Effect of endotoxin pretreatment on the pulmonary vascular response to hypoxia in O2-exposed lambs

1988 ◽  
Vol 65 (4) ◽  
pp. 1586-1591 ◽  
Author(s):  
T. A. Hazinski ◽  
K. A. Kennedy ◽  
M. L. France
Keyword(s):  
Respiratory Failure ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Pressor Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Oxidant Stress ◽  
Lung Edema ◽  
Vascular Response ◽  
Edema Formation ◽  
Constrictor Response

We recently reported that endotoxin infusion before O2 exposure significantly reduced or delayed the onset of pulmonary edema formation and respiratory failure by reducing the oxidant stress of O2 exposure. Despite these beneficial effects of endotoxin treatment, lung microvascular permeability eventually increased, but postmortem lung water content was less than expected. Prolonged O2 breathing blunts or abolishes the pulmonary constrictor response to alveolar hypoxia in some species, and it is possible that the loss of this response could contribute further to edema formation. To determine whether the reduction in lung edema observed in endotoxin-treated, O2-exposed lambs was linked to the preservation of hypoxic pulmonary vasoconstriction (HPV), we measured pulmonary vascular resistance before and after 8 min of isocarbic hypoxia (inspired O2 fraction 0.12) during each day of O2 exposure. In six control lambs, the pressor response to hypoxia was abolished after 72 h in O2, and the lambs developed respiratory failure shortly thereafter. In six endotoxin-treated lambs, HPV was preserved for as long as 144 h of O2 exposure. In two control O2-exposed lambs in whom HPV was abolished, the infusion of either angiotensin or prostaglandin H2 analogue increased pulmonary vascular resistance by greater than 75%. We conclude that in lambs 1) hyperoxia abolishes the pulmonary vascular response to hypoxia, 2) endotoxin pretreatment reduces acute O2-induced lung injury and preserves the pulmonary constrictor response to hypoxia, and 3) the loss of HPV during O2 exposure may be the result of oxidant-mediated injury to the hypoxia response itself and not the result of diffuse damage to the vasoconstrictor effector mechanism.

Desferrioxamine elevates pulmonary vascular resistance in humans: potential for involvement of HIF-1

2002 ◽  
Vol 92 (6) ◽  
pp. 2501-2507 ◽  
Author(s):  
George M. Balanos ◽  
Keith L. Dorrington ◽  
Peter A. Robbins
Keyword(s):  
Pressure Gradient ◽  
Continuous Infusion ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Gene Activation ◽  
Maximum Pressure ◽  
Vascular Response ◽  
Vascular Regulation ◽  
End Tidal

Hypoxia-inducible factor (HIF)-1 is stabilized by hypoxia and iron chelation. We hypothesized that HIF-1 might be involved in pulmonary vascular regulation and that infusion of desferrioxamine over 8 h would consequently mimic hypoxia and elevate pulmonary vascular resistance. In study A, we characterized the pulmonary vascular response to 4 h of isocapnic hypoxia; in study B, we measured the pulmonary vascular response to 8 h of desferrioxamine infusion. For study A, 11 volunteers undertook two protocols: 1) 4 h of isocapnic hypoxia (end-tidal Po2= 50 Torr), followed by 2 h of recovery with isocapnic euoxia (end-tidal Po2= 100 Torr), and 2) 6 h of air breathing (control). For study B, nine volunteers undertook two protocols while breathing air: 1) continuous infusion of desferrioxamine (4 g/70 kg) over 8 h and 2) continuous infusion of saline over 8 h (control). In both studies, pulmonary vascular resistance was assessed at 0.5- to 1-h intervals by Doppler echocardiography via the maximum pressure gradient during systole across the tricuspid valve. Results show a progressive rise in pressure gradient over the first 3–4 h with both isocapnic hypoxia ( P < 0.001) and desferrioxamine infusion ( P < 0.005) to increases of ∼16 and 4 Torr, respectively. These results support a role for HIF-regulated gene activation in human hypoxic pulmonary vasoconstriction.

Effect of protein kinase C inhibition on hypoxic pulmonary vasoconstriction

2001 ◽  
Vol 280 (5) ◽  
pp. L888-L895 ◽  
Author(s):  
Scott A. Barman
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Pressor Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Pulmonary Vasculature ◽  
Kinase C ◽  
Vasoconstrictor Response ◽  
Voltage Dependent

The current study was done to test the hypothesis that protein kinase C (PKC) inhibitors prevent the increase in pulmonary vascular resistance and compliance that occurs in isolated, blood-perfused dog lungs during hypoxia. Pulmonary vascular resistances and compliances were measured with vascular occlusion techniques. Hypoxia significantly increased pulmonary arterial resistance, pulmonary venous resistance, and pulmonary capillary pressure and decreased total vascular compliance by decreasing both microvascular and large-vessel compliances. The nonspecific PKC inhibitor staurosporine (10−7 M), the specific PKC blocker calphostin C (10−7 M), and the specific PKC isozyme blocker Gö-6976 (10−7 M) inhibited the effect of hypoxia on pulmonary vascular resistance and compliance. In addition, the PKC activator thymeleatoxin (THX; 10−7 M) increased pulmonary vascular resistance and compliance in a manner similar to that in hypoxia, and the L-type voltage-dependent Ca2+channel blocker nifedipine (10−6 M) inhibited the response to both THX and hypoxia. These results suggest that PKC inhibition blocks the hypoxic pressor response and that the pharmacological activation of PKC by THX mimics the hypoxic pulmonary vasoconstrictor response. In addition, L-type voltage-dependent Ca2+channel blockade may prevent the onset of the hypoxia- and PKC-induced vasoconstrictor response in the canine pulmonary vasculature.

