NO Activity and Rho Kinase Activity

General Considerations on Nitric Oxide Purpose and Rationale The endothelium releases a labile, diffusible, vasorelaxing substance that has been termed endotheliumderived relaxing factor (EDRF) (Furchgott and Zawadzki 1980). Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor (Palmer et al. 1987; Vanhoutte 1999). Nitric oxide plays a role in a wide range of physiological processes including regulation of blood flow and arterial pressure via endothelium-dependent relaxation of blood vessels (Rees et al. 1989; Moncada et al. 1991; Umans and Levi 1995; Huraux et al. 1999; McIntyre et al. 1999; Zanzinger 1999; Hropot et al. 2003), ischemia/reperfusion injury (Gao et al. 2002; Schulz et al. 2004), peripheral nitrergic transmission at smooth muscle (Rand and Li 1995), intracellular communication in the CNS with activation of guanylyl cyclase in target neurons (Southam and Garthwaite 1993), experimental stroke (Willmot et al. 2005), learning and memory (Susswein et al. 2004), neurogenic inflammation (Kajekar et al. 1995), regulation of leukocyte recruitment (Hickey 2001), and macrophage defense mechanisms following exposure to bacterial products (Forstermann et al. 1992; Forstermann and Kleinert 1995; Knowles and Moncada 1994). Fiorucci et al. (2002) discussed the effects of nitric oxide-releasing NSAIDs. NO-donor drugs, such as sodium nitrite, sodium nitroprusside, S-nitroso-N-acetyl-D,L-penicillamine (SNAP), and 3-morpholino-sydnonimine (SIN-1), are used as vasodilators (Schror et al. 1989; Megson 2000). N-Nitro-L-arginine was described as an antagonist of endothelium-dependent dilator responses by inhibiting endothelium-derived relaxing factor release (Moore et al. 1990; Lamontagne et al. 1991). Ribero et al. (1992) proposed inhibition of nitric oxide synthesis by long-term treatment of rats with nitroL-arginine as a new model of arterial hypertension. Excessive production of NO damages DNA and activates poly(ADP-ribose)polymerase (PARP) (Pieper et al. 1999). In cases of massive NO production, neurons enter the PARP-suicide pathway. NO damages DNAvia two major pathways: the first involves nitrosation of primary or secondary amines and nucleic acid bases, whereas the second involves the combination of NO with superoxide to form peroxynitrite (Szabo 1996, Szabo et al. 1997). The most likely reactive oxidant intermediate responsible for DNA breakage is peroxynitrous acid which rapidly oxidizes sulfhydryl groups and also nitrates and hydroxylates aromatic compounds including tyrosine, tryptophan, and guanosine (Halliwell 1997). Downstream DNA damage that follows excessive NO production results in significant activation of poly(ADP-ribose)polymerase which leads to rapid energy depletion and cell death (Feihl et al. 2001). Davis et al. (2001) reviewed the non-30,50-cyclic guanosine-monophosphate-mediated effects of NO including modifications of proteins, lipids, and nucleic acids. Andreadis et al. (2003) described oxidative and nitrosative events in asthma.