Endothelium derived vasodilators – prostacyclin (PGI2) and nitric oxide (NO) and vasoconstrictor (endothelin, ET-1). Cyclooxygenase (COX) and prostacyclin synthase (PGIS) are involved in the production of prostacyclin. Prostacyclin acts on its receptor (IP) in the smooth muscle cell and stimulates adenylate cyclase (AC) to produce cyclic adenosine monophosphate (cAMP). Cyclic AMP is broken down by phosphodiesterase 3A (PDE 3A, the enzyme most prevalent in vasculature) in the smooth muscle cell. Milrinone inhibits PDE 3A and increases cAMP levels in arterial smooth muscle cells and cardiac myocytes resulting in pulmonary (and systemic) vasodilation and inotropy. Nitric oxide (NO) stimulates PDE 3A [151,152]. Endothelin is a powerful vasoconstrictor and acts on ET-A receptors in the smooth muscle cell and increases ionic calcium concentration. A second endothelin receptor (ET-B) on the endothelial cell stimulates NO release and vasodilation. Endothelial nitric oxide synthase (eNOS) produces NO which diffuses from the endothelium to the smooth muscle cell and stimulates soluble guanylate cyclase (sGC) enzyme to produce cyclic guanosine monophosphate (cGMP). Cyclic GMP is broken down by PDE5 enzyme in the smooth muscle cell. Sildenafil inhibits PDE5 and increases cGMP levels in pulmonary arterial smooth muscle cells. Natriuretic peptides stimulate particulate guanylate cyclase (pGC) to produce cGMP. Cyclic AMP and cGMP reduce cytosolic ionic calcium concentrations and induce smooth muscle cell relaxation and pulmonary vasodilation. Nitric oxide is a free radical and can avidly combine with superoxide anions to form a toxic vasoconstrictor, peroxynitrite. Hence, the bioavailability of NO in a tissue is determined by the local concentration of superoxide anions. Hyperoxic ventilation with 100% oxygen can increase the risk of formation of superoxide anions in the pulmonary arterial smooth muscle cells and limit the bioavailability of NO and stimulate PDE5 activity . Medications used in PPHN are shown in black boxes (copyright Satyan Lakshminrusimha).