NO and reactive oxygen species are involved in biphasic hypoxic vasoconstriction of isolated rabbit lungs

2001 ◽  
Vol 280 (4) ◽  
pp. L638-L645 ◽  
Author(s):  
Norbert Weissmann ◽  
Stefan Winterhalder ◽  
Matthias Nollen ◽  
Robert Voswinckel ◽  
Karin Quanz ◽  
...  
Keyword(s):  
Pressor Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Oxidase Inhibitor ◽  
No Formation ◽  
Vasoconstrictor Response ◽  
Hypoxic Vasoconstriction ◽  
Chronic Pulmonary Hypertension ◽  
Alveolar Hypoxia ◽  
Pulmonary Arterial ◽  
Synthase Inhibitor

Hypoxic pulmonary vasoconstriction (HPV) matches lung perfusion with ventilation but may also result in chronic pulmonary hypertension. It has not been clarified whether acute HPV and the response to prolonged alveolar hypoxia are triggered by identical mechanisms. We characterized the vascular response to sustained hypoxic ventilation (3% O2for 120–180 min) in isolated rabbit lungs. Hypoxia provoked a biphasic increase in pulmonary arterial pressure (PAP). Persistent PAP elevation was observed after termination of hypoxia. Total blockage of lung nitric oxide (NO) formation by N G-monomethyl-l-arginine caused a two- to threefold amplification of acute HPV, the sustained pressor response, and the loss of posthypoxic relaxation. This amplification was only moderate when NO formation was partially blocked by the inducible NO synthase inhibitor S-methylisothiourea. The superoxide scavenger nitro blue tetrazolium and the superoxide dismutase inhibitor triethylenetetramine reduced the initial vasoconstrictor response, the prolonged PAP increase, and the loss of posthypoxic vasorelaxation to a similar extent. The NAD(P)H oxidase inhibitor diphenyleneiodonium nearly fully blocked the late vascular responses to hypoxia in a dose that effected a decrease to half of the acute HPV. In conclusion, as similarly suggested for acute HPV, lung NO synthesis and the superoxide-hydrogen peroxide axis appear to be implicated in the prolonged pressor response and the posthypoxic loss of vasorelaxation in perfused rabbit lungs undergoing 2–3 h of hypoxic ventilation.

Does leukotriene C4 mediate hypoxic vasoconstriction in isolated ferret lungs?

1990 ◽  
Vol 68 (1) ◽  
pp. 253-259 ◽  
Author(s):  
C. M. Tseng ◽  
M. McGeady ◽  
T. Privett ◽  
A. Dunn ◽  
J. T. Sylvester
Keyword(s):  
Pulmonary Arterial Pressure ◽  
Pressor Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Physiological Salt Solution ◽  
Leukotriene C4 ◽  
Prostaglandin F2 Alpha ◽  
Pulmonary Vasoconstriction ◽  
Vasoconstrictor Response ◽  
Hypoxic Vasoconstriction ◽  
Pulmonary Arterial

To evaluate leukotriene (LT) C4 as a mediator of hypoxic pulmonary vasoconstriction, we examined the effects of FPL55712, a putative LT antagonist, and indomethacin, a cyclooxygenase inhibitor, on vasopressor responses to LTC4 and hypoxia (inspired O2 tension = 25 Torr) in isolated ferret lungs perfused with a constant flow (50 ml.kg-1.min-1). Pulmonary arterial injections of LTC4 caused dose-related increases in pulmonary arterial pressure during perfusion with physiological salt solution containing Ficoll (4 g/dl). FPL55712 caused concentration-related inhibition of the pressor response to LTC4 (0.6 micrograms). Although 10 micrograms/ml FPL55712 inhibited the LTC4 pressor response by 61%, it did not alter the response to hypoxia. At 100 microgram/ml, FPL55712 inhibited the responses to LTC4 and hypoxia by 73 and 71%, respectively, but also attenuated the vasoconstrictor responses to prostaglandin F2 alpha (78% at 8 micrograms), phenylephrine (68% at 100 micrograms), and KCl (51% at 40 mM). At 0.5 microgram/ml, indomethacin significantly attenuated the pressor response to arachidonic acid but did not alter responses to LTC4 or hypoxia. These results suggest that in isolated ferret lungs 1) the vasoconstrictor response to LTC4 did not depend on release of cyclooxygenase products and 2) LTC4 did not mediate hypoxic vasoconstriction.

