Role of leukotriene C4 in pulmonary hypertension: platelet-activating factor vs. hypoxia

1990 ◽  
Vol 68 (4) ◽  
pp. 1628-1633 ◽  
Author(s):  
D. Davidson ◽  
M. Singh ◽  
G. F. Wallace
Keyword(s):  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Platelet Activating Factor ◽  
Lung Parenchyma ◽  
Base Line ◽  
Leukotriene C4 ◽  
Pulmonary Vasoconstriction ◽  
Pulmonary Arterial

The aim of this study was to determine whether leukotriene C4 (LTC4) is a mediator of hypoxic pulmonary vasoconstriction. We hypothesized that similar increases in LTC4, detected in the lung parenchyma and pulmonary vascular compartment during cyclooxygenase blockade with indomethacin (INDO), would be observed during an equal increase in pulmonary arterial pressure caused by acute alveolar hypoxia (HYP, 100% N2) or platelet-activating factor (PAF, 10 micrograms into the pulmonary artery). Rat lungs were perfused at constant flow in vitro with an albumin-Krebs-Henseleit solution. Mean pulmonary arterial pressure (n = 6 per group) increased from a base line of 10.9 +/- 1.2 to 15.8 +/- 2.1 (HYP + INDO) and 15.5 +/- 1.9 (SE) Torr (PAF + INDO). LTC4 levels increased only in response to PAF + INDO; perfusate levels increased from 0.4 +/- 0.07 to 5.3 +/- 1.1 ng/40 ml, and lung parenchymal levels increased from 1.9 +/- 0.07 to 22.8 +/- 5.3 ng/lung. Diethylcarbamazine (lipoxygenase inhibitor) reduced PAF-induced lung parenchymal levels of LTC4 by 68% and pulmonary hypertension by 63%. We conclude that 1) LTC4 is not a mediator of hypoxic pulmonary vasoconstriction and 2) intravascular PAF is a potent stimulus for LTC4 production in the lung parenchyma.

Nitric oxide inhalation: effects on the ovine neonatal pulmonary and systemic circulations

1996 ◽  
Vol 8 (3) ◽  
pp. 431 ◽  
Author(s):  
V DeMarco ◽  
JW Skimming ◽  
TM Ellis ◽  
S Cassin
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Pulmonary Circulation ◽  
Pulmonary Arterial Pressure ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Minimum Concentration ◽  
Pulmonary Vasoconstriction ◽  
Pulmonary Arterial ◽  
Inhaled No

Others have shown that inhaled nitric oxide causes reversal of pulmonary hypertension in anaesthetized perinatal sheep. The present study examined haemodynamic responses to inhaled NO in the normal and constricted pulmonary circulation of unanaesthetized newborn lambs. Three experiments were conducted on each of 7 lambs. First, to determine a minimum concentration of NO which could reverse acute pulmonary hypertension caused by infusion of the thromboxame mimic U46619, the haemodynamic effects of 5 different doses of inhaled NO were examined. Second, the effects of inhaling 80 ppm NO during hypoxic pulmonary vasoconstriction were examined. Finally, to determine if tachyphalaxis occurs during NO inhalation, lambs were exposed to 80 ppm NO for 3 h during which time pulmonary arterial pressure was doubled by infusion of U46619. Breathing NO (80 ppm) caused a slight but significant decrease in pulmonary vascular resistance (PVR) in lambs with normal pulmonary arterial pressure (PAP). Nitric oxide, inhaled at concentrations between 10 and 80 ppm for 6 min (F1O2 = 0.60), caused decreases in PVR when PAP was elevated with U46619. Nitric oxide acted selectively on the pulmonary circulation, i.e. no changes occurred in systemic arterial pressure or any other measured variable. Breathing 80 ppm NO for 6 min reversed hypoxic pulmonary vasoconstriction. In the chronic exposure study, inhaling 80 ppm NO for 3 h completely reversed U46619-induced pulmonary hypertension. Although arterial methaemoglobin increased during the 3-h exposure to 80 ppm NO, there was no indication that this concentration of NO impairs oxygen loading. These data demonstrate that NO, at concentrations as low as 10 ppm, is a potent, rapid-action, and selective pulmonary vasodilator in unanaesthetized newborn lambs with elevated pulmonary tone. Furthermore, these data support the use of inhaled NO for treatment of infants with pulmonary hypertension.

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.

