction (HPV)] of bovine pulmonary arteries (BPA) through removal of a peroxide-mediated relaxation. This study examines the roles of BPA Nox oxidases and mitochondria in the HPV response. Inhibitors of Nox2 (0.1 mM apocynin and 50 μM gp91-dstat) and mitochondrial electron transport (10 μM antimycin and rotenone) decreased superoxide generation in BPA without affecting contraction to 25 mM KCl or the HPV response. Transfection of BPA with small inhibitory RNA (siRNA) for Nox2 and Nox4 decreased Nox2 and Nox4 protein expression, respectively, associated with an attenuation of superoxide detection, without affecting 25 mM KCl contraction. However, Nox4 siRNA, but not Nox2, attenuated HPV in BPA. A Nox4 inhibitor plumbagin (10 μM) increased basal force, decreased superoxide detection and peroxide release, and caused BPA to relax under hypoxia. Although acute removal of peroxide with 0.1 mM ebselen increased 25 mM KCl contraction and decreased hypoxic contraction, prolonged treatment with ebselen only decreased hypoxic contraction without affecting 25 mM KCl contraction, suggesting basal peroxide levels also maintain a contractile mechanism not removed by acute hypoxia. Organ culture of BPA with transforming growth factor (TGF)-β1 (4 nM) increased Nox4 expression, superoxide, peroxide, and the HPV response. Thus Nox2 and mitochondria are sources for superoxide generation in BPA, which do not appear to influence the HPV response. However, peroxide derived from superoxide generated by Nox4 appears to maintain a basal relaxation in BPA under normoxic conditions, which is removed under hypoxia leading to HPV. Peroxide generated by Nox4 may also function to maintain a contractile mechanism, which is not reversed by acute hypoxia.

Acute hypoxia increases intracellular [Ca2+] in pulmonary arterial smooth muscle by enhancing capacitative Ca2+ entry

2005 ◽  
Vol 288 (6) ◽  
pp. L1059-L1069 ◽  
Author(s):  
Jian Wang ◽  
Larissa A. Shimoda ◽  
Letitia Weigand ◽  
Wenqian Wang ◽  
Dejun Sun ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Acute Hypoxia ◽  
Primary Cultures ◽  
Fluorescent Microscopy ◽  
Pulmonary Arteries ◽  
Arterial Smooth Muscle ◽  
Fura 2 ◽  
Pulmonary Arterial ◽  
Pulmonary Arterial Smooth Muscle

Hypoxic pulmonary vasoconstriction (HPV) requires influx of extracellular Ca2+ in pulmonary arterial smooth muscle cells (PASMCs). To determine whether capacitative Ca2+ entry (CCE) through store-operated Ca2+ channels (SOCCs) contributes to this influx, we used fluorescent microscopy and the Ca2+-sensitive dye fura-2 to measure effects of 4% O2 on intracellular [Ca2+] ([Ca2+]i) and CCE in primary cultures of PASMCs from rat distal pulmonary arteries. In PASMCs perfused with Ca2+-free Krebs Ringer bicarbonate solution (KRBS) containing cyclopiazonic acid to deplete Ca2+ stores in sarcoplasmic reticulum and nifedipine to prevent Ca2+ entry through L-type voltage-operated Ca2+ channels (VOCCs), hypoxia markedly enhanced both the increase in [Ca2+]i caused by restoration of extracellular [Ca2+] and the rate at which extracellular Mn2+ quenched fura-2 fluorescence. These effects, as well as the increased [Ca2+]i caused by hypoxia in PASMCs perfused with normal salt solutions, were blocked by the SOCC antagonists SKF-96365, NiCl2, and LaCl3 at concentrations that inhibited CCE >80% but did not alter [Ca2+]i responses to 60 mM KCl. In contrast, the VOCC antagonist nifedipine inhibited [Ca2+]i responses to hypoxia by only 50% at concentrations that completely blocked responses to KCl. The increased [Ca2+]i caused by hypoxia was completely reversed by perfusion with Ca2+-free KRBS. LaCl3 increased basal [Ca2+]i during normoxia, indicating effects other than inhibition of SOCCs. Our results suggest that acute hypoxia enhances CCE through SOCCs in distal PASMCs, leading to depolarization, secondary activation of VOCCs, and increased [Ca2+]i. SOCCs and CCE may play important roles in HPV.

