EDRF

Three years later Robert F Furchgott discov ered that the relaxing of smooth muscles such as blood vessel walls was stimulated by an unknown substance produced in the lining of the blood vessels (the endothelium) He called this substance the endothelium-dependent relaxing factor or EDRF and in 1986 showed that EDRF was NO Louis J Ignarro reached the same conclusion at about the same time Further support was provided by Salvador Moncada who showed that endothelial cells did in deed produce NO and that the l arginine to l citrulline conversion was responsible... 

Receptors linked to guanylyl cyclase and which catalyze the formation of guanosine triphosphate (GMP) to guanosine-3A -cychc monophosphate (cychc GMP) include those for atrial natriuretic factor (ANF) and endothehal-derived relaxing factor (EDRF), mediating vasodilatation, and nitric oxide [10102 3-9], NO, or a clearly related derivative. 

Vasodilators dilate or relax the smooth muscles of the vasculatures directly or iadirecfly by releasiag endogenous vasodepressors or antagoni2iag the endogenous vasopressors or vasopressor systems (200,243,244). Vasodilators may iaterfere with the entry, iatraceUular release, and utili2ation of calcium, the activation of the proteia kinase C system, cGMP formation, and EDRF turnover. 

Vasodilating molecule(s) liberated from vascular endothelial cells in response to chemical substances (i.e., Acetylcholine, bradykinin, substance P, etc.) or mechanical stimuli (i.e., shear stress, transmural pressure, etc.). The EDRF includes NO, prostaglandin J2 (prostacyclin), and endothelium-derived hypeipolarizing factor (EDHF). 

Furchgott and Zawadzki [1] first discovered that endothelial cells release a substance(s) responsible for the relaxation of vascular smooth muscle by acetylcholine this substance was named endothelium-derived relaxing factor (EDRF). This epoch-making discovery answers the question raised for nearly one hundred years by pharmacologists about why vascular smooth muscle is relaxed by acetylcholine, which however elicits contraction of the other smooth muscles. Because of its instability, the true chemical nature of EDRF was not easily identified. Several years later, several research groups independently found that the biological activities and biochemical properties of EDRF were identical... 

Quite unexpectedly, EDRF was found to be the gas nitric oxide (NO). NO is formed by the action of the enzyme NO synthase, which is cytosolic. The endothe-hal and neuronal forms of NO synthase are activated by Ca + (Table 49-8). The substrate is arginine, and the products are citmUine and NO ... 

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). 

Iwata, F., Joh, T., Kawai, T., Kasugai, K., Itoh, M. and Takeuchi, T. (1992). Role of endogenous EDRF in ischaemia-reperfiision injury of rat gastric mucosa. Gastroenterology 102, A89. 

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... 

Langensttoer, P. and Pieper, G.M. (1992). R ulation of spontaneous EDRF release in diabetic rat aorta by ox) n fire radicals. Am. J. Physiol. 262, H257-H265. 

Bassenge, E. (1992). Clinical relevance of endothelium-derived relaxing fiictor (EDRF). Br. J. Clin. Pharmacol. 34, 37S-42S. 

ED35 Eflective dose producing 35% maximum response EDso Effective dose producing 50% maximum response EDF Eosinophil differentiation 6ctor EDL Extensor digitorum longus EDN Eosinophil-derived neurotoxin EDRF Endothelium-derived relaxing factor... 

P2Y receptors that are found on endothelial cells elicit a Ca2+-dependent release of endothelium-dependent relaxing factor (EDRF) and vasodilation. A secondary activation of a Ca2+-sensitive phospholipase A2 increases the synthesis of endothelial prostacyclin, which limits the extent of intravascular platelet aggregation following vascular damage and platelet stimulation. The P2Y-mediated vasodilation opposes a vasoconstriction evoked by P2X receptors located on vascular smooth muscle cells. The latter elicit an endothelial-independent excitation (i.e. constriction). P2Y receptors are also found on adrenal chromaffin cells and platelets, where they modulate catecholamine release and aggregation respectively. 

EDRF endothelium-derived relaxing factor GPDH glycerol phosphate dehydrogenase... 

All are explosive but require detonation and their explosive nature has not restricted their use in medicine. GTN was used in the early experiments to identify the EDRF as NO. Also, it was probably the vasodilator action of GTN which first suggested that NO could be the endogenous EDRF [55]. As GTN requires metabolism to convert it into NO it was fortunate that this occurred within the tissue used for the seminal, ex vivo experiments. 

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 ...

---