Cyclooxygenase inhibition during phorbol-induced granulocyte stimulation in awake sheep

1984 ◽  
Vol 56 (4) ◽  
pp. 999-1007 ◽  
Author(s):  
J. H. Newman ◽  
J. E. Loyd ◽  
M. L. Ogletree ◽  
B. O. Meyrick ◽  
K. L. Brigham
Keyword(s):  
Pulmonary Hypertension ◽  
Arachidonic Acid ◽  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Thromboxane B2 ◽  
Base Line ◽  
Plasma Protein Concentration ◽  
Pulmonary Vascular Permeability ◽  
Pulmonary Arterial ◽  
Lung Lymph

In vitro, phorbol myristate acetate (PMA) causes sheep granulocytes to release superoxide. Infused into sheep, PMA causes leukopenia, hypoxemia, pulmonary hypertension, and increased flow of protein-rich lung lymph. Lung lymph thromboxane B2 and 6-ketoprostaglandin F1 alpha levels rise markedly after PMA infusion. To see whether cyclooxygenase products of arachidonic acid mediate the lung vascular responses to PMA, we infused 5 micrograms/kg PMA twice in each of six sheep, once in the presence of sodium meclofenamate and once alone. We varied the order of paired experiments and allowed 4–7 days between experiments. Meclofenamate (5 mg/kg loading dose + 3 mg X kg-1 X h-1 infusion) given alone had no effect on base-line variables. Meclofenamate inhibited or delayed the initial pulmonary hypertension and hypoxemia after PMA but exaggerated the later increase in pulmonary arterial pressure; it prevented any increase in thromboxane B2 and 6-ketoprostaglandin F1 alpha after PMA. Meclofenamate did not affect the degree of leukopenia or the severity of the later hypoxemia nor did it prevent accumulation of granulocytes in the lung. Lung lymph flow was higher with meclofenamate + PMA than with PMA alone, but lymph-to-plasma protein concentration ratio was lower, suggesting that the main effect of meclofenamate on lymph production after PMA was related to the degree of pulmonary hypertension. We conclude that the early increase in pulmonary arterial pressure caused by PMA is mediated by a cyclooxygenase product of arachidonic acid, possibly thromboxane A2, but the later pulmonary hypertension and the increase in pulmonary vascular permeability are not the result of cyclooxygenase products.

Pulmonary hypertension with muscular exercise in the newborn calf

1965 ◽  
Vol 20 (2) ◽  
pp. 249-252 ◽  
Author(s):  
John T. Reeves ◽  
James E. Leathers
Keyword(s):  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Pressor Response ◽  
Muscular Exercise ◽  
Arterial Oxygen ◽  
Mixed Venous Blood ◽  
Fetal Life ◽  
Pulmonary Vasoconstriction ◽  
Pulmonary Arterial

Two types of pulmonary hypertension occur with muscular exercise (walking) in the calf on the day of birth: a) Pulmonary arterial pressure increased in all calves during exercise. The increase was greatest in the youngest calves. Pulmonary arterial pressures did not rise to systemic levels and arterial oxygen saturations remained normal. Pulmonary hypertension subsided in 2 min after stopping exercise. Pulmonary arterial pressure rose again when exercise was repeated. Both an increased pulmonary flow and pulmonary vasoconstriction may have contributed to the increased pulmonary arterial pressure during exercise. b) Pulmonary hypertension was observed in five calves for 30-50 min after exercise ceased. When pulmonary arterial pressure exceeded aortic pressure, arterial oxygen unsaturation occurred. This pulmonary hypertension which occurred only once per calf resembled"spontaneous" pulmonary vasoconstriction observed in resting calves on the day of birth. It is postulated that some substance remaining in the lung after fetal life, rather than the acutely reduced oxygenation of mixed venous blood, initiated this pressor response. hypoxia; pulmonary vasoconstriction Submitted on May 11, 1964

Lowered pulmonary arterial pressure prevents edema after endotoxin in sheep

1987 ◽  
Vol 63 (3) ◽  
pp. 1008-1011 ◽  
Author(s):  
S. J. Allen ◽  
R. E. Drake ◽  
J. Katz ◽  
J. C. Gabel ◽  
G. A. Laine
Keyword(s):  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Venous Pressure ◽  
Dry Weight ◽  
Base Line ◽  
Capillary Membrane ◽  
Significant Difference ◽  
Pulmonary Arterial ◽  
The Difference

Escherichia coli endotoxin causes increased capillary membrane permeability and increased pulmonary arterial pressure (PAP) in sheep. If the pulmonary hypertension extends to the level of the microvasculature, then the increased microvascular pressure may contribute to the pulmonary edema caused by endotoxin. We tested the hypothesis that reducing the pulmonary hypertension would reduce the amount of edema caused by endotoxin. Twelve sheep were chronically instrumented with catheters to measure PAP, left atrial pressure, and central venous pressure. The sheep were divided into two groups. One group (E) of six sheep received an intravenous infusion of 4 micrograms/kg of E. coli endotoxin. The second group (E + SNP) received the same dose of endotoxin as well as a continuous infusion of sodium nitroprusside (SNP) to reduce PAP. Three hours after the endotoxin infusions, the sheep were terminated and the extravascular fluid-to-blood-free dry weight ratios of the lungs were determined (EVF). The base-line PAP was 17.5 +/- 2.7 mmHg. A two-way analysis of variance demonstrated a significant difference (P less than 0.01) in PAP between the E and E + SNP groups. Although PAP in each group varied as a function of time, the difference between the two groups did not. The mean PAP for the E + SNP group (20.9 +/- 1.5 mmHg) was lower than the E group PAP of 27.3 +/- 2.1 mmHg after the endotoxin spike. Furthermore, the E + SNP group EVF (3.9 +/- 0.2) was significantly less than the EVF of the E group (4.7 +/- 0.5).(ABSTRACT TRUNCATED AT 250 WORDS)

