A single thin layer of endothelial cells comprises the innermost layer of all blood vessels from capillaries to large arteries and veins. One of the more recently discovered functions of the endothelial cell layer is that of a modulator of vascular tone. Endothelial cells are capable of responding to numerous physiological stimuli (such as circulating humoral factors, sheer stress, and so on) by producing vasoactive substances that are then released to the adjacent smooth muscle cells. Two of the most well known endothelium-derived vasoactive substances, prostacyclin (PGI2) and nitric oxide (NO), are capable of producing vasodilatation upon reaching the smooth muscle. PGI2 is one of several potential products produced by the cellular metabolism of arachidonic acid. NO is a gaseous factor produced from the conversion of L-arginine to L-citrulline by nitric oxide synthase. NO (or an NO-containing compound) was identified as endothelium-derived relaxing factor (EDRF). The physiological importance of these two vasodilatory factors was recognized by the awarding of the Nobel Prize in Physiology/Medicine in 1982 and 1998 for work leading to the discovery and physiological role for PGI2 and NO, respectively.
In the mid-1980s, it became apparent that endothelium-dependent vasorelaxation could not always be completely accounted for by the actions of PGI2 and NO. It had been known for some time that isolated arteries could be relaxed (or dilated) by factors such as acetylcholine (ACh), bradykinin (BK), and adenosine diphosphate (ADP). However, whereas the relaxation could be abolished by the removal or damaging of the endothelial layer, the relaxation was not always completely blocked by the combined inhibition of PGI2 and NO synthesis. It was further noted that the PGI2/NO-independent relaxation was associated with smooth muscle hyperpolarization. These findings prompted some investigators to conclude that an additional relaxing factor must exist; they termed it endothelium-derived hyperpolarizing factor (EDHF) .
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