Inhalation of nitric oxide in acute respiratory distress syndrome

Abstract

simple, highly reactive toxic molecule and an environmental pollutant in cigarette smoke and smog. In 1987 Palmer et al1 discovered NO to be EDRF. The relevance of NO opened up a new era of biologic research. In 1992 the American Association for the Advancement of Science voted NO as the Molecule of the Year.2 NO has become the focus of intense clinical and basic science research as an important mediator of inflammation and vasomotor tone. NO is a potent pulmonary vasodilator, and its use as an inhalational agent has been proposed in a number of cardiopulmonary disease states. Because inhaled NO reliably produces clinically significant increases in arterial oxygenation (PaO2) in animals and human patients with ARDS, its potential to alter clinical outcome in ARDS was approached with great enthusiasm. CHEMISTRY AND PHARMACOLOGY In 1980, intact endothelium was demonstrated to be crucial for acetylcholine-induced vasodilation of isolated strips of arteries.3 EDRF is the substance released on stimulation of the endothelial cells. NO is now known to account for the biologic activity of EDRF. Nitric oxide is a simple, unstable, gaseous free radical that is freely diffusible across cell membranes.4,5 Because of its rapid conversion to nitrates by oxygen, its half-life has been approximated from 3 to 50 seconds.5,6 In the vascular endothelial cell, NO is synthesized from the terminal guanidine nitrogen of L-arginine by the enzyme NO synthase. Molecular oxygen is incorporated into the terminal nitrogen group, forming NO and citrulline.7 NO diffuses rapidly into subjacent vascular smooth muscle, where it binds to the heme iron complex of soluble guanylate cyclase. The resulting nitrosyl-heme activates guanylate cyclase, stimulating the production of cGMP. cGMP produces relaxation of vascular smooth muscle by decreasing intracellular calcium. Additionally, NO directly stimulates calciumdependent K channels, causing hyperpolarization and vascular smooth muscle cell relaxation via a cGMPindependent mechanism.8 One of the unique properties of NO is that once it diffuses into the intravascular space, it is rapidly inactivated by binding avidly to hemoglobin. In fact, the combination of NO with reduced hemoglobin is the fastest direct action so far measured of an oxygenInhalation of nitric oxide in acute respiratory distress syndrome