Inhalation of the ETAreceptor antagonist LU-135252 selectively attenuates hypoxic pulmonary vasoconstriction

2008 ◽  
Vol 294 (2) ◽  
pp. R601-R605 ◽  
Author(s):  
Bodil Petersen ◽  
Maria Deja ◽  
Roland Bartholdy ◽  
Bernd Donaubauer ◽  
Sven Laudi ◽  
...  
Keyword(s):  
Arterial Pressure ◽  
Receptor Antagonist ◽  
Experimental Model ◽  
Pulmonary Arterial Pressure ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Pulmonary Vasculature ◽  
Mean Pulmonary Arterial Pressure ◽  
Pulmonary Vasoconstriction ◽  
Pulmonary Arterial ◽  
To Receive

Endogenous endothelin (ET)-1 modulates hypoxic pulmonary vasoconstriction (HPV). Accordingly, intravenously applied ETAreceptor antagonists reduce HPV, but this is accompanied by systemic vasodilation. We hypothesized that inhalation of an ETAreceptor antagonist might act selectively on the pulmonary vasculature and investigated the effects of aerosolized LU-135252 in an experimental model of HPV. Sixteen piglets (weight: 25 ± 1 kg) were anesthetized and mechanically ventilated at an inspiratory oxygen fraction (FiO2) of 0.3. After 1 h of hypoxia at FiO20.15, animals were randomly assigned either to receive aerosolized LU-135252 as bolus (0.3 mg/kg for 20 min; n = 8, LU group), or to receive aerosolized saline ( n = 8, controls). In all animals, hypoxia significantly increased mean pulmonary arterial pressure (32 ± 1 vs. 23 ± 1 mmHg; P < 0.01; means ± SE) and increased arterial plasma ET-1 (0.52 ± 0.04 vs. 0.37 ± 0.05 fmol/ml; P < 0.01) compared with mild hyperoxia at FiO20.3. Inhalation of LU-135252 induced a significant and sustained decrease in mean pulmonary arterial pressure compared with controls (LU group: 27 ± 1 mmHg; controls: 32 ± 1 mmHg; values at 4 h of hypoxia; P < 0.01). In parallel, mean systemic arterial pressure and cardiac output remained stable and were not significantly different from control values. Consequently, in our experimental model of HPV, the inhaled ETAreceptor antagonist LU-135252 induced selective pulmonary vasodilation without adverse systemic hemodynamic effects.

Pulmonary arterial pressure-flow plots in dogs: effects of isoflurane and nitroprusside

1987 ◽  
Vol 63 (3) ◽  
pp. 969-977 ◽  
Author(s):  
R. Naeije ◽  
P. Lejeune ◽  
M. Leeman ◽  
C. Melot ◽  
T. Deloof
Keyword(s):  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Arachidonic Acid Metabolism ◽  
Minimal Alveolar Concentration ◽  
Vascular Effects ◽  
Pulmonary Vasoconstriction ◽  
Anesthetized Dogs ◽  
Pulmonary Arterial ◽  
End Tidal

We investigated the effects of nitroprusside and isoflurane on multipoint pulmonary arterial pressure (PAP)/cardiac index (Q) plots in pentobarbital sodium-anesthetized dogs ventilated alternatively in hyperoxia (fraction of inspired O2, FIO2, 0.4) and hypoxia (FIO2 0.1). Over the entire range of Q studied, 2–5 l.min-1.m-2, hypoxia increased PAP in 16 dogs (“responders”) and did not affect PAP in 16 other dogs (“nonresponders”). A hypoxic pulmonary vasoconstriction (HPV) was restored in the nonresponders by intravenous administration of 1 g of acetylsalicylic acid (ASA). Nitroprusside (5 micrograms.kg-1.min-1) inhibited HPV in responders (n = 8) and nonresponders treated with ASA (n = 8). End-tidal 1.41% isoflurane (a minimal alveolar concentration equal to one for dogs) did not affect HPV in responders (n = 8) and nonresponders treated with ASA (n = 8). In the latter group isoflurane increased PAP at the highest Q studied (3–5 l.min-1.m-2) in hyperoxia and hypoxia. In a final group of eight dogs with Q kept constant, PAP remained unchanged during two consecutive sequences of alternated 30-min periods (maximum time to generate a PAP/Q plot) successively at FIO2 0.4 and 0.1, and the hypoxia-induced increase in PAP was reproducible. Thus the present experimental model appeared suitable for the study of the effects of hypoxia and drugs on pulmonary vascular tone of intact dogs. At the given doses HPV was inhibited by nitroprusside and not affected by isoflurane. Products of arachidonic acid metabolism possibly could be implicated in the pulmonary vascular effects of isoflurane.

