Fig. 3.

Mechanism of action of phosphodiesterase inhibitors in PPHN. PDEs play a critical role in regulating cGMP and cAMP within the vascular smooth muscle. Elevations in cGMP and cAMP lead to vasorelaxation by decreasing intracellular calcium via decreasing calcium efflux from the sarcoplasmic reticulum and increasing calcium efflux from the cell. PDEs hydrolyze cGMP and cAMP, thereby preventing cyclic nucleotide-mediated vasorelaxation. Thus, PDE inhibitors such as sildenafil and milrinone represent promising therapies for neonates with PPHN resistant to traditional therapy with inhaled nitric oxide. Dashed lines represent inhibition. Figure kindly provided by Dr. Satyan Lakshminrusimha