Pulmonary vascular tone is regulated by a complex interaction of vasoactive substances such as nitric oxide (NO) and endothelin-1 (ET-1) that are produced by vascular endothelial cells and control smooth muscle relaxation and vascular remodeling. NO is synthesized from L-arginine by the enzyme, NO synthase (NOS); the hemodynamic effects of ET-1 are mediated by at least two receptors, ETA and ETB. Alterations in the balance of these substances may account for the hemodynamic changes in the perinatal pulmonary circulation with development, the decrease in pulmonary vascular resistance with ventilation at birth, and a variety of pathological disorders affecting the pulmonary circulation of newborns, infants and children. Newborns with persistent pulmonary hypertension (PPHN) have failure of normal postnatal pulmonary vasodilation. Infants and children with congenital heart disease and increased pulmonary vascular resistance have altered pulmonary vasodilation. Adults with pulmonary vascular disease secondary to chronic lung disease have impaired endothelium-dependent but not -independent vasodilation. Physiologic studies have raised questions about the control of pulmonary vascular tone in the perinatal period and during pulmonary hypertension secondary to lung injury. To answer these questions, cellular and molecular biological techniques need to be used in concert with physiologic studies. To this end, this proposal will evaluate the effects of endothelium-dependent and -independent vasodilators in intact fetal and newborn lambs, and sheep (normal and those with pulmonary hypertension), and will correlate these observations with cellular and molecular biological studies of NOS , ET-1, and ET receptor gene expression and protein activity. This proposal has 4 specific aims: (1) to determine whether there are age- dependent differences in the hemodynamic response of the intact pulmonary circulation to vasodilators and vasoconstrictors, and whether these differences correlate with changes in NOS gene expression and localization, protein levels and activity; (2) to determine whether chronic in utero stress, a cause of PPHN, alters the hemodynamic response of the pulmonary circulation to vasodilators and vasoconstrictors, and whether it changes NOS gene expression, protein levels and activity; (3) to determine the hemodynamic effects of ET-1 and ET receptor agonists and antagonists on the pulmonary circulation in sheep and in fetal lambs with chronic in utero stress, and whether development or stress changes ET-1 and ET receptor gene expression; and (4) to determine whether acute or chronic lung injury alters the hemodynamic response of the pulmonary circulation to vasodilators and vasoconstrictors, and whether it changes NOS, ET-1, and ET receptor gene expression. A better understanding of the mechanisms controlling pulmonary vascular tone during development and during pulmonary hypertension secondary to in utero stress or lung injury will lead to improved clinical care for newborns, infants and children.
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