Therapeutic Role of Nitric Oxide in Respiratory Disease

Thomas E. Siddons, BSc, Mohammed Asif, MA, BMBCh, FRCS, and Tim W. Higenbottam, MD, MA, BSc, FRCP, University of Sheffield, Sheffield, United Kingdom

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Formation and Fate of Endogenous NO

Endogenous NO is formed by the calcium-dependent enzyme NO synthase III from L-arginine.[2] It is released as a gas and subsequently hydrolyzes to form the oxides NO2-, NO3- , and molecular oxygen. (The gaseous NO is the principle pharmacologically active entity.) NO rapidly reacts with oxyhemoglobin in erythrocytes to form methemoglobin and nitrates.[3] Methemoglobin is rapidly reduced back to hemoglobin and the nitrates are excreted in the urine. This inherent property of instantaneous inactivation is what makes inhalation therapy with NO attractive.

The anatomic target of inhaled NO is the vascular smooth muscle cells that surround the small resistance arteries. As NO diffuses through the alveolar membrane, it reaches these smooth muscle cells, causing an increase in the levels of cyclic guanosine monophosphate, which in turn sets off the chain of events that results in reduction of smooth muscle tone.[4] The NO then diffuses into the bloodstream and is subsequently inactivated. The concentration of NO needed to relax vascular smooth muscle is 10-10M.[5]

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