Endothelium-Derived Relaxing Factor (EDRF)
Recent investigations have greatly improved our understanding of the chemical nature of endothelium-derived relaxing factor (EDRF) and the regulation and metabolic pathway of its production. EDRF is a potent but labile relaxing factor with a biologic half-life of between 6.3 and 50 seconds in an oxygenated aqueous medium.1,2 The production of EDRF from the endothelium requires an increase in intracellular calcium.3,6 Following its production and release from the endothelial cell, EDRF is transferred to the vascular smooth muscle (VSM) where it activates soluble guanylate cyclase resulting in an increase in smooth muscle cyclic GMP concentration, which correlates with its relaxing action.7–13 Extremes of both high and low oxygen tension inhibit the production or stability of EDRF.14–15 Early investigations into the chemical nature of EDRF implicated an unstable, non-prostanoid oxidation product of arachidonic acid or some type of free radical.1,16–18 A great deal of recent evidence, however, suggests that EDRF is nitric oxide or a similar nitrogen oxide species.19–29 EDRF can be formed from L-arginine by a pathway involving a calcium-, calmodulin-and NADPH-dependent enzyme.30–39 EDRF synthesis has now been described in a wide range of cell types in addition to the endothelium, and indeed EDRF may be the second messenger responsible for the activation of guanylate cyclase in most cells containing the enzyme.34,35,38–43 This manuscript will present data from our laboratory which support these and other pharmacologic characteristics of EDRF.
KeywordsNitric Oxide Sodium Nitroprusside Soluble Guanylate Cyclase Branch Pulmonary Artery Microcarrier Bead
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- 5.N. J. Izzo, A. L. Loeb, R. A. Johns and M. J. Peach, Intracellular calcium flux accompanies the release of endothelium-derived relaxing factor (EDRF) and prostacyclin (PGI2) from cultured endothelial cells, Fed Proc 45:198 (1986).Google Scholar
- 8.R. Rapoport and F. Murad, Endothelium-dependent and nitrovasodilator-induced relaxation of vascular smooth muscle, role of cyclic GMP, J Cyclic Nucleotide Prot Phos Res 9:281–296 (1983).Google Scholar
- 9.R. Furchgott and D. Jothianandan, Relation of cyclic GMP levels to endothelium-dependent relaxation by acetylcholine in rabbit aorta, Fed Proc 42:619 (1983).Google Scholar
- 13.A. L. Loeb, R. A. Johns, P. Milner and M. J. Peach, Studies on endothelium-derived relaxing factor from cultured cells, Hypertension 9(Suppl III):186–192 (1987).Google Scholar
- 15.J. G. DeMey and P. M. Vanhoutte, Anoxia and endothelium-dependent reactivity of the canine femoral artery, J Physiol (Lond) 335:65–74 (1983).Google Scholar
- 26.L. J. Ignarro, R. E. Byrns, G. M. Buga, K. S. Wood and G. Chaudhuri, Pharmacological evidence that endothelium-derived relaxing factor is nitric oxide: use of pyrogallol and Superoxide dismutase to study endothelium-dependent and nitric oxide-elicited vascular smooth muscle relaxation, J Pharmacol Exp Ther 244:181–189 (1988).PubMedGoogle Scholar
- 27.L. J. Ignarro, M. E. Gold, G. M. Buga, R. E. Byrns, K. S. Wood, G. Chaudhuri and G. Frank, Basic polyamino acids rich in arginine, lysine, or ornithine cause both enhancement of and refractoriness to formation of endothelium-derived nitric oxide in pulmonary artery and vein, Circ Res 64:315–329 (1989).PubMedGoogle Scholar
- 31.B. Mayer, K. Schmidt, P. Humbert and E. Bohme, Biosynthesis of endothelium-derived relaxing factor: A cytosolic enzyme in porcine aortic endothelial cells Ca++-dependently converts L-arginine into an activator of soluble guanylal cyclase, Biochem Biophys Res Comm 164:678–685 (1989).PubMedCrossRefGoogle Scholar
- 36.A. Mulsch, E. Bassenge and R. Busse, Nitric oxide synthesis in endothelial cytosol: Evidence for a calcium-dependent and a calcium-independent mechanism, Naunyn-Schmiedeberg’s Arch Pharmacol 340:767–770 (1989).Google Scholar
- 40.U. Forstermann, K. Ishii, L. D. Gorsky and F. Murad, The cytosol of N1E-115 neuroblastoma cells synthesizes an EDRF-like substance that relaxes rabbit aorta, Naunyn-Schmiedeberg’s Arch Pharmacol 340:771–774 (1989).Google Scholar
- 44.R. A. Johns, M. J. Peach, J. M. Linden and A. Tichotsky, NG-monomethyl-L-arginine causes specific, dose-dependent inhibition of cyclic GMP accumulation in cocultures of bovine pulmonary endothelium and rat vascular smooth muscle through an action specific to the endothelium, Circ Res 67:979–985 (1990).PubMedGoogle Scholar