Abstract 276: Heme Oxygenase-1 Induction Modulates Hypoxic Pulmonary Vasoconstriction

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Mansoor Ahmad ◽  
Nader G Abraham ◽  
Michael S Wolin
Keyword(s):  
Organ Culture ◽  
Heme Oxygenase ◽  
Cobalt Chloride ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Pulmonary Arteries ◽  
Heme Oxygenase 1 ◽  
Force Development ◽  
Pulmonary Vasoconstriction ◽  
Copper Chelator ◽  
Relaxing Effect

Endothelium removed Bovine pulmonary arteries (BPA) contract to hypoxia through a mechanism potentially involving lowering of superoxide-derived hydrogen peroxide and removing its basal relaxing effect. Induction of heme oxygenase-1 (HO-1) in BPA by 24 hr organ culture with 0.1mM cobalt chloride was accompanied by a decrease in 5μM lucigenin-detectable superoxide and an increase in horseradish peroxidase-luminol detectable peroxide levels. Force development to 20mM KCl in BPA was not affected by HO-1, but hypoxic pulmonary vasoconstriction (HPV) was significantly reduced. Organ culture with a HO-1 inhibitor (10μM chromium mesoporphyrin) reversed the effects of HO-1 on HPV and peroxide. Pretreatment of BPA with a copper chelator 10mM diethyldithiocarbamate (DETCA) to inactivate Cu,Zn-SOD, prevented the conversion of superoxide to peroxide, and attenuated HPV. DETCA treatment increased superoxide and decreased peroxide to similar levels in control and HO-1 induced BPA. Peroxide scavenging with 0.1mM ebselen increased force development to 20mM KCl and partially reversed the decrease in HPV seen on induction of HO-1. Thus HO-1 induction in BPA causes an increase in superoxide scavenging by Cu,Zn-SOD resulting in increased levels of peroxide, leading to an attenuation of HPV. The generation of superoxide in BPA is not affected by HO-1 induction as DETCA treated control and HO-1 BPA show similar levels of superoxide. Thus, HO-1 induction appears to attenuate HPV in BPA by increasing the conversion of superoxide to peroxide, leading to peroxide levels which may not be adequately lowered by hypoxia.

Hypoxic induction of Ca2+-dependent action potentials in small pulmonary arteries of the cat

1985 ◽  
Vol 59 (5) ◽  
pp. 1389-1393 ◽  
Author(s):  
D. R. Harder ◽  
J. A. Madden ◽  
C. Dawson
Keyword(s):  
Action Potentials ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Pulmonary Arteries ◽  
Input Resistance ◽  
Potential Generation ◽  
Applied Current ◽  
Pulmonary Vasoconstriction ◽  
Ionic Conductances ◽  
The Relationship ◽  
K Permeability

Small pulmonary arteries (less than 300 micron) from cats were mounted in myographs to record mechanical and electrical responses to hypoxia. When these preparations were exposed to a PO2 of 30–50 Torr after equilibration at 300 Torr they consistently developed active force, which increased or decreased in amplitude as [Ca2+] was raised or lowered, respectively, and was blocked on addition of verapamil. Intracellular electrical recording with glass microelectrodes demonstrated membrane depolarization and action potential generation when PO2 was lowered. Steady-state voltage vs. applied current curves obtained before and during hypoxia showed a significant reduction in input resistance. The relationship between membrane potential and extracellular K+ was not different during hypoxia compared with control, suggesting that there were not marked changes in K+ permeability under this condition. In the presence of verapamil to block Ca2+ inward current the hypoxia-induced action potentials were abolished concomitant with partial membrane repolarization. The results of these studies suggest that in certain isolated pulmonary arteries hypoxia induces contraction by a mechanism involving an increased Ca2+ conductance. These data suggest that the sensor involved in hypoxic pulmonary vasoconstriction may lie within the vessel wall and somehow mediates changes in smooth muscle ionic conductances.

