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

Abstract

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...

Hypoxic Pulmonary Vasoconstriction

“…Factors released from pulmonary endothelium are thought to be crucial for pulmonary vasodilation at birth. Early investigations provided evidence that PGI 2 and possibly other vasodilating prostanoids are important for the response to lung ventilation, but perhaps less important for the response to increasing blood PO 2 (5,1061,1063,1915,1971). Interest in the involvement of NO developed quickly upon its identification as EDRF, and it was found that NOS inhibitors markedly attenuated the perinatal fall in PVR (6,336,1313).…”

Physiologic characterization of endothelin A and B receptor activity in the ovine fetal pulmonary circulation.

“…Although mechanisms maintaining high pulmonary vascular resistance in the fetus are uncertain, possible explanation for this high resistance include lack of an air liquid interface or ventilation, low oxygen tension (2-7), decreased vasodilators, such as prostacyclin, bradykinin or endothelium-derived nitric oxide or increased vasoconstrictors such as platelet activating factor or leukotrienes (28)(29)(30)(31)(32)(33)(34)(35)(36)(37). Endothelin has potent vasoconstrictor properties (9), but its role in the fetal lung is poorly understood.…”

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

“…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).…”