as an EDHF in some vascular beds; although the validity of this observation is debated because it may have an inhibitory action on K+ channels, at least, in some vascular beds. It has been suggested that EDHF is potassium ions (K+), as the activation of endothelial K-Ca+ channels causes an efflux of K+ from endothelial cells toward the extracellular space. An increase in extracellular K+ has been shown to activate an ouabain-sensitive electrogenic Na+–K+-ATPase followed by hyperpolarization and smooth muscle cell relaxation. However, the involvement of K+ ions in EDHF-mediated relaxation does not necessarily involve the activation Na+–K+-ATPase channels. It is more likely that K+ ions and gap junctions can be involved in EDHF-mediated relaxation simultaneously, and may also act synergistically. Subsequently, it was suggested that EDHF is a sulfur signal that results in activation of K channels via sulfhydration of a cysteine residue (formation of a cysteine persulfide) (https://doi.org/10.1161/CIRCRESAHA.111.240242) C-type natriuretic peptide (CNP) has been shown to exert a variety of cardiovascular effects including vasodilation and hyperpolarization of arteries through the opening of KCa+-channels. CNP is widely distributed in the cardiovascular system and it has been found at high concentrations, in particular in endothelial cells. Endothelium-derived CNP has been proposed to act as an EDHF via specific C-subtype of natriuretic peptide receptor, however the evidence in favour of CNP's acting as EDHF has yet to be determined. An alternative explanation for the EDHF phenomenon is that direct intercellular communication via gap junctions allows passive spread of agonist-induced endothelial hyperpolarization through the vessel wall. In some arteries, eicosanoids and K+ ions may themselves initiate a conducted endothelial hyperpolarization, thus suggesting that electrotonic signalling may represent a general mechanism through which the endothelium participates in the regulation of vascular tone. EDHF and Hypertension Recently, EDHF has been implicated in gender-related differences in blood pressure control. The generation of animals that lack both endothelial nitric oxide synthase (eNOS) and COX-1 (Cyclooxygenase-1, a protein that acts as an enzyme to speed up the production of certain chemical messengers), has allowed a direct assessment of the involvement of EDHF to endothelium-dependent relaxation in small arteries. In mice lacking both eNOS and COX-1, EDHF-mediated response appeared to compensate the absence of endothelial NO in females but not in males. In female mice, the deletion of eNOS and COX-1 did not affect mean arterial blood pressure, while males become hypertensive In accordance with this study, EDHF