Nitric Oxide (NO) is a gaseous compound that is naturally produced by many cells of the body.  It plays an important role in the regulation of blood flow.  Nitric oxide relaxes the smooth muscle in the walls of the arterioles.  At each beat of the heart, the endothelial cells that line the blood vessels release a puff of NO.  This diffuses into the underlying muscle cells, causing them to relax and permitting the surge of blood to pass through easily. One of the many causes of pulmonary hypertension is the lack of production or response to nitric oxide.  Abnormal production of NO, such as occurs in disorders like pulmonary hypertension, can adversely affect blood flow and other vascular functions.  When inhaled, NO acts as a selective pulmonary vasodilator.  In addition, it has anti-thrombolytic, anti-inflammatory and anti-proliferative effects.

Currently, the only FDA approved indication for INOmax® is for adjunctive treatment of Persistant Pulmonary Hypertension of the Newborn (PPHN).  Inhaled Nitric Oxide (NO) is also used as a vasodilator during a vasoreactivity trial.  Off-label uses have included the treatment of acutely ill patients with severe pulmonary hypertension.

INOmax® (nitric oxide gas) is administered by inhalation through a special delivery system with monitoring for PaO2, methemoglobin, and NO2 levels.

Inhalation of low levels of NO, within the therapeutic dose range, appears to be safe. The major concern regarding clinical toxicity is due to the formation of NO2 and methemoglobinemia as byproducts of it’s breakdown.  Increased levels of NO2 may cause increased airway reactivity and pulmonary edema.  Tissue hypoxia may occur with excessive circulating levels of methemoglobulin.  Significant methemoglobinemia or NO2 formation is uncommon in patients breathing NO at doses ≤80 ppm.  Normally, the dose for treatment of pulmonary hypertension is <20 ppm and most often in the range of less than 2 ppm.

After inhalation, NO diffuses rapidly across the alveolar-capillary membrane into the smooth muscle of pulmonary vessels and activates the enzyme sGC (soluble guanylate cyclase).  This enzyme mediates many of the biological effects of NO and is in turn responsible for the conversion of GTP to cGMP.  Increased intracellular concentrations of cGMP relax smooth muscle via several mechanisms:

 

 

The physiological actions of cGMP are limited to its area of synthesis by its hydrolysis to GMP by cyclic nucleotide phosphodiesterases (PDE) or by its export from the cell.  Of the 11 reported PDE isozymes, PDE5 is considered to be the most active cGMP-hydrolyzing PDE in smooth muscle. PDE5 has a high affinity for cGMP and is selectively inhibited by compounds such as zaprinast, sildenafil, and verdenafil.  Because of the central role of cGMP in NO-mediated vasodilation, drugs (e.g., Revatio®) that inhibit the breakdown of cGMP are used to enhance NO-mediated vasodilation.

Inhaled nitric oxide (NO) has gained acceptance as a relatively safe and effective selective pulmonary vasodilator. However, specialized equipment is required for its delivery, making its use difficult and cumbersome.  Although it’s use is widely accepted as an adjunctive treatment of PPHN, it has not gained an accepted role in the treatment of pulmonary hypertension in the adult except in an acute setting.  More studies would be needed to determine if it confers any greater benefit in survival or other meaningful endpoints as compared to the current medications on the market.

Use of inhaled nitric oxide in patients with pulmonary hypertension

Authors:  Christopher D O'Brien, MD; Scott Manaker, MD, PhD

 

Inhaled Nitric Oxide - A Selective Pulmonary Vasodilator: Current Uses and Therapeutic Potential

 

The Toxicology of Inhaled Nitric Oxide