MULTIPLE FUNCTIONS OF NITRIC-OXIDE IN PATHOPHYSIOLOGY AND MICROBIOLOGY - ANALYSIS BY A NEW NITRIC-OXIDE SCAVENGER

A wide range of biological functions of nitric oxide (NO) was analyzed using a newly discovered nitric oxide scavenger, 2-phenyl-4,4,5,5-tetramethylimidazolineoxyl-1-oxyl-3-oxide (PTIO) or its water-soluble derivative carboxy-PTIO. The chemistry is very simple in that NO was oxidized by PTIO, yielding one mole each of NO2 and 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl. Based on the potent NO-scavenging activity of PTIO derivatives, the diverse functions of NO under physiological states as well as various pathological conditions such as endotoxin shock and viral diseases are now explicated. It was found that PTIO and carboxy-PTIO showed significant inhibitory activity against a series of biological actions of NO: (1) endothelium-dependent vascular relaxation in an ex vivo system, (2) pathogenicity of NO produced excessively in endotoxin shock in rats and in influenza virus pneumonitis in mice, and (3) enhanced vascular permeability in solid tumors mediated by NO. PTIO directly extinguishes NO generated by NO synthase (NOS) without affecting NOS activity, which is a clear contrast to NOS inhibitors. Therefore, characterization of this unique mode of action of PTIO appears to be helpful not only in understanding of the pathophysiological role of NO but also in the treatment of various diseases caused by excessive production of NO.