SOD and inhaled nitric oxide normalize phosphodiesterase 5 expression and activity in neonatal lambs with persistent pulmonary hypertension

作者：Farrow Kathryn N^*; Lakshminrusimha Satyan; Czech Lyubov; Groh Beezly S; Gugino Sylvia F; Davis Jonathan M; Russell James A; Steinhorn Robin H

来源：American Journal of Physiology - Lung Cellular and Molecular Physiology, 2010, 299(1): L109-L116.

DOI：10.1152/ajplung.00309.2009

• reactive oxygen species
• cGMP

Farrow KN, Lakshminrusimha S, Czech L, Groh BS, Gugino SF, Davis JM, Russell JA, Steinhorn RH. SOD and inhaled nitric oxide normalize phosphodiesterase 5 expression and activity in neonatal lambs with persistent pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 299: L109-L116, 2010. First published April 16, 2010; doi:10.1152/ajplung.00309.2009.-Phosphodiesterase 5 (PDE5) and soluble guanylate cyclase (sGC) are key regulators of cGMP and pulmonary vascular tone. We sought to determine the impact of mechanical ventilation with O(2) with or without inhaled nitric oxide (iNO) or recombinant human Cu/Zn SOD (rhSOD) on sGC, PDE5, and cGMP in the ovine ductal ligation model of persistent pulmonary hypertension of the newborn (PPHN). PPHN lambs were ventilated with 100% O(2) for 24 h alone or combined with either inhalation of 20 parts per million (ppm) iNO continuously or a single intratracheal dose of rhSOD (5 mg/kg). Ventilated PPHN lambs were compared with PPHN fetuses, control fetuses, and 1-day-old spontaneously breathing lambs (1DSB). In the small pulmonary arteries of 1DSB lambs, sGC expression increased, PDE5 expression decreased, and cGMP concentrations increased relative to fetal levels. In PPHN lambs ventilated with 100% O(2), sGC activity increased to levels comparable with 1DSB levels. However, PDE5 expression and activity increased, and cGMP levels remained at fetal levels. Addition of either iNO or rhSOD decreased PDE5 expression and activity in PPHN lambs and increased cGMP levels to levels comparable with 1DSB lambs. These data suggest that ventilation of PPHN lambs with 100% O(2) impairs cGMP-mediated vasodilation in part due to increased PDE5 expression and activity. The addition of either iNO or rhSOD normalized PDE5 and cGMP levels. Thus therapies designed to decrease PDE5 and increase cGMP, such as iNO and rhSOD, may prove useful in the treatment of PPHN in newborn infants.

• 出版日期2010-7
• 单位西北大学