Relaxing factor, endothelial-derived

Chin, J.H., Azhar, S. and Hoffman, B.B. (1992). Inactivation of endothelial derived relaxing factor by oxidized lipoproteins. 

A. Wennmalm, B. Lanne, and A.S. Petersson, Detection of endothelial-derived relaxing factor in human plasma in die basal state and following ischemia using electron-paramagnetic resonance spectrometry. Anal. Biochem. 187, 359-363 (1990). 

The second indication came from studies of vascular regulation. Several molecules, such as acetylcholine, were known to cause relaxation of blood vessels. This effect occurred only when the vessels were prepared so that the luminal endothelial cells covering the smooth muscle of the vessel wall were retained. Subsequent studies showed that endothelial cells respond to these vasorelaxants by releasing a soluble endothelial-derived relaxing factor (EDRF). EDRF acts on vascular muscle to elicit relaxation. These findings prompted an intense search for the identity of EDRF. 

Nitric oxide, a precursor of nitrogen dioxide, occurs naturally in the human body, where it acts as endothelial derived relaxing factor (EDRF), a neurotransmitter, and in unidentified ways in the nose, sinuses, and lower airways. Up to 15 ppm can be found normally in the nose and sinuses (DuBois et al. 1998). The substrate is 1-arginine, and the enzymes consist of different forms of nitric oxide synthase, which turn arginine into citrulline. Inhaled nitric oxide gas is used at concentrations of up to 50 ppm to decrease pulmonary arterial pressure. Nitric oxide reacts in tissues to form nitrites and nitrates. 

Endothelial-derived relaxing factor (EDRF) a small, diffusible molecule that is released by the vascular endothehal cell and diffuses to the overlying smooth muscle cell, where it induces relaxation and resulting vasodilation. EDRF is either NO alone or a bound form of -NO... 

BH4 = Tetrahydrobiopterin CAM = Cytotoxic activated macrophage cNOS = Constitutive nitric oxide synthase CPR = Cytochrome P450 reductase EDRF = Endothelial-derived relaxation factor EPR = Electron paramagnetic resonance spectroscopy IL-1 = Interleukin-1 iNOS = Inducible nitric oxide synthase EPS = Lipopolysaccharide, or endotoxin NMMA = ISp-monomethyl-L-arginine NOS = Nitric oxide synthase ROS = Reactive oxygen species SOD = Superoxide dismutase TNF = Tumor necrosis factor. 

Endothelial-derived relaxing factor (EDRF) (e.g., nitric oxide) and the atrial natriuretic factor(s) increase [cGMP] in smooth muscle. They relax arterial smooth muscle by three mechanisms decreasing [Ca +Jj, decreasing the [Ca2+]i sensitivity of phosphorylation, and uncoupling force from myosin phosphorylation (the latter two are pharmacomechanical mechanisms ... 

TABLE I Properties of Endothelial-Derived Relaxing Factor and Nitric Oxide... 

Pinacidil is three- and tenfold more potent than hydralazine and minoxidil, respectively. It does not interact with alpha, beta, cholinergic, or histaminergic receptors, and also does not produce vasodilation via an indirect effect that is mediated by adenosine, prostaglandin, or endothelial-derived relaxant factor. Its vasodilating activity does not resemble that brought about by the conventional calcium-channel antagonists. Thus, pinacidil-induced vascular relaxation is a direct effect mediated by a novel mechanism. 

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