Platelet antiserum inhibits hypoxic pulmonary vasoconstriction in the dog

1976 ◽  
Vol 41 (2) ◽  
pp. 211-215 ◽  
Author(s):  
E. K. Weir ◽  
J. Mlczoch ◽  
J. Seavy ◽  
J. J. Cohen ◽  
R. F. Grover
Keyword(s):  
Platelet Count ◽  
Pressor Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Hypoxic Response ◽  
Pulmonary Vasoconstriction ◽  
Vasoconstrictor Response ◽  
Hypoxic Vasoconstriction ◽  
Prior Administration ◽  
Temporary Inhibition

The literature suggests that platelets might help mediate the pulmonary vascular pressor response to hypoxia. This study evaluated the hypoxic response in dogs rendered acutely thrombocytopenic by the administration of platelet antiserum. Between 30 and 90 min after the antiserum the pulmonary vasoconstrictor response to hypoxia was virtually abolished, but subsequently returned at a time when the number of circulating platelets remained very low. The prior administration of meclofenamate completely preserved the hypoxic response, though the platelet count still fell precipitously. We conclude that circulating platelets are not necessary for hypoxic vasoconstriction. It is possible that the reaction between platelets and antiserum evokes the synthesis of a dilator prostaglandin which might be responsible for the temporary inhibition of the pressor response to hypoxia but this remains to be proven.

Pulmonary hypoxic vasoconstriction: not affected by chemical sympathectomy

1979 ◽  
Vol 46 (3) ◽  
pp. 529-533 ◽  
Author(s):  
C. A. Hales ◽  
D. M. Westphal
Keyword(s):  
Hypoxic Pulmonary Vasoconstriction ◽  
Systemic Blood Pressure ◽  
Lung Perfusion ◽  
Chemical Sympathectomy ◽  
Test Lung ◽  
Systemic Blood ◽  
Pulmonary Vasoconstriction ◽  
Hypoxic Vasoconstriction ◽  
Alveolar Hypoxia ◽  
6 Hydroxydopamine

The influence of chemical sympathectomy with 6-hydroxydopamine (6-OHDA) on regional alveolar hypoxic vasconstriction and on global hypoxic pulmonary vasoconstriction was investigated. In eight dogs a double-lumened endotracheal tube allowed ventilation of one lung with nitrogen as an alveolar hypoxic challenge while ventilation of the other lung with 100% O2 maintained adequate systemic oxygenation. Distribution of perfusion to the two lungs was determined with 133Xe and external counters. Mean perfusion to the test lung was 50.9 +/- 4.9% of total lung perfusion on room air and decreased by 32.4% (P smaller than 0.01) during alveolar hypoxia. Following 6-OHDA the test lung continued to reduce perfusion during alveolar hypoxia by 27.3%. In five dogs global hypoxia induced a 106% increase in pulmonary vascular resistance (PVR) prior to 6-OHDA and a 90% increase in PVR after 6-OHDA. After 6-OHDA no rise in PRV or systemic blood pressure occurred in response to tyramine, confirming effective sympathectomy by the 6-OHDA. Thus, sympathectomy with 6-OHDA failed to substantially block regional alveolar hypoxic vasoconstriction or global hypoxic pulmonary vasconstriction.

Effects of ouabain, low K+, and aldosterone on hypoxic pressor reactivity of rat lungs

1985 ◽  
Vol 248 (1) ◽  
pp. H55-H60 ◽  
Author(s):  
J. Herget ◽  
I. F. McMurtry
Keyword(s):  
Angiotensin Ii ◽  
Energy Metabolism ◽  
Atpase Activity ◽  
Pressor Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Response Curves ◽  
Hypoxic Response ◽  
Rat Lungs ◽  
Hypoxic Vasoconstriction ◽  
Low K

