Nitric-oxide synthases oxidation states

Figure 19.17 The biochemistiy and physiology responsible for penile erection. Sexual activity itself begins with a state of arousal that leads to erection. Arousal results in part from stimulation of the sense organs. The hypothalamus coordinates the sensations and activates the autonomic nervous system. Sensory nerves from the skin of the penis and other erogenous zones stimulate the parasympathetic system. This activates nitric oxide synthase and the resultant nitric oxide, via cyclic GMP, causes vasodilation of the arterioles. This increases blood flow through the corpora cavernosa which then expands producing an erection. Pheromones secreted by the female can stimulate the odour detecting system in the nasal cavity of the male (Chapter 12 and see above). Stress, however, activates the sympathetic system releases cyclic AMP which can result in vasoconstriction of the arterioles. Other factors that can interfere with an erection are physical fatigue and alcohol.

Many pathological conditions, including ischemia/reperfusion, inflammation, and sepsis may induce tissues to simultaneously produce both superoxide and nitric oxide. For example, ischemia allows intracellular calcium to accumulate in endothelium (Fig. 20). If the tissue is reperfused, the readmission of oxygen will allow nitric oxide as well as superoxide to be produced (Beckman, 1990). For each 10-fold increase in the concentration of nitric oxide and superoxide, the rate of peroxynitrite formation will increase by 100-fold. Sepsis causes the induction of a second nitric oxide synthase in many tissues, which can produce a thousand times more nitric oxide than the normal levels of the constitutive enzyme (Moncada et al., 1991). Nitric oxide and indirectly peroxynitrite have been implicated in several important disease states. Blockade of nitric oxide synthesis with N-methyl or N-nitroarginine reduces glutamate-induced neuronal degeneration in primary cortical cultures (Dawson et al., 1991). Nitroarginine also decreases cortical infarct volume by 70% in mice subjected to middle cerebral artery occlusion (Nowicki et al., 1991). Myocardial injury from a combined hy-... 

Wolthers, Kirsten R., Schimerlik, Michael I. (2002) Neuronal nitric oxide synthase substrate and solvent kinetic isotope effects on the steady-state kinetic parameters for the reduction of 2, 6-dichloroindophenol and cytochrome C3+, Biochemistry 41, 196-204. 

Kaneda K, Makita K, Yokoyama K. Toyooka H and Amaha K. Detrimental effect of a non-selective nitric oxide synthase inhibitor on the energy state of the liver following acute endotoxemia in rabbits. 1998. 

NITRERGIC STIMULANTS mimic, or cause the production and release of nitric oxide (NO), which is an important mediator that is synthesized on demand. The actions of nitric oxide are very widespread, and imbalance is likely to be involved in a number of disease states. Nitric oxide synthase (NOS) has a widespread distribution in the body, and isoforms are recognized specifically constitutive and inducible (iNOS) forms. Both forms are cytosolic, Ca /calmodulin and NADPH-dependent, and inhibited by L-arginine derivatives. Induction of iNOS is by various inflammatory cytokines, particularly those stimulated by bacterial lipopolysaccarides, including tumour necrosis factor a. interferon 7 and interleukin 1 p. Induction of iNOS only is inhibited by GLUCOCORTICOIDS. 

It should be noted that agents other than catecholamines have been used as inotropes and vasopressors in shock states. These include phosphodiesterase 111 inhibitors, naloxone, nitric oxide synthase inhibitors, calcium sensitizers, and vasopressin. However, the focus of this chapter is on catecholamines. 

Chronic inflammatory states associated with infection or xenobiotic chemical exposure from the environment can produce genomic lesions that, in time, can become initiated tumors. It is known that hosts do fight microbial infections by moderate production of various free radicals reactive oxygen species (ROS) [e.g., hydroxyl radical (OH ) and the superoxide radical (OT)] or reactive nitrogen species (RNS) [e.g., nitric oxide (NO ) and the strong oxidant, peroxynitrite (ONOO )]. Within limits inflammatory signaling pathways of the host can control excessive free radical concentrations by means of enzymes such as NADPH oxidase, myeloperoxidase, nitric oxide synthase, and others (Federico et al. 2007 Rakoff-Nahonm 2006). 

Increased cytokine production may also play a role in silica-induced autoimmune vascular disease. Adhesion molecule expression is elevated on vascular endothelial cells in response to TNF-a and IL-1. Adhesion molecules such as endothelial leukocyte adhesion molecule-1 (ELAM-1) and intercellular adhesion molecule-1 (ICAM-1) recruit inflammatory cells to specific sites on the vascular endothelium, and it has been hypothesized that vascular pathology following silica exposure may be the result of this interaction (Nowack et al., 1998). IFN-y is expressed at elevated levels by lymphocytes in silicotic thoracic lymph nodes and may be responsible for the long-lasting inducible nitric oxide synthase (iNOS) expression in these tissues (Friedetzky et al., 2002). The increase in IFN-y may also cause a shift towards a dominant Thl response, contributing to the maintenance of a chronic inflammatory state in silica-containing lymph nodes (Gam et al., 2000). 

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