Endothelium-derived mediators, release

A. Influence of PO2 on Signaling Mechanisms Regulating the Release of Endothelium-Derived Mediators... 

Flow-dependent changes in vessel diameter contribute to the optimization of circulatory function and are mediated via shear stress-induced release of NO, vasodilator prostanoids, and a putative endothelium-derived hyperpolarization factor or EDHF (Griffith, 2002). There is growing evidence that NO/prostanoid-independent relaxations involve direct hetero-cellular signaling between endothelium and smooth muscle cells via gap junctions. 

The first demonstration of the chemical existence of free radicals had been made with the isolation of the nitroxyl radical in the form of Fremy s salt (KS03)2N0 in 1845 [5], Surprisingly, it was only in 1987 that nitric oxide release was shown to be associated with the production of an endothelium-derived relaxing factor (EDRF) which is biosynthesized from arginine and released by the vascular system of mammals [6,7]. Nitric oxide has since been shown to serve as a cytotoxic mediator of macrophages against tumor cells, yeasts, mycobacteria and parasites, and it is actually secreted by a variety of mammalian cells [8,9],... 

A number of factors, including tissue damage, allergic reactions, viral infections, and other inflammatory events, activate a series of proteolytic reactions that generate bradykinin and kallidin in tissues. These peptides contribute to inflammatory responses as autacoids that act locally to produce pain, vasodilation, and increased vascular permeability. Much of their activity is due to stimulation of the release of potent mediators such as prostaglandins, NO, or endothelium-derived hyperpolarizing factor (EDHF). 

Anandamide has been shown to act via the release of endothelium-derived nitric oxide in the rat kidney (Dentsch et al., 1997). A range of human blood vessels and the right atrium have also been shown to release nitric oxide in response to anandamide (Bilfinger et al., 1998). However, in many instances (see Randall etal., 1996 White and Ehley, 1997 Jarai etal., 1999), vasorelaxant responses to anandamide are insensitive to inhibition of nitric oxide synthase. In HUVECs, Maccarrone et al. (2000) reported that anandamide and the CB agonist, HU210, both cause an upregulation of the expression and activity of the inducible nitric oxide synthase. Mukhopadhyay et al. (2002) demonstrated that the endothelium-dependent component was G protein coupled and mediated via nitric oxide, whereas the endothehum-independent component was due to activation of vanilloid receptors, at least in rabbit aortic rings. 

Endothelin-1 is a potent vasoconstrictor peptide derived from endothelial cells.100 Its physiological function is mediated by two receptors the ET-A and ET-B. Table 1. Figure 11. ET-A and ET-B receptors are located in vascular smooth muscle and their activation causes vasoconstriction, whereas ET-B receptor is also located in the endothelium and its activation results in vasodilation by increasing nitric oxide or prostacyclin. Endothelin is released following myocardial ischemia and reperfusion. Endothelin reduces infarct size in a perfused rat heart model of ischemia and reperfusion through activation of protein kinase C and KATp channel.101 Furthermore, in neonatal rat ventricular myocytes, endothelin is shown to activate the calcineurin-NFAT (nuclear factor of activated cells) pathways and enhance the expression of Bcl-2.102 However, endogenous blockade of endothelin at the level of the ET-A receptor reduced infarct size in a pig model of coronary occlusion and reperfusion.103... 

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