The Rho kinase inhibitor azaindole-1 has long-acting vasodilator activity in the pulmonary vascular bed of the intact chest rat

2012 ◽  
Vol 90 (7) ◽  
pp. 825-835 ◽  
Author(s):  
Edward A. Pankey ◽  
Ryuk J. Byun ◽  
William B. Smith ◽  
Manish Bhartiya ◽  
Franklin R. Bueno ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Kinase Inhibitor ◽  
Pulmonary Arterial Pressure ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Rho Kinase ◽  
Rock Inhibitor ◽  
Vasodilator Activity ◽  
Pulmonary Arterial ◽  
Vascular Beds

Responses to a selective azaindole-based Rho kinase (ROCK) inhibitor (azaindole-1) were investigated in the rat. Intravenous injections of azaindole-1 (10–300 µg/kg), produced small decreases in pulmonary arterial pressure and larger decreases in systemic arterial pressure without changing cardiac output. Responses to azaindole-1 were slow in onset and long in duration. When baseline pulmonary vascular tone was increased with U46619 or L-NAME, the decreases in pulmonary arterial pressure in response to the ROCK inhibitor were increased. The ROCK inhibitor attenuated the increase in pulmonary arterial pressure in response to ventilatory hypoxia. Azaindole-1 decreased pulmonary and systemic arterial pressures in rats with monocrotaline-induced pulmonary hypertension. These results show that azaindole-1 has significant vasodilator activity in the pulmonary and systemic vascular beds and that responses are larger, slower in onset, and longer in duration when compared with the prototypical agent fasudil. Azaindole-1 reversed hypoxic pulmonary vasoconstriction and decreased pulmonary and systemic arterial pressures in a similar manner in rats with monocrotaline-induced pulmonary hypertension. These data suggest that ROCK is involved in regulating baseline tone in the pulmonary and systemic vascular beds, and that ROCK inhibition will promote vasodilation when tone is increased by diverse stimuli including treatment with monocrotaline.

Intratracheal mesenchymal stem cell administration attenuates monocrotaline-induced pulmonary hypertension and endothelial dysfunction

2007 ◽  
Vol 292 (2) ◽  
pp. H1120-H1128 ◽  
Author(s):  
Syed R. Baber ◽  
Weiwen Deng ◽  
Ryan G. Master ◽  
Bruce A. Bunnell ◽  
Bradley K. Taylor ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Arterial Pressure ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Pulmonary Arterial Pressure ◽  
Smooth Muscle Actin ◽  
Lung Parenchyma ◽  
Intratracheal Administration ◽  
Pulmonary Arterial

The administration of mesenchymal stem cells (MSCs) has been proposed for the treatment of pulmonary hypertension. However, the effect of intratracheally administered MSCs on the pulmonary vascular bed in monocrotaline-treated rats has not been determined. In the present study, the effect of intratracheal administration of rat MSCs (rMSCs) on monocrotaline-induced pulmonary hypertension and impaired endothelium-dependent responses were investigated in the rat. Intravenous injection of monocrotaline increased pulmonary arterial pressure and vascular resistance and decreased pulmonary vascular responses to acetylcholine without altering responses to sodium nitroprusside and without altering systemic responses to the vasodilator agents when responses were evaluated at 5 wk. The intratracheal injection of 3 × 106 rMSCs 2 wk after administration of monocrotaline attenuated the rise in pulmonary arterial pressure and pulmonary vascular resistance and restored pulmonary responses to acetylcholine toward values measured in control rats. Treatment with rMSCs decreased the right ventricular hypertrophy induced by monocrotaline. Immunohistochemical studies showed widespread distribution of lacZ-labeled rMSCs in lung parenchyma surrounding airways in monocrotaline-treated rats. Immunofluorescence studies revealed that transplanted rMSCs retained expression of von Willebrand factor and smooth muscle actin markers specific for endothelial and smooth muscle phenotypes. However, immunolabeled cells were not detected in the wall of pulmonary vessels. These data suggest that the decrease in pulmonary vascular resistance and improvement in response to acetylcholine an endothelium-dependent vasodilator in monocrotaline-treated rats may result from a paracrine effect of the transplanted rMSCs in lung parenchyma, which improves vascular endothelial function in the monocrotaline-injured lung.

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