Inhaled Nitric Oxide in Treatment of Persistent Pulmonary Hypertension of Neonate: An Insight into Biochemical Pathways

Abstract

Persistent pulmonary hypertension of neonate (PPHN) is a syndrome of failed circulatory adaptation in the neonatal period and is defined by sustained elevation of PVR and is often associated with hypoxemia, severe cyanosis, and cardiac dysfunction and normal or low systemic vascular resistance. Stability of pulmonary vessels is achieved through the formation of vascular complexes and Nitric oxide (NO). The decline in the secretion of endothelial diastolic factors in the pulmonary vasculature aggravates the injury of endothelial cells, which induces shrinkage of the vasculature. Currently available agents in the treatment of PPHN include oxygen, inhaled nitric oxide (iNO), prostanoids, sildenafil, milrinone, and bosentan. NO the smallest signaling molecule known is synthesized from L-arginine in the presence of nicotinamide adenine dinucleotide phosphate (NADPH) and oxygen by four major isoforms of NO synthase (NOS). The most important physiological signaling pathway stimulated by NO is the activation of soluble guanylyl cyclase and the generation of cyclic GMP. NO can also bind to the ferrous heme forming iron nitrosyl Hb, FeIINO Hb and to ferric heme, but with a substantially lower affinity. Both of these reactions end up inactivating NO. There are several diffusional factors that contribute to the negative modulation of the reaction of NO with ferrous hemoglobin and include the erythrocyte membrane, or sub-membrane network of protein, an unstirred layer surrounding the erythrocyte and an erythrocyte-free zone within the lumen nearest to the endothelial layer that results from dynamic, flow-mediated, axial concentration of the red cells. Such an effect is believed to be the cause of pulmonary and systemic hypertension and many other diseases. Inhaled NO can disperse to vascular smooth muscle cells, and soluble guanylate cyclase can increase the levels of NO, which causes specific expansion of the pulmonary vasculature. NO has allosteric effects on hemoglobin, which increases the exchange of oxygen and carbon dioxide, and causes blood flow distribution from oxygenation tissue to hypoxic tissue, which improves systemic and pulmonary circulation. iNO has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of PPHN.