Indomethacin Does Not Diminish the Pulmonary Vascular Response of the Fetus to Increased Oxygen Tension

Morin, Frederick C.; Egan, Edmund A.; Norfleet, W. T.

doi:10.1203/00006450-198812000-00009

Cited by 39 publications

(15 citation statements)

References 22 publications

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“…Our studies indicate that adenosine and ATP are pulmonary vasodilators capable of increasing the pulmonary blood flow to postnatal levels in fetal sheep. The pulmonary vasodilation caused by ATP is independent of prostaglandin synthesis, as previously shown for oxygen (8). An increase in ATP concentrations in the pulmonary artery of fetal lambs to levels seen in postnatal lambs resulted in pulmonary vasodilation of the magnitude seen at birth.…”

Section: Resultssupporting

confidence: 50%

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Adenosine Triphosphate and Adenosine Increase the Pulmonary Blood Flow to Postnatal Levels in Fetal Lambs

et al. 1992

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ABSTRAa. We investigated the hypothesis that purine nucleotides may mediate the pulmonary vasodilation that occurs at birth in fetal lambs. We studied nine fetal lambs 3 d after placement of intravascular catheters, a flow transducer around the left pulmonary artery, and an inflatable vascular occluder around the ductus arteriosus. The pressure-flow relationship of left lung during a brief occlusion of the ductus arteriosus was studied as an index of pulmonary vascular resistance. We investigated the pulmonary vascular effects of adenosine, ATP, or saline (control) in doses of 0.01-2.50 pmol/kg/min infused into the right atrial line, and measured blood adenosine and ATP levels in samples from the pulmonary artery and left atrium. We also investigated the mechanism of pulmonary vascular effects of adenosine and ATP. Adenosine and ATP caused significant decreases in pulmonary vascular resistance and increases in pulmonary blood flow in doses of 0.08-2.5 pmol/kg/min. The pulmonary blood flow increased to levels seen in postnatal lambs at doses of 1.2 and 2.5 pmol/kg/min of adenosine and ATP. The baseline blood adenosine and ATP levels in fetus were 8 and 70% of levels in postnatal lambs. ATP concentrations increased to postnatal levels and adenosine levels increased to 20% of postnatal levels at infusion rates of 1.2 and 2.5 wmol/ kg/min. The pulmonary vasodilation caused by adenosine and ATP was attenuated by 8-phenyltheophylline and cibacron blue, respectively, but not by indomethacin. We conclude that adenosine and ATP are pulmonary vasodilators and increase the fetal pulmonary flow to postnatal levels in doses that increase their blood concentrations to I postnatal levels. The effects of adenosine and ATP are mediated by stimulation of PI and P2 purinergic receptors and are independent of prostacyclin synthesis. Purine nucleotides may be important mediators of pulmonary vasodilation that occurs in the perinatal lamb. The fetal lung undergoes significant changes at birth to prepare itself for the function of gas exchange during postnatal life. These changes include a rapid decrease in PVR and a 10-fold increase in pulmonary blood flow (I). The factors that decrease the PVR at birth include onset of ventilation (2) and exposure to higher oxygen tension (3, 4). Studies done in fetal lambs have shown that both factors have independent effects (2, 3) on fetal pulmonary vessels, although they appear to act in concert at birth. The pulmonary vasodilation caused by ventilation of fetal lamb's lungs can be blocked by indomethacin (5,6) and is accompanied by increased release of prostacyclin into pulmonary circulation (7). However, the increase in pulmonary flow in response to an increase in oxygen tension in the fetal lamb appears to be independent of prostaglandin synthesis ( 5 , 8).We previously reported (9, 10) that adenosine and ATP are pulmonary vasodilators in postnatal lambs and that they dilate the pulmonary vessels during hypoxia-induced pulmonary hypertension in lambs. We proposed the hypothesis that increased...

