The effect of repeated intermittent hypoxia on pulmonary vasoconstriction in the newborn

1990 ◽  
Vol 68 (3) ◽  
pp. 355-362 ◽  
Author(s):  
Jaques Belik ◽  
Anna Sienko ◽  
R. Bruce Light
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Vascular Resistance ◽  
Intermittent Hypoxia ◽  
Vascular Tone ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Experimental Animals ◽  
Pulmonary Vasoconstriction ◽  
Air Ventilation ◽  
Experimental Group

The effect of repeated intermittent hypoxia upon the basal pulmonary vascular tone in the newborn period is unknown. We therefore studied the central hemodynamic response to seven repeated intermittent hypoxic challenges in acutely prepared piglets under 2 weeks of age. Catheters were placed in the aorta, pulmonary artery, and atria, and an electromagnetic flow probe was positioned around the main pulmonary artery. Each hypoxic challenge (Fio2 = 0.14) lasted 5 min, and was separated by an equal duration of ventilation with air. Nine control animals were ventilated with air for 90 min, a period of time equivalent to the seven challenges in the experimental group, and subjected to one hypoxic challenge at the end. Hypoxia uniformly induced pulmonary vasoconstriction. Repeated intermittent hypoxic challenges produced a progressive increase in pulmonary artery pressure and vascular resistance, both during air ventilation and hypoxia. For each challenge, the vascular resistance value achieved during hypoxia was directly related to the immediately preceding air ventilation one, and the magnitude of hypoxic pulmonary vasoconstriction, defined as the incremental change in resistance from air to hypoxia, was not different from the first to the last challenge in the experimental group. In the control group the pulmonary vascular tone did not change during the 90 min of air ventilation, and the single hypoxic challenge induced an increase in pulmonary vascular pressure and resistance similar in magnitude to the first challenge in the experimental group. Indomethacin administration to five experimental animals, after the last challenge, reversed the increase in air ventilation pulmonary artery pressure and vascular resistance. Plasma levels of thromboxane B2 and 6-keto-PGF1α were also measured by an enzyme immunoabsorbent assay in half the experimental animals. Surgical stress was associated with a significant rise in both prostaglandin metabolites. Repeated hypoxic challenges led to a further increase in thromboxane B2 and also in the ratio of this metabolite and 6-keto-PGF1α (p < 0.05). The percentage increase in the latter was linearly correlated with the increase in pulmonary arterial pressure and vascular resistance from the first to the last hypoxic challenge. These data indicate that repeated intermittent hypoxia in the newborn pig increases the pulmonary vascular resistance on air ventilation. This phenomenon is possibly related to the release of the potent pulmonary vasoconstrictor thromboxane A2, and may play a role in the pathogenesis of the persistent pulmonary hypertension in human infants who underwent repeated perinatal hypoxic insults.Key words: persistent pulmonary hypertension syndrome, hypoxic pulmonary vasoconstriction, newborn, prostaglandins.

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.

Effects of endogenous nitric oxide on pulmonary vascular tone in intact dogs

1994 ◽  
Vol 266 (6) ◽  
pp. H2343-H2347 ◽  
Author(s):  
M. Leeman ◽  
V. Z. de Beyl ◽  
M. Delcroix ◽  
R. Naeije
Keyword(s):  
Nitric Oxide ◽  
Methylene Blue ◽  
Pulmonary Artery ◽  
Vascular Tone ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Balloon Catheter ◽  
Hypoxic Response ◽  
Pulmonary Vasoconstriction ◽  
Endogenous Nitric Oxide ◽  
Anesthetized Dogs

The interaction between inspiratory fraction of O2 (FIO2) and endogenous nitric oxide (NO) regulation of pulmonary vascular tone was examined in intact anesthetized dogs. Stimulus (FIO2 of 1, 0.4, 0.21, 0.12, and 0.1)-response (changes in pulmonary artery pressure minus pulmonary artery occlusion pressure) curves were constructed with cardiac output kept constant (by opening a femoral arteriovenous bypass or inflating an inferior vena cava balloon catheter), before and after administration of compounds acting at different levels of the L-arginine-NO pathway, NG-nitro-L-arginine (L-NNA, 10 mg/kg iv, n = 16), a NO synthase inhibitor, and methylene blue (8 mg/kg iv, n = 16), a guanylate cyclase inhibitor. L-NNA and methylene blue did not influence pulmonary vascular tone in hyperoxic and in normoxic conditions, but they increased it during hypoxia, thus enhancing the vasopressor response to hypoxia (from 4.5 +/- 0.9 to 10.4 +/- 1.2 mmHg and from 4.2 +/- 0.8 to 9 +/- 1.5 mmHg, respectively, both P < 0.01). Hypoxic pulmonary vasoconstriction was augmented in dogs with a baseline hypoxic response (“responders”) and restored in dogs without hypoxic response (“nonresponders”). These results suggest that endogenous NO does not influence hyperoxic and normoxic pulmonary vascular tone, but that it inhibits hypoxic pulmonary vasoconstriction in intact anesthetized dogs.

