Therapeutic approaches using nitric oxide in infants and children

Abstract

Pulmonary hypertension contributes significantly to the morbidity and mortality associated with many pediatric pulmonary and cardiac diseases. Nitric oxide, a gas molecule, is a unique pharmaceutical agent that can be inhaled and thus delivered directly to the lung. Inhaled nitric oxide was approved by the FDA in 1999 as a therapy for infants with persistent pulmonary hypertension. Since then, the use of inhaled nitric oxide has expanded to other neonatal and pediatric conditions, and our knowledge of its properties and mechanisms of action has increased tremendously. This review discusses the physiology of nitric oxide signaling, the most common indications for its clinical use, and promising new investigations that may enhance endogenous production of nitric oxide and/or improve vascular response to it.

Figure 1

Nitric oxide (NO) signaling pathways in the regulation of pulmonary vascular tone. NO is synthesized by nitric oxide synthase (NOS) from the terminal nitrogen of L-arginine. NO from endogenous sources, or delivered as an inhaled gas, stimulates soluble guanylate cyclase (sGC) to increase intracellular cGMP, which indirectly decreases free cytosolic calcium, resulting in smooth muscle relaxation. Specific phosphodiesterases such as PDE5 hydrolyze cGMP, thus regulating the intensity and duration of its vascular effects. Inhibition of cGMP phosphodiesterases with agents such as sildenafil may enhance pulmonary vasodilation.

Figure 2

Proposed role for reactive oxygen species and their metabolites in mediating increased pulmonary arterial contractility following exposure to 100% oxygen. Exposure to high oxygen concentrations results in formation of superoxide anions (O2·^-). Superoxide anions combine with nitric oxide (NO) to form peroxynitrite, a potent pulmonary vasoconstrictor. Superoxide dismutase (SOD) enzyme converts superoxide anions to hydrogen peroxide (H₂O₂), also a pulmonary vasoconstrictor. When membrane lipids (arachidonic acid and poly unsaturated fatty acids, PUFA) are exposed to reactive oxygen species such as superoxide anions and hydrogen peroxide or peroxynitrite, a variety of isoprostanes are formed. Isoprostanes are known constrictors of pulmonary arteries. From (90), with permission.

Figure 3

Response to sildenafil infusion without iNO. Seven infants were enrolled before the need for iNO. OI was improved by 1 hour (24.6±4.6 to 16.1±9.9; *P=0.0502), with significant and sustained improvement by 4 hours after the initiation of sildenafil (14.7±6.4, p=0.0088). From (91), with permission.