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Section: Resultssupporting

confidence: 50%

“…However, the mechanism by which oxygen increases the pulmonary blood flow is not known. Indomethacin does not appear to prevent the oxygen-induced decrease in PVR (8). Our studies indicate that adenosine and ATP are pulmonary vasodilators capable of increasing the pulmonary blood flow to postnatal levels in fetal sheep.…”

Section: Resultsmentioning

confidence: 71%

Adenosine Triphosphate and Adenosine Increase the Pulmonary Blood Flow to Postnatal Levels in Fetal Lambs

et al. 1992

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“…(9) further determined that mechanical ventilation offetallungs, and not oxygenation, resulted in pulmonary prostacyclin production, which was concluded to be due to tissue distortion as a consequence of establishing rhythmic ventilation and gaseous expansion of the lungs. Additional support for this conclusion was provided by the finding that indomethacin pretreatment did not alter the increased pulmonary blood flow due to increased fetal P0 2 (18). Our results of the effects of indomethacin on ventilation-and oxygenation-induced decreases in PVR are in agreement with these previous studies.…”

Section: Resultssupporting

confidence: 82%

Indomethacin Prevents Ventilation-Induced Decreases in Pulmonary Vascular Resistance of the Middle Region in Fetal Lambs

1991

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ABSTRACT. Previously, we reported that the major site of pulmonary vascular resistance in fetal lambs occurred in the middle region defined by vascular occlusion, and that this region exhibited the greatest decrease upon ventilation with Oz. To assess the relative individual contributions of ventilation and oxygenation to this decrease, we determined the distribution of pressures across the pulmonary circulation in isolated perfused lungs from 20 fetal lambs (131-137 d gestation) by inflow and outflow vascular occlusions. A membrane oxygenator was included in the extracorporeal circuit to control the POz at 4 kPa (30 torr) in the unventilated fetal lungs. Half of the fetal lungs were ventilated first without changing the initial gas tensions, and the others were oxygenated first by changing the initial gas tensions to a hyperoxic mixture [Paz = 26.6 kPa (200 torr)] without ventilation. Finally, both groups of lungs were ventilated and oxygenated. In addition, indomethacin was added to the perfusate (0.112 mM, or 40 J,LgfmL) in half of the preparations in each group to determine the effect of prostaglandins on the distribution of pressures during these conditions. The decrease in the total pulmonary vascular resistance with ventilation and/or oxygenation was primarily due to changes in the middle pressure gradient (aPm). In fetal lungs without indomethacin, ventilation without oxygenation reduced aPm from 6.1 ± 0.8 to 2.5 ± 1.0 kPa, or 74% of the total ventilation-and oxygenation-induced decrease in aPm (final value = 1.2 ± 0.6 kPa). In contrast, oxygenation without ventilation produced a decrease in aPm from 5.5 ± 0.7 to 3.8 ± 0.5 kPa, only 40% of the total decrease in aPm (1.2 ± 0.4 kPa).Furthermore, in fetal lungs with indomethacin, only oxygenation first caused a reduction in the resistance of the middle region, suggesting that dilator prostaglandins are not involved in the response to increased oxygen. We conclude that recruitment and/or distension of the small pulmonary vessels functionally located in the middle region by the mechanical effect of ventilation is dependent on dilator cyclooxygenase products, and that this mechanical effect is a major factor involved in the decrease in pulmonary vascular resistance occurring at birth. (Pediatr Res 29: 449-454, 1991) Abbreviations PVR, pulmonary vascular resistance Ppa, pulmonary artery pressure Ppa', pulmonary artery pressure immediately after inflow occlusion Pia', left atrial pressure immediately after outflow occlusion aPt, total pressure gradient aPm, middle pressure gradient U30, unventilated, hypoxic condition V30, ventilated, hypoxic condition V200, ventilated, hyperoxic conditionThe dramatic fall in PVR that occurs at birth is due to a combination of factors, including: 1) ventilation with a gas, resulting in establishment of an air-liquid interface; 2) increasing arterial Paz; and 3) decreasing arterial Pco, (1-3). Although these factors normally act in concert to result in the decrease in PVR, each has been found to exert independent effects on t...

