Role of nitroso radicals as drug targets in circulatory shock

Abstract

A vast amount of circumstantial evidence implicates oxygen-derived free radicals (especially, superoxide and hydroxyl radical) and high-energy oxidants [such as peroxynitrite (OONO(-))] as mediators of shock and ischaemia/reperfusion injury. Reactive oxygen species can initiate a wide range of toxic oxidative reactions. These include initiation of lipid peroxidation, direct inhibition of mitochondrial respiratory chain enzymes, inactivation of glyceraldehyde-3 phosphate dehydrogenase, inhibition of membrane sodium/potassium adenosine 5'-triphosphate-ase activity, inactivation of membrane sodium channels and other oxidative modifications of proteins. All these toxicities are likely to play a role in the pathophysiology of shock and ischaemia and reperfusion. Moreover, various studies have clearly shown that treatment with either OONO(-) decomposition catalysts, which selectively inhibit OONO(-), or with superoxide dismutase (SOD) mimetics, which selectively mimic the catalytic activity of the human SOD enzymes, have been shown to prevent in vivo the delayed vascular decompensation and the cellular energetic failure associated with shock and ischaemia/reperfusion injury.

Figure 1

In the process of normal cellular metabolism, oxygen undergoes a series of univalent reductions, leading sequentially to the production of superoxide, hydrogen peroxide (H₂O₂) and H₂O. Reactive oxygen species, which are thought to have relevance to vascular biology, include superoxide, hydrogen peroxide, peroxynitrite, lipid hydroperoxides and hydroperoxy-radicals and probably hydroxyl-like radicals. Both hydrogen peroxide and peroxynitrite are generated as reaction products of the superoxide anion. While hydrogen peroxide mainly emerges from intra and extracellular dismutation of superoxide by the abundantly present superoxide dismutases, peroxynitrite is formed by the rapid reaction of superoxide with nitric oxide.

Figure 2

Synthetic superoxide dismutase mimetics superoxide is shown. MnTBAP, Mn(III)tetrakis (4-benzoic acid) porphyrin; EUK-8, manganese N,N′-bis(salicyldene)ethylenediamine chloride; EUK-134, manganese 3-methoxy-N,N′-bis(salicyldene)ethylenediamine chloride; M40403 and M40401, Mn(II)(penta-azamacrocyclic ligand)-based complexes SC-55858, M40403 and M40401.

Figure 3

Peroxynitrite decomposition catalysts are shown. FeTMPS, iron(III) meso-tetra(2,4,6-trimethyl-3,5-disulfonato)porphirin chloride; FeTMPyP, iron (III) tetrakis(N-methyl-4′-pyridyl)porphyrin; MnTMPyP, manganese (III) tetrakis (1-methyl-4-pyridyl)porphyrin; FP15, FeCl tetrakis-2-(triethylene glycol monomethyl ether) pyridyl porphyrin.