It can be postulated that inhibition of lung tissue Na+-K+-ATPase might potentiate hypoxic pulmonary vasoconstriction by depolarizing some excitable cell or, in contrast, that it might blunt the hypoxic response by reducing cellular metabolic rate and sensitivity to hypoxia. Thus the purpose of this study was to test in isolated rat lungs whether hypoxic pressor reactivity was related inversely or positively to Na+-K+-ATPase activity. Dose-pressor response curves to hypoxia, angiotensin II, or KCl were measured under control conditions and after exposure either to one of two inhibitors of Na+-K+-ATPase, ouabain, and low-K+ solution or to a stimulator of Na+-K+ pumping, aldosterone. Ouabain and low K+ depressed the response to hypoxia but had little effect on that to angiotensin II. The response to KCl was increased by ouabain. Aldosterone potentiated the hypoxic response. These results do not support the idea that membrane depolarization due to inhibition Na+-K+ pumping is a component of hypoxic vasoconstriction. They do suggest a positive relationship between Na+-K+-ATPase activity and hypoxic pressor reactivity and are consistent with the idea that Na+-K+-ATPase activity might influence hypoxic reactivity indirectly by altering cellular energy metabolism. It is also possible that the results were somehow due to changes in intracellular [Na+] or transmembrane Na+ gradient, rather than to changes in energy metabolism.

Prostaglandin synthetase inhibitors do not decrease hypoxic pulmonary vasoconstriction

1976 ◽  
Vol 41 (5) ◽  
pp. 714-718 ◽  
Author(s):  
E. K. Weir ◽  
I. F. McMurtry ◽  
A. Tucker ◽  
J. T. Reeves ◽  
R. F. Grover
Keyword(s):  
Pressor Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Prostaglandin Synthesis ◽  
Pulmonary Vasoconstriction ◽  
Pressor Responses ◽  
Hypoxic Vasoconstriction ◽  
Before And After ◽  
Anesthetized Dogs ◽  
Prostaglandin Antagonists ◽  
The Stability

Prostaglandins are naturally occurring substances with powerful vasoactive effects that are released from tissues during hypoxia or ischemia. Several workers have suggested that a prostaglandin may help to mediate the pulmonary vascular pressor response to alveolar hypoxia. To investigate this possibility, we have measured the pressor responses to hypoxia before and after prostaglandin synthesis antagonism with meclofenamate in eight anesthetized dogs, two groups of awake calves (n=10 and =5), and nine isolated, perfused rat lungs. In addition, synthesis was inhibited by the use of indomethacin in nine additional dogs. The stability of the pulmonary vascular response to repeated hypoxic challenges was demonstrated in nine other dogs. In each species and with both prostaglandin antagonists, the pulmonary pressorresponses to hypoxia were significantly increased rather than reduced. We conclude that prostaglandins do not mediate the pulmonary vasoconstriction caused by hypoxia. The consistent increase observed suggests that hypoxic vasoconstriction stimulates prostaglandin synthesis, the net effect of which is pulmonary vasodilatation which opposes the constriction.

Lipoxygenase and cyclooxygenase blockade by BW 755C enhances pulmonary hypoxic vasoconstriction

1987 ◽  
Vol 62 (1) ◽  
pp. 129-133 ◽  
Author(s):  
R. C. Garrett ◽  
S. Foster ◽  
H. M. Thomas
Keyword(s):  
Sulfur Hexafluoride ◽  
Pressor Response ◽  
Lower Lobe ◽  
Shunt Fraction ◽  
Lipoxygenase Pathway ◽  
Hypoxic Vasoconstriction ◽  
Anesthetized Dogs ◽  
Receptor Blockers ◽  
Alveolar Hypoxia ◽  
Leukotriene Receptor

Lipoxygenase products (leukotrienes) have been proposed as the mediators of pulmonary hypoxic vasoconstriction. However, the supporting data are inconclusive because the lipoxygenase and leukotriene receptor blockers that reduce hypoxic vasoconstriction (such as diethylcarbamazine and the FPL's) have confounding effects. We investigated BW 755C, a potent inhibitor of both lipoxygenase and cyclooxygenase, in eight intact anesthetized dogs with acute left lower lobe atelectasis. We examined two manifestations of hypoxic vasoconstriction: shunt fraction, as an inverse indicator of regional constriction in response to local hypoxia, and the pulmonary pressor response to global alveolar hypoxia, as an index of general hypoxic vasoconstriction. During normoxia, shunt fraction, measured using a sulfur hexafluoride infusion, was 32.0 +/- 7.0%. The pulmonary pressor response to hypoxia, defined as the increase in pulmonary end-diastolic gradient produced by 10% O2 inhalation, averaged 4.5 +/- 1.8 mmHg. Then, during normoxia, BW 755C was administered. Shunt fraction fell in all eight dogs from the previous mean of 32% to 25.5 +/- 6.1% (t = 6.5, P less than 0.0005). The hypoxic pressor response rose in all dogs, from the previous 4.5 mmHg to 9.0 +/- 3.5 mmHg (t = 4.5, P less than 0.005). BW 755C enhances hypoxic vasoconstriction, an effect consistent with its activity as a cyclooxygenase inhibitor. These data do not support a substantive role for the lipoxygenase pathway in hypoxic vasoconstriction.