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.

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.

Hypoxic Pulmonary Vasoconstriction and Chronic Lung Disease

2013 ◽  
Vol 12 (3) ◽  
pp. 135-144 ◽  
Author(s):  
Erik R. Swenson
Keyword(s):  
Pulmonary Hypertension ◽  
Lung Disease ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
World Health ◽  
Disease States ◽  
Pulmonary Vasoconstriction ◽  
Local Ventilation ◽  
Pulmonary Vascular Endothelium ◽  
Health And Disease ◽  
Health Organization

Hypoxic vasoconstriction in the lung is a unique and fundamental characteristic of the pulmonary circulation. It functions in health and disease states to better preserve ventilation-perfusion matching by diverting blood flow to better ventilated regions when local ventilation is compromised. As more areas of lung become hypoxic either with high altitude or global lung disease, then hypoxic pulmonary vasoconstriction (HPV) becomes less effective in ventilation-perfusion matching and can lead to pulmonary hypertension. HPV is intrinsic to the vascular smooth muscle and its mechanisms remain poorly understood. In addition, the pulmonary vascular endothelium, red cells, lung innervation, and numerous circulating vasoactive agents also affect the strength of HPV. This review will discuss the pathophysiology of HPV and address its role in pulmonary hypertension associated with World Health Organization Group 3 diseases. When sustained beyond many hours, HPV may initiate pulmonary vascular remodeling and lead to more fixed and less oxygen-responsive pulmonary hypertension if the hypoxic stimulus is maintained.

scholarly journals Cinaciguat, a soluble guanylate cyclase activator, causes potent and sustained pulmonary vasodilation in the ovine fetus

2009 ◽  
Vol 297 (2) ◽  
pp. L318-L325 ◽  
Author(s):  
Marc Chester ◽  
Pierre Tourneux ◽  
Greg Seedorf ◽  
Theresa R. Grover ◽  
Jason Gien ◽  
...  
Keyword(s):  
Blood Flow ◽  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Left Pulmonary Artery ◽  
Flow Transducer ◽  
Pulmonary Vasodilation

Impaired nitric oxide-cGMP signaling contributes to severe pulmonary hypertension after birth, which may in part be due to decreased soluble guanylate cyclase (sGC) activity. Cinaciguat (BAY 58-2667) is a novel sGC activator that causes vasodilation, even in the presence of oxidized heme or heme-free sGC, but its hemodynamic effects have not been studied in the perinatal lung. We performed surgery on eight fetal (126 ± 2 days gestation) lambs (full term = 147 days) and placed catheters in the main pulmonary artery, aorta, and left atrium to measure pressures. An ultrasonic flow transducer was placed on the left pulmonary artery to measure blood flow, and a catheter was placed in the left pulmonary artery for drug infusion. Cinaciguat (0.1–100 μg over 10 min) caused dose-related increases in pulmonary blood flow greater than fourfold above baseline and reduced pulmonary vascular resistance by 80%. Treatment with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), an sGC-oxidizing inhibitor, enhanced cinaciguat-induced pulmonary vasodilation by >120%. The pulmonary vasodilator effect of cinaciguat was prolonged, decreasing pulmonary vascular resistance for >1.5 h after brief infusion. In vitro stimulation of ovine fetal pulmonary artery smooth muscle cells with cinaciguat after ODQ treatment resulted in a 14-fold increase in cGMP compared with non-ODQ-treated cells. We conclude that cinaciguat causes potent and sustained fetal pulmonary vasodilation that is augmented in the presence of oxidized sGC and speculate that cinaciguat may have therapeutic potential for severe neonatal pulmonary hypertension.

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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