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“…These findings suggest that different mechanisms may be responsible for the fall in pulmonary vascular resistance during rhythmic distension and oxygenation. Additionally supporting this possibility are the findings that PGIl is produced by the lungs during rhythmic distension (1 1) and that inhibition of PGs does not change pulmonary vasodilation in response to oxygenation without ventilation (10).…”

Section: Pg12 Prostacyclinsupporting

confidence: 58%

Prostaglandin Inhibition Prevents the Fall in Pulmonary Vascular Resistance as a Result of Rhythmic Distension of the Lungs in Fetal Lambs

1991

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ABSTRACT. Prostaglandins (PG) are vasoactive factors involved in the regulation of pulmonary vascular resistance at birth. However, their physiologic importance is unclear. We hypothesized that PG are important regulators of pulmonary vascular resistance during static and rhythmic distension of the lungs. To test this hypothesis, we studied seven near-term fetal lambs treated with meclofenamate (a PG synthetase inhibitor) and six controls. The fetal lambs were instrumented on a long-term basis with vascular catheters to measure pulmonary arterial pressures, left atrial pressures, and pulmonary blood flow (radionuclidelabeled microsphere method). The fetal airway was intubated, and the ductus arteriosus wall was infiltrated with formalin to assure full patency during the study period. Pulmonary vascular resistance was calculated during baseline and during sequential in utero static distension of the fetal lungs, rhythmic distension, and ventilation with oxygenation. We found that during rhythmic distension, inhibition of PG synthesis abolished the 4-fold decrease in pulmonary vascular resistance seen in the control group. In contrast, during static distension, pulmonary vascular resistance did not change in either group, and during ventilation with oxygenation, pulmonary vascular resistance decreased 12-fold in both groups. We conclude that PG are important regulators of pulmonary vascular resistance during rhythmic distension but are not essential for the regulation of pulmonary vascular resistance during static distension or during ventilation with oxygenation. ( The sudden and dramatic decrease in pulmonary vascular resistance that occurs at birth is essential for the normal transition from fetal to neonatal circulation (1). This decrease in pulmonary vascular resistance is regulated by a complex and incompletely understood interplay between metabolic and mechanical factors the most important PG in the perinatal pulmonary circulation (3), is produced by the lungs of fetal goats and newborn lambs at the onset of mechanical ventilation (4) and at the onset of spontaneous breathing (5). However, inhibition of PG synthesis results in only moderate attenuation of the normal decrease in pulmonary vascular resistance at birth in acutely exteriorized full-term fetal goats (6) and in newborn lambs that were instrumented on a long-term basis (7). Therefore, the physiologic importance of PGs in the regulation of the perinatal pulmonary vascular resistance has been questioned (7).To put these observations in perspective, an understanding of the ventilatory and circulatory changes that occur simultaneously with the fall in pulmonary vascular resistance at birth is essential. These changes include rhythmic distension of the lungs, removal of fluid from the alveolar spaces, and changes in pH, arterial 0 2 tension, cardiac output, and systemic arterial pressures. All these changes, individually or in various combinations, can influence pulmonary vascular resistance. For instance, both rhythmic distension without oxygenation (...

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Indomethacin Does Not Diminish the Pulmonary Vascular Response of the Fetus to Increased Oxygen Tension

Cited by 39 publications

References 22 publications

Adenosine Triphosphate and Adenosine Increase the Pulmonary Blood Flow to Postnatal Levels in Fetal Lambs

Adenosine Triphosphate and Adenosine Increase the Pulmonary Blood Flow to Postnatal Levels in Fetal Lambs

Indomethacin Prevents Ventilation-Induced Decreases in Pulmonary Vascular Resistance of the Middle Region in Fetal Lambs

Prostaglandin Inhibition Prevents the Fall in Pulmonary Vascular Resistance as a Result of Rhythmic Distension of the Lungs in Fetal Lambs

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