Effect of indomethacin on pulmonary vascular response to ventilation of fetal goats

1978 ◽  
Vol 234 (4) ◽  
pp. H346-H351 ◽  
Author(s):  
C. W. Leffler ◽  
T. L. Tyler ◽  
S. Cassin
Keyword(s):  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Fetal Lung ◽  
Rapid Decrease ◽  
Vascular Response ◽  
Pulmonary Vasodilation ◽  
Prostaglandin Synthase ◽  
Perfused Lung ◽  
Lung Preparation ◽  
Indomethacin Treatment

The effect of indomethacin treatment of the pulmonary vasodilation caused by ventilation of the fetal lung with air was evaluated in anesthetized, exteriorized, fetal goats by means of an open-chest, pump-perfused lung preparation. The decrease in pulmonary vascular resistance that occurs when the fetal lung is ventilated with air consists of two components: 1) a rapid decrease in pulmonary vascular resistance during the first 30 s of ventilation; 2) a slower decline, which continues through the first 10-20 min or more of ventilation. Indomethacin has no effect on the first component. The second component is absent following indomethacin pretreatment. The effect of indomethacin treatment is more pronounced in immature fetuses (less than 90% gestation) than in mature fetuses. Prostaglandin synthase activity appears to be important in the pulmonary vasodilation caused by ventilation of the fetal lungs with air.

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.

Modulation of Pulmonary Vascular Resistance and Edema Formation by Short-Term Infusion of a 10% Fish Oil Emulsion

1993 ◽  
Vol 20 (6) ◽  
pp. 291-300 ◽  
Author(s):  
T. Koch ◽  
H.P. Duncker ◽  
A. Klein ◽  
E. Schlotzer ◽  
B.M. Peskar ◽  
...  
Keyword(s):  
Fish Oil ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Short Term ◽  
Edema Formation ◽  
Oil Emulsion

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.

Interactions of tumor necrosis factor and granulocytes with pulmonary vascular resistance

1991 ◽  
Vol 71 (6) ◽  
pp. 2338-2345 ◽  
Author(s):  
I. Mayers ◽  
D. Johnson ◽  
T. Hurst ◽  
T. To
Keyword(s):  
Tumor Necrosis Factor ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Whole Blood ◽  
Tumor Necrosis ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Tnf Alpha ◽  
Group 2 ◽  
Necrosis Factor ◽  
Group 1

We studied the effects of endotoxin and tumor necrosis factor (TNF-alpha) on hypoxic pulmonary vasoconstriction (HPV) in 12 isolated perfused canine lung lobes. Group 1 lobes were perfused with whole blood, and group 2 lobes were perfused with granulocyte-depleted blood. All lobes were sequentially ventilated with control (35% O2) and hypoxic (3% O2) gas mixtures before and after receiving TNF-alpha. After TNF-alpha, group 2 lost HPV but group 1 retained HPV. After TNF-alpha, total pulmonary vascular resistance decreased in group 2 from 0.085 +/- 0.013 to 0.049 +/- 0.016 cmH2O.ml-1.min (P less than 0.05). We conclude that TNF-alpha acts as a pulmonary vascular vasodilator. In lobes perfused with whole blood, HPV is paradoxically preserved. We speculate that in the presence of cells rich in TNF-alpha receptors, i.e., granulocytes, the circulating levels of TNF-alpha are depressed and full expression of its vascular effects is blunted.

Dependency of hypoxic pulmonary vasoconstriction on temperature

1977 ◽  
Vol 42 (1) ◽  
pp. 56-58 ◽  
Author(s):  
J. L. Benumof ◽  
E. A. Wahrenbrock
Keyword(s):  
Blood Flow ◽  
Pulmonary Vascular Resistance ◽  
Temperature Change ◽  
Vascular Resistance ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Lower Lobe ◽  
Effect Of Temperature ◽  
Hypoxic Response ◽  
Pulmonary Vasoconstriction ◽  
Mechanism Of Inhibition

We studied the effect of temperature change on hypoxic pulmonary vasoconstriction. Selective hypoxia on the left lower lobe of the lung in open-chested dogs at 37 degrees C caused the electromagnetically measured blood flow to the lobe to decrease 51 +/- 5 (SE)% and its vascular resistance to increase 155 +/- 25%. Testing hypoxic response. The hypoxic response at 31.1 +/- 0.4 degrees C was only a 26 +/- 6% decrease in lobar blood flow compared to the hypoxic response at 40.0 +/- 0.5 degrees C which was a 60 +/- 5% decrease in lobar blood flow. Hypothermia itself was associated with a significant increase in pulmonary vascular resistance. We conclude that hypothermia inhibits and hyperthermia enhances hypoxic pulmonary vasoconstriction. The mechanism of inhibition may involve prehypoxic vasoconstriction.

