Role of Oxidative Phosphorylation in Mediating Pulmonary Vasodilation at Birth in Fetal Lambs 1691

Abstract

Background: We previously reported that the high energy nucleotide ATP and its nucleoside, adenosine play a role in causing pulmonary vasodilation at birth in fetal lambs. We proposed the hypothesis that the increase in oxidative phosphorylation in red blood cells occurring with exposure to higher PaO2 at birth causes increased ATP release and pulmonary vasodilation. The objective of the present experiments was to investigate the effects of 2,4-Dinitrophenol (DNP), an uncoupler of oxidative phosphorylation and antimycin A (AMA), an inhibitor of cytochrome electron transport, on ATP release and pulmonary vasodilation occuring at birth in intact fetal lambs.Methods: 14 fetal lambs were instrumented at 124 days of gestation(term=140 d) to measure pulmonary and systemic pressures, left pulmonary flow and pulmonary vascular resistance (PVR). A tracheostomy was also done to insert a 3.5 ETT and animals were allowed to recover for 3 days before experiments were done. Animals were divided into 3 groups - Control (n=6), Pretreatment with DNP (n=5) and AMA (n=3). For each study, baseline variables were recorded and blood samples were obtained from left pulmonary artery and left atrium for determination of ATP levels by a sensitive Luciferin-Luciferase assay. Fetal lambs were sequentially ventilated with 10%, 21% and 100% oxygen. Hemodynamic measurements, arterial blood gases and samples for ATP measurements were obtained 10 minutes after ventilation at each FIO2. The FIO2s were selected to cause distension of lung with no change in PO2 and distension with 2 fold or 6 fold increases in PO2.Results: The red cell and plasma ATP levels in pulm artery did not change during ventilation with 10% O2 and increased with 21% O2 and 100% O2 in control studies. ATP levels did not change in DNP or AMA treated animals during ventilation. The decreases in PAP and PVR during ventilation with 21% and 100% oxygen were attenuated by DNP and AMA. The increase in pulmonary flow during ventilation at 21% and 100% O2 was lower in animals pretreated with DNP or AMA compared to Controls. Conclusion: These data show that inhibition of oxidative phosphorylation and ATP release causes an attenuation of pulmonary vasodilation at birth in fetal lambs. Oxidative phosphorylation and ATP release play a role in mediating birth related transition in pulmonary circulation.