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

Abstract

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 (...

Pulmonary hemodynamic responses to in utero ventilation in very immature fetal sheep

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Estradiol improves pulmonary hemodynamics and vascular remodeling in perinatal pulmonary hypertension

“…E 2 also increases the release of and response to PGI 2 in several vascular beds (30,33). Although PGI 2 is an important mediator of pulmonary vascular tone in the perinatal period (45) and has been used clinically to treat neonatal pulmonary hypertension (8), alterations in the cyclooxygenase-PGI 2 axis and its contribution to the pathogenesis of perinatal pulmonary hypertension after DA ligation have not been investigated. Further studies are necessary to determine the interaction between E 2 , ET-1, and PGI 2 in this model of pulmonary hypertension.…”

“…At birth, PVR falls, and the lungs assume their normal postnatal role in gas exchange. Factors that mediate the fall in PVR are incompletely understood but include rhythmic distension of the lung, increased oxygenation, shear stress, and the release of several vasoactive mediators, including nitric oxide (NO) and prostacyclin (PGI 2 ) (1,7,45,52). Failure to achieve the normal fall in PVR results in persistent pulmonary hypertension of the newborn (PPHN), a syndrome characterized by right-to-left shunting of blood with severe hypoxemia, loss of pulmonary vasoreactivity, and muscularization of small pulmonary arteries (24).…”

Ventilation/perfusion mismatch during lung aeration at birth

“…Increased oxygenation and mechanical shear stress, caused by ventilation onset, are thought to increase nitric oxide (NO) and prostaglandin synthesis causing vasodilation of pulmonary vessels (5,12,36). In addition, the development of surface tension at the air-liquid interface following lung aeration increases transmural pressures across the fused capillary/alveolar wall, causing an increase in capillary recruitment and reduction in capillary resistance (7,13,25).…”