Prostaglandin D2 inhibits hypoxic pulmonary vasoconstriction in neonatal lambs

1983 ◽  
Vol 54 (6) ◽  
pp. 1585-1589 ◽  
Author(s):  
J. B. Philips ◽  
R. K. Lyrene ◽  
M. McDevitt ◽  
W. Perlis ◽  
C. Satterwhite ◽  
...  
Keyword(s):  
Arterial Pressure ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Inferior Vena ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Vena Cava ◽  
Systemic Arterial Pressure ◽  
Prostaglandin D2 ◽  
Pulmonary Vasoconstriction ◽  
Neonatal Lambs

Intrapulmonary injections of prostaglandin D2 (PGD2) reduce pulmonary arterial pressure and resistance in fetal and hypoxic neonatal lambs without affecting systemic arterial pressure. This apparently specific pulmonary effect of PGD2 could be explained by inactivation of the agent during passage through the pulmonary capillary bed. We therefore studied the effects of both pulmonary and systemic infusions of PGD2 on the acute vascular response to a 1-min episode of hypoxia in newborn lambs. Since PGD2 has been reported to be a pulmonary vasoconstrictor in normoxic lambs, we also evaluated its effects during normoxemia. Pulmonary vascular pressures were not affected by either 1- or 10-micrograms . kg-1 . min-1 infusions into the left atrium or inferior vena cava during normoxia. Infusion of 1 microgram . kg-1 . min-1 PGD2 into the inferior vena cava decreased pulmonary vascular resistance and increased systemic arterial pressure. These two parameters were unchanged with the other three infusion regimens. Mean pulmonary vascular resistance rose 83% with hypoxia and no PGD2. PGD2 prevented any change in pulmonary vascular resistance with hypoxia, while systemic arterial pressure increased (1-microgram . kg-1 . min-1 doses) or was unchanged. Thus PGD2 specifically prevents hypoxic pulmonary vasoconstriction while maintaining systemic pressures, regardless of infusion site. PGD2 may be indicated in treatment of persistent pulmonary hypertension of the newborn and other pulmonary hypertensive disorders.

Inhaled nitric oxide partially reverses hypoxic pulmonary vasoconstriction in the dog

1994 ◽  
Vol 76 (3) ◽  
pp. 1350-1355 ◽  
Author(s):  
J. A. Romand ◽  
M. R. Pinsky ◽  
L. Firestone ◽  
H. A. Zar ◽  
J. R. Lancaster
Keyword(s):  
Nitric Oxide ◽  
Arterial Pressure ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Canine Model ◽  
Systemic Arterial Pressure ◽  
Vasomotor Tone ◽  
Pulmonary Vasoconstriction ◽  
Pulmonary Arterial

Nitric oxide (NO) inhaled during a hypoxia-induced increase in pulmonary vasomotor tone decreases pulmonary arterial pressure (Ppa). We conducted this study to better characterize the hemodynamic effects induced by NO inhalation during hypoxic pulmonary vasoconstriction in 11 anesthetized ventilated dogs. Arterial and venous systemic and pulmonary pressures and aortic flow probe-derived cardiac output were recorded, and nitrosylhemoglobin (NO-Hb) and methemoglobin (MetHb) were measured. The effects of 5 min of NO inhalation at 0, 17, 28, 47, and 0 ppm during hyperoxia (inspiratory fraction of O2 = 0.5) and hypoxia (inspiratory fraction of O2 = 0.16) were observed. NO inhalation has no measurable effects during hyperoxia. Hypoxia induced an increase in Ppa that reached plateau levels after 5 min. Exposure to 28 and 47 ppm NO induced an immediate (< 30 s) decrease in Ppa and calculated pulmonary vascular resistance (P < 0.05 each) but did not return either to baseline hyperoxic values. Increasing the concentration of NO to 74 and 145 ppm in two dogs during hypoxia did not induce any further decreases in Ppa. Reversing hypoxia while NO remained at 47 ppm further decreased Ppa and pulmonary vascular resistance to baseline values. NO inhalation did not induce decreases in systemic arterial pressure. MetHb remained low, and NO-Hb was unmeasurable. We concluded that NO inhalation only partially reversed hypoxia-induced increases in pulmonary vasomotor tone in this canine model. These effects are immediate and selective to the pulmonary circulation.

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