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Latest evidence in endothelium-derived hyperpolarizing factor research.

Discovery of the Nature of Endothelium-Derived Hyperpolarizing Factor (EDHF) in Animals and Humans Endothelial cells play an essential role in the regulation of vascular structure and function. The endothelium elaborates and liberates 3 major vasodilator substances: prostacyclin (PGI2), nitric oxide (NO) and EDHF. The importance of PGI2 and NO has been widely recognized, and PGI2and NO-related therapeutic agents are already being applied in the clinical setting. The scientists who contributed to the discovery and identification of these substances were awarded the Nobel prize. On the other hand, although the existence of EDHF was proposed in 1988, advances in EDHF research have not been made until recently, because the nature of EDHF had not been identified. Although that has still not been fully elucidated, several distinct EDHFs, including epoxyeicosatrienoic acids, K+ ion, and gap junctions, have been suggested to exist, depending on species, vascular bed, and the size of the blood vessel being studied. In such a situation, Shimokawa and colleagues have identified, for the first time, that endothelium-derived hydrogen peroxide (H2O2) is an EDHF in mice (mesenteric arteries),1 pigs (coronary microvessels),2 and, most importantly, humans (mesenteric arteries).3 In agreement with these results, other groups have also reported that H2O2 is an EDHF in humans (coronary arterioles).4,5 Shimokawa’s groups have further elucidated the following important findings: (1) endotheliumderived NO mediates large conduit arteries, whereas EDHF plays an important role in modulating vascular tone in small resistance arteries;6 (2) endothelium-derived NO-mediated relaxation is easily impaired in atherosclerosis, whereas EDHFmediated relaxation is fairly resistant to atherosclerosis, contributing to the maintenance of cardiovascular homeostasis as a backup system for NO-mediated responses;7 (3) endothelial copper, zinc-superoxide dismutase (Cu,Zn-SOD) synthesizes H2O2/EDHF from superoxide anions that are produced predominantly by endothelial NO synthase (eNOS);8 and (4) not only eNOS but also neuronal (nNOS) and inducible NOS (ie, all 3 NOS isoforms) are involved in the synthesis of H2O2/ EDHF under physiological conditions.9