Gender differences in hypoxic vascular response of isolated sheep lungs

1983 ◽  
Vol 55 (1) ◽  
pp. 100-104 ◽  
Author(s):  
R. C. Wetzel ◽  
J. T. Sylvester
Keyword(s):  
Pressor Response ◽  
Response Relationship ◽  
Stimulus Response ◽  
Vasoconstrictor Response ◽  
Wide Range ◽  
Pulmonary Arterial ◽  
Isolated Lungs ◽  
Relationship Of ◽  
Female Sheep

We compared the steady state stimulus-response relationship of the pulmonary circulation to graded hypoxia in isolated, in situ, blood-perfused lungs of postpubertal male and female sheep and male sheep of similar age that had been castrated within 1 wk of birth. The flow-resistive properties of the pulmonary circuit were assessed by pressure-flow curves generated over a wide range of flows (0-150 ml X min-1 X kg-1 body wt-1) at six different levels of inspired oxygen tension (PIo2) between 200 and 0 Torr. The stimulus-response relationship was quantitated by determining the pulmonary arterial pressures at a flow of 50 ml X min-1 X kg-1 (Ppa50) directly from these curves. We found that this relationship was biphasic, as previously described for other species, with a peak vasoconstrictor response at a PIo2 = 30 Torr. The isolated lungs of males and castrated males achieved a greater maximal pressor response (Ppa50 = 33 +/- 3.7 and 34.5 +/- 8 Torr, respectively) than did those of females (Ppa50 = 20.2 +/- 5.6 Torr, P less than 0.01). When the pulmonary vascular bed was maximally dilated (PIo2 = 0 Torr), there were no significant differences in the Ppa50 among the groups (Ppa50 = 15.8 +/- 4.6 in males, 11 +/- 3.5 in females, and 11.5 +/- 1.9 Torr in castrated males). There were no differences between males and castrated males at any PIo2. We conclude that the hypoxic pulmonary vasomotor response was attenuated in isolated lungs of postpubertal female sheep possibly due to the effect of female hormones.

Relationship of leukotriene C4 and D4 to hypoxic pulmonary vasoconstriction in dogs

1988 ◽  
Vol 64 (6) ◽  
pp. 2538-2543 ◽  
Author(s):  
A. J. Lonigro ◽  
R. S. Sprague ◽  
A. H. Stephenson ◽  
T. E. Dahms
Keyword(s):  
Hypoxic Pulmonary Vasoconstriction ◽  
Lavage Fluid ◽  
Pulmonary Hemodynamics ◽  
Mean Pulmonary Arterial Pressure ◽  
Pulmonary Vasoconstriction ◽  
Time Period ◽  
Pulmonary Arterial ◽  
Synthase Inhibitor ◽  
Leukotriene A4 ◽  
Relationship Of

Leukotrienes C4 and D4 have been implicated as possible mediators of hypoxic pulmonary vasoconstriction. To test this hypothesis, the relationship between pulmonary leukotriene (LT) synthesis in response to hypoxia and alterations in pulmonary hemodynamics was evaluated in pentobarbital sodium-anesthetized, neuromuscular-blocked, male, mongrel dogs. A reduction in the fraction of inspired O2 (FIO2) in vehicle-treated animals (n = 12) from 0.21 to 0.10 was associated with increases in LTC4 and LTD4 in bronchoalveolar lavage fluid (BALF). After 30 min of continuous hypoxia, LTC4 and LTD4 increased from control values of 59.4 +/- 10.4 and 91.7 +/- 18.1 ng/lavage to 142.7 +/- 31.8 (P less than 0.05) and 156.3 +/- 25.3 (P less than 0.01) ng/lavage, respectively. Concomitantly, mean pulmonary arterial pressure (Ppa) and pulmonary vascular resistance (PVR) were increased over control by 67 +/- 7 (P less than 0.001) and 62 +/- 7% (P less than 0.001), respectively. In contrast, in animals treated with diethylcarbamazine (n = 5), a leukotriene A4 synthase inhibitor, identical reductions in FIO2 were not associated with increases in LTC4 and LTD4 in BALF, although at the same time period, Ppa and PVR were increased over control by 60 +/- 13 (P less than 0.05) and 112 +/- 31% (P less than 0.05), respectively. These results, therefore, do not support the contention that leukotrienes mediate hypoxic pulmonary vasoconstriction in dogs.

