The Significance of Endothelium-Derived Hyperpolarizing Factor in the Human Circulation

Abstract

Although nitric oxide (NO) is recognized as the primary vasodilator derived from vascular endothelium in regulating the vascular tone, another factor, i.e. the endothelium-derived hyperpolarizing factor (EDHF), has recently gained much attention and has been demonstrated to participate in vasodilatation in various blood vessels from different species, despite its unidentified nature. Most of the studies were conducted in animals and the knowledge of this factor in the human vasculature is relatively limited. This review attempts to address the relevance of EDHF-mediated function in humans with the possible identity of EDHF and mechanisms involved. We consider the human vasculature where EDHF involvement has been documented including the systemic, coronary, and visceral (gastrointestinal, renal and reproductive) circulation. In these vascular systems, EDHF plays a role under physiological conditions either as another mechanism or as the "back-up" for NO. Furthermore, the contribution of EDHF changes under certain physiological conditions, such as ageing and pregnancy. In addition, altered EDHF function has been suggested in various pathological conditions including heart diseases, atherosclerosis, hypertension, diabetes, eclampsia, glaucoma, chronic renal failure, erectile dysfunction and ischemia-reperfusion period during open heart surgery. Pharmacological agents such as potassium channel openers or cytochrome P450 metabolites have been used to either protect or recover EDHF-dependent mechanisms. To further develop new therapeutic strategies that target EDHF, a better understanding is essential with regard to the function of EDHF under pathophysiological conditions in humans. Furthermore, the interaction between NO and EDHF as well as their relative contributions in various conditions are critical.

Assessment of Human Skin Microcirculation and Its Endothelial Function Using Laser Doppler Flowmetry

“…It has been established that NO is involved predominantly in the control of vascular tone in larger conductance vessels, whereas in microcirculation, the role of EDHF seems to be more important (Pohl & deWit, 1999;Urakami-Harasawa et al, 1997). Most observations are based predominantly on animal studies and little is known about the impact of EDHF in humans in vivo (Yang et al, 2007). In spite of several investigations, the exact interaction of these mechanisms is still not well defined, specially not in human skin microcirculation.…”

“…The existence of endothelium-dependent, NO/PGI 2 -independent relaxations, potentially attributable to an EDHF, has been confirmed in humans in vivo. Based on studies in patients who exhibited a NO/PGI 2 -independent response to an endothelial challenge, it has been suggested that EDHF might serve as a backup vasodilator in the settings of compromised endothelial function (Fichtlscherrer et al, 2004;Fischer et al, 2007;Taddei et al, 2006;Yang, 2007). Different putative mechanisms are proposed to mediate the EDHF-mediated vasodilation:…”

Sex differences in the role of NADPH oxidases in endothelium-dependent vasorelaxation in porcine isolated coronary arteries

“…We have previously reported a clear sex difference in endothelial function, where the non-nitric oxide, noncyclooxygenase products attributed to the endothelium-derived hyperpolarization (EDH)-type response, plays a greater role in females compared to males [11,12]. The EDH-type responses play a role under physiological conditions either in health or in disease [13,14]. In cardiovascular diseases, endothelial dysfunctions have been reported, where the release of NO, one of the important endothelium-derived vasodilators is compromised [15][16][17].…”

Sex differences in the coronary vasodilation induced by 17 β‐oestradiol in the isolated perfused heart from spontaneously hypertensive rats

“…Several mechanisms contribute to the EDHF phenomenon and their contribution to vasodilatation varies depending on the species and vascular bed studied (Shimokawa et al 1996, Busse et al 2002, Yanga et al 2007) as well as on the agonist used to stimulate the endothelium (Taddei et al 2006, de Wit & Wolfle 2007, Lenasi 2009). Several mechanisms contribute to the EDHF phenomenon and their contribution to vasodilatation varies depending on the species and vascular bed studied (Shimokawa et al 1996, Busse et al 2002, Yanga et al 2007) as well as on the agonist used to stimulate the endothelium (Taddei et al 2006, de Wit & Wolfle 2007, Lenasi 2009).…”