Modulation of peroxynitrite- and hypochlorous acid-induced inactivation ofalpha(1)-antiproteinase by mercaptoethylguanidine

1 Peroxynitrite is a cytotoxic species that can be formed, among other mech anisms, by the rapid reaction of superoxide with nitric oxide. Peroxynitrit e formation has been implicated in a wide range of neurodegenerative and ch ronic inflammatory diseases, as has the formation of hypochlorous acid by m yeloperoxidase. 2 There is considerable interest in the development of peroxynitrite scaven gers as therapeutic agents. The thiol compound mercaptoethylguanidine has b een suggested to fulfil this role since it has recently been shown to be no t only a potent inhibitor of inducible nitric oxide synthase but also a sca venger of peroxynitrite. Indeed, it has been shown to be protective in some experimental models of circulatory shock and inflammation at plasma levels in the approximate range 100-300 mu M. 3 One protein inactivated by peroxynitrite is the major inhibitor of serine proteinases in human body fluids, alpha(1)-antiproteinase. At high (250-10 00 mu M) concentrations, mercaptoethylguanidine was found to be effective i n preventing peroxynitrite-mediated tyrosine nitration and alpha(1)-AP inac tivation. 4 By contrast, lower concentrations of mercaptoethylguanidine (1-60 mu M) e nhanced the inactivation of alpha(1)-antiproteinase by peroxynitrite. 5 At all concentrations tested (1-1000 mu M), mercaptoethylguanidine decrea sed the inactivation of alpha(1)-antiproteinase by hypochlorous acid. 6 We suggest that products of reaction of mercaptoethylguanidine with perox ynitrite or peroxynitrite-derived products could cause damage to alpha(1)-a ntiproteinase, and possibly other proteins in vivo, whereas scavenging of h ypochlorous acid by mercaptoethylguanidine could contribute to its anti-inf lammatory action in vivo.