Attenuated Beta Adrenergic Receptor Mediated Pulmonary Vasodilation In High Altitude Term-Fetal Sheep

Abstract

Purpose of Study: Beta adrenergic receptors (beta-AR) are important for pulmonary artery vasodilation. An increase in circulating catecholamines and increase in beta-AR density associated with birth is thought to contribute to the vasodilatory responses and the increase in lung blood flow in the newborn. Lambs born at high altitude have pulmonary hypertension and chronic hypoxia in newborn piglets attenuates the increase in beta-AR density and may contribute to pulmonary hypertension in newborns. Yet, in adult mice beta-AR pulmonary vasorelaxation is preserved following chronic hypoxia induced pulmonary hypertension. What is more, calcium and voltage activated K channels (KCa) are important to beta-AR mediated pulmonary vasorelaxation, suggesting KCa channel dynsfunction may contribute to chronic hypoxia induced pulmonary hypertension in the newborn. Methods Used: In this series of studies, we tested the hypothesis that beta- AR dependent pulmonary arterial vasorelaxation is dependent on KCa channels and that vasodilatory responses increase following birth in sheep that live at high altitude, a naturally occuring chronic hypoxic environment. The vasorelaxant ability of the selective beta-AR agonist isoproterenol (ISO;1 micromolar) were examined in serotonin (1 - 5 micromolar) preconstricted endothelium intact pulmonary arterial rings from term-fetal sheep, ~10 days old newborns, and in adult ewes that lived at 3,200 meters for <100 days. Summary of Results: Serotonin-induced tension was reduced substantially by ISO (~ 35%) in pulmonary arteries from 3 newborn and 6 adult sheep, but the reduction was smaller (~15%) in arteries from 7 fetal sheep. Tetraethylammonium (1 mM), a KCa channel inhibitor attenuated the vasodilatory response by roughly one-half in newborns and adults, but did not affect vasodilation in fetuses. Conclusions: Results suggest beta-adrenergic agonists may provide therapeutic benefit in newborn infants with pulmonary hypertension.