Pulmonary venous pressure increases during alveolar hypoxia in isolated lungs of newborn pigs

1992 ◽  
Vol 73 (2) ◽  
pp. 552-556 ◽  
Author(s):  
C. D. Fike ◽  
M. R. Kaplowitz
Keyword(s):  
Airway Pressure ◽  
Left Atrial ◽  
Pulmonary Arterial Pressure ◽  
Venous Pressure ◽  
Co2 Gas ◽  
Hypoxic Vasoconstriction ◽  
Alveolar Hypoxia ◽  
Pulmonary Arterial ◽  
Newborn Pigs ◽  
Isolated Lungs

The purpose of this study was to determine whether pulmonary venous pressure increases during alveolar hypoxia in lungs of newborn pigs. We isolated and perfused with blood the lungs from seven newborn pigs, 6–7 days old. We maintained blood flow constant at 50 ml.min-1.kg-1 and continuously monitored pulmonary arterial and left atrial pressures. Using the micropuncture technique, we measured pressures in 10 to 60-microns-diam venules during inflation with normoxic (21% O2–69–74% N2–5–10% CO2) and hypoxic (90–95% N2–5–10% CO2) gas mixtures. PO2 was 142 +/- 21 Torr during normoxia and 20 +/- 4 Torr during hypoxia. During micropuncture we inflated the lungs to a constant airway pressure of 5 cmH2O and kept left atrial pressure greater than airway pressure (zone 3). During hypoxia, pulmonary arterial pressure increased by 69 +/- 24% and pressure in small venules increased by 40 +/- 23%. These results are similar to those obtained with newborn lambs and ferrets but differ from results with newborn rabbits. The site of hypoxic vasoconstriction in newborn lungs is species dependent.

Hypoxic Pulmonary Vasoconstriction

2012 ◽  
Vol 92 (1) ◽  
pp. 367-520 ◽  
Author(s):  
J. T. Sylvester ◽  
Larissa A. Shimoda ◽  
Philip I. Aaronson ◽  
Jeremy P. T. Ward
Keyword(s):  
Hypoxic Pulmonary Vasoconstriction ◽  
Pulmonary Vessels ◽  
Pulmonary Vasoconstriction ◽  
Neonatal Life ◽  
High Altitude Pulmonary Edema ◽  
Alveolar Hypoxia ◽  
Pulmonary Arterial ◽  
Pulmonary Arterial Smooth Muscle ◽  
Isolated Lungs

It has been known for more than 60 years, and suspected for over 100, that alveolar hypoxia causes pulmonary vasoconstriction by means of mechanisms local to the lung. For the last 20 years, it has been clear that the essential sensor, transduction, and effector mechanisms responsible for hypoxic pulmonary vasoconstriction (HPV) reside in the pulmonary arterial smooth muscle cell. The main focus of this review is the cellular and molecular work performed to clarify these intrinsic mechanisms and to determine how they are facilitated and inhibited by the extrinsic influences of other cells. Because the interaction of intrinsic and extrinsic mechanisms is likely to shape expression of HPV in vivo, we relate results obtained in cells to HPV in more intact preparations, such as intact and isolated lungs and isolated pulmonary vessels. Finally, we evaluate evidence regarding the contribution of HPV to the physiological and pathophysiological processes involved in the transition from fetal to neonatal life, pulmonary gas exchange, high-altitude pulmonary edema, and pulmonary hypertension. Although understanding of HPV has advanced significantly, major areas of ignorance and uncertainty await resolution.

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