Pulmonary vasodilation by acetazolamide during hypoxia is unrelated to carbonic anhydrase inhibition

2007 ◽  
Vol 292 (1) ◽  
pp. L178-L184 ◽  
Author(s):  
Claudia Höhne ◽  
Philipp A. Pickerodt ◽  
Roland C. Francis ◽  
Willehad Boemke ◽  
Erik R. Swenson
Keyword(s):  
Carbonic Anhydrase ◽  
Pulmonary Artery ◽  
Pulmonary Vascular Resistance ◽  
Pulmonary Artery Pressure ◽  
Vascular Resistance ◽  
Low Dose ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Artery Pressure ◽  
Pulmonary Vasoconstriction ◽  
Mean Pulmonary Artery Pressure

Acute hypoxic pulmonary vasoconstriction can be inhibited by high doses of the carbonic anhydrase inhibitor acetazolamide. This study aimed to determine whether acetazolamide is effective at dosing relevant to human use at high altitude and to investigate whether its efficacy against hypoxic pulmonary vasoconstriction is dependent on carbonic anhydrase inhibition by testing other potent heterocyclic sulfonamide carbonic anhydrase inhibitors. Six conscious dogs were studied in five protocols: 1) controls, 2) low-dose intravenous acetazolamide (2 mg·kg−1·h−1), 3) oral acetazolamide (5 mg/kg), 4) benzolamide, a membrane-impermeant inhibitor, and 5) ethoxzolamide, a membrane-permeant inhibitor. In all protocols, unanesthetized dogs breathed spontaneously during the first hour (normoxia) and then breathed 9–10% O2 for the next 2 h. Arterial oxygen tension ranged between 35 and 39 mmHg during hypoxia in all protocols. In controls, mean pulmonary artery pressure increased by 8 mmHg and pulmonary vascular resistance by 200 dyn·s·cm−5 ( P <0.05). With intravenous acetazolamide, mean pulmonary artery pressure and pulmonary vascular resistance remained unchanged during hypoxia. With oral acetazolamide, mean pulmonary artery pressure increased by 5 mmHg ( P < 0.05), but pulmonary vascular resistance did not change during hypoxia. With benzolamide and ethoxzolamide, mean pulmonary artery pressure increased by 6–7 mmHg and pulmonary vascular resistance by 150–200 dyn·s·cm−5 during hypoxia ( P < 0.05). Low-dose acetazolamide is effective against acute hypoxic pulmonary vasoconstriction in vivo. The lack of effect with two other potent carbonic anhydrase inhibitors suggests that carbonic anhydrase is not involved in the mediation of hypoxic pulmonary vasoconstriction and that acetazolamide acts on a different receptor or channel.

Pulmonary vascular resistance in adult rats exposed to hypoxia in the neonatal period

1990 ◽  
Vol 68 (3) ◽  
pp. 419-424 ◽  
Author(s):  
T. S. Hakim ◽  
J. P. Mortola
Keyword(s):  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Flow Rate ◽  
Vascular Reactivity ◽  
Neonatal Period ◽  
Pressor Response ◽  
Autologous Blood ◽  
Venous Pressure ◽  
Pulmonary Vasculature ◽  
Adult Rats

Newborn rats were exposed to hypoxia (10% O2 + N2) from 24 h to day 6 of neonatal life and then returned to room air until 45 days of age (experimental). The rats were anaesthetized, heparinized, and exsanguinated. The chest was opened and the lungs were perfused with diluted autologous blood at a constant flow rate (Q). The pulmonary arterial pressure (Pa) and venous pressure (Pv) were monitored. The properties of the pulmonary vasculature were assessed by measuring baseline vascular resistance, PVR = (Pa−Pv)/Q, segmental pressure gradients (double occlusion technique), pressure–flow relationship, hypoxic pressor response (HPR, 3% O2), and the response to 0.5 μg bolus of angiotensin II (AII). These were compared with similar measurements on age-matched control animals never exposed to hypoxia. The perfusate hematocrit and gases were not significantly different between the two groups. The PVR normalized to body weight was 30% higher in the experimental groups (p < 0.005). The double occlusion results (obtained at a flow rate of 13 mL/min) revealed that this increase in resistance was primarily due to the increase in the postcapillary resistance. HPR was primarily in the upstream segment in both groups but was larger in the experimental group. In contrast, the response to AII occurred in both the upstream as well as in the downstream vascular segments and did not differ between the two groups. We conclude that adult rats exposed to hypoxia in the neonatal period have elevated pulmonary vascular resistance and increased vascular reactivity to hypoxia.Key words: resistance, angiotensin, lung development, pulmonary hypertension.

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