Endothelium-derived relaxation oxide

Endothelium-derived relaxing factor (nitric oxide)... 

The results of a number of studies demonstrate that the gas nitric oxide (NO) plays a functional role in the central nervous system. This all originated with the discovery that the so-called endothelium-derived relaxing factor (EDRF), found in blood vessels, and thought to be a peptide, was in fact NO. The potential roles of this freely diffusible gas have subsequently been extended to many other tissues and organs but we will concentrate on the possible neuronal roles of what is obviously a novel mediator. There are also suggestions that the closely related carbon monoxide may also have a function in the central nervous system. 

Not all oxidants formed biolc cally have the potential to promote lipid peroxidation. The free radicals superoxide and nitric oxide [or endothelium-derived relaxing aor (EDRF)] are known to be formed in ww but are not able to initiate the peroxidation of lipids (Moncada et tU., 1991). The protonated form of the superoxide radical, the hydroperoxy radical, is capable of initiating lipid peroxidation but its low pili of 4.5 effectively precludes a major contribution under most physiological conditions, although this has been suggested (Aikens and Dix, 1991). Interestingly, the reaction product between nitric oxide and superoxide forms the powerful oxidant peroxynitrite (Equation 2.6) at a rate that is essentially difiiision controlled (Beckman eta/., 1990 Huie and Padmaja, 1993). 

Moncada, S., Radomski, M.W. and Palmer, R.M. (1988). Endothelium-derived relaxing factor identification as nitric oxide and role in the control of vascular tone and platelet function. Biochem. Pharmacol. 37, 2495-2501. 

A relationship between polyol pathway activity and reduction in endothelium-dependent relaxation in aorta from chronic STZ-diabetic rats has recently been reported (Cameron and Cotter, 1992). In agreement with several previous studies (Oyama et al., 1986 Kamata et al., 1989), endothelial-dependent relaxation was defective in the diabetic rats but the deficit was prevented by prior treatment with an AR inhibitor. The mechanism underlying the defect has been speculated to be due to decreased production of endothelium-derived relaxing factor (EDRF) or nitric oxide, NO (Hattori et al., 1991). It has been speculated that these vascular abnormalities may lead to diminished blood flow in susceptible tissues and contribute to the development of some diabetic complications. NO is synthesized from the amino-acid L-arginine by a calcium-dependent NO synthase, which requires NADPH as a cofactor. Competition for NADPH from the polyol pathway would take place during times of sustained hyperglycaemia and... 

First described in the 1980s as "endothelium-derived relaxing factor," nitric oxide (NO) is a vasodilator believed to play a role in regulation of blood pressure under physiologic and pathophysiological conditions. For example, inhibition of NO synthesis under normal conditions and during septic shock results in a significant elevation of blood pressure. 

L.J. Ignarro, G.M. Buga, K.S. Wood, R.E. Byrns, and G. Chaudhuri, Endothelium-derived relaxing factor produced and released from artery and vein is nitric-oxide. Proc. Natl. Acad. Sci. U.S.A. 84, 9265-9269 (1987). 

T. Akaike, M. Yoshida,Y. Miyamoto, K. Sato, M. Kohno, K. Sasamoto, K. Miyazaki, S. Ueda, and H. Maeda, Antagonistic action of imidazolineoxyl N-oxides against endothelium-derived relaxing factor. NO through a radical reaction. Biochemistry 32, 827-832 (1993). 

Fig. 9.1 Nitric oxide mediated inhibition of platelet activation. Abbreviations used NO, nitric oxide EDRF, endothelium-derived relaxing factor GC, guanylyl cyclase PDE, phosphodiesterase cGMP-PK, GMP-dependent protein kinase Raplb, small GTPase Raplb ...

Palmer, R. M., Ferrige,A. G., Moncada, S., Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor, Nature 327 (1987), p. 524-526... 

Duchenne muscular dystrophy dimethyl formamide 5,5-dimethyl-1 -pyrroline-1 -oxide deoxynucleic acid diphenylene iodonium endothelium-derived relaxing factor epidermal growth factor early growth phase response gene ethyleneglycol- bis- (p- aminoethyl)-N,N,N, N -tetraacetic acid... 

S-Nitroso derivatives of the biological thiols—glutathione, cysteine (115) and homocysteine—have been considered as bioactive intermediates in the metabolism of organic nitrates and the endothelium-derived relaxing factor with properties of nitric oxide. A simple, rapid and reproducible method for separating these thiols from their... 

NO (molecular weight = 30) is small but plays a big role in physiological regulation, not least in the vasculature where its effects were first seen (see Chapter 4). Endothelium-derived relaxation factor (EDRF) was discovered its ability to cause dilatation of vessels by relaxing the arterial muscle layer. Only much later was EDRF discovered to be a gas, nitric oxide. More recent interest in NO is based on the evidence that it is antiatherogenic. The pathogenesis of atherosclerosis is complex but many of the known effects of NO can be implicated in this common and serious condition. 

Release form the endothelium of substances that relax (e.g. endothelium derived relax factor, nitric oxide) or contract (e.g. endothelium)... 

E. Thiols, Nitric Oxide, Nitrosothiols, and Endothelium-Derived Relaxing Factor... 

Myers, P. R., Minor, R. L., Jr., Guerra, R., Jr., Bates, J. N., and Harrison, D. G. (1990). Vasorelaxant properties of the endothelium-derived relaxing factor more closely resemble S-nitrosocysteine than nitric oxide. Nature (London) 345, 161-163. 

Tracey, W. R., Linden, J., Peach, M. J., and Johns, R. A. (1991). Comparison of spectro-photometric and biological assays for nitric oxide (NO) and endothelium-derived relaxing factor (EDRF) Nonspecificity of the diazotization reaction for NO and failure to detect EDRF. J. Pharmacol. Exp. Ther. 252, 922-928. 

Buga, G. M., Gold, M. E., Wood, K. S., Chaudhuri, G., and Chaudhuri, G. (1989). Endothelium-derived nitric oxide relaxes nonvascular smooth muscle. Eur. ]. Phar-macol. 161, 61-72. 

Forstermann, U., Gorsky, L. D., Pollock, J. S., Ishii, K., Schmidt, H. H. H. W., Heller, M., and Murad, F. (1990). Hormone-induced biosynthesis of endothelium-derived relaxing factor/nitric oxide-like material in NlE-115 neuroblastoma cells requires calcium and calmodulin. Mol. Pharmacol. 38, 7-13. 

Ignarro, L. J., Byrns, R. E., Buga, G. M., and Wood, K. S. (1987b). Endothelium-derived relaxing factor from pulmonary artery and vein possesses pharmacological and chemical properties that are identical to those for nitric oxide radical. Circ. Res. 61, 866-879. 

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