The EDHF Story

Abstract

See related article, pages 1247–1255 The dilator function of the vascular endothelium is critical for optimal tissue perfusion, and this is brought into stark reality in a number of diseases, such as hypertension, diabetes, and preeclampsia, in which endothelium-dependent vasodilator function is impaired. Prostacyclin and nitric oxide (NO) were the earliest identified endothelium-dependent vasodilators, but it was soon found that in many vascular beds, particularly in resistance vessels, vasorelaxation persisted when production of these autacoids was suppressed. This residual vasorelaxation was invariably associated with hyperpolarization of the vascular smooth muscle and the entity was dubbed “endothelium-derived hyperpolarizing factor” (EDHF).1 From the outset, the identity of EDHF has been the subject of vigorous debate. Nonetheless, that the “EDHF effect” is blocked by agents that target calcium-activated K+ channels is among the few aspects of EDHF on which there is apparent consensus. There was also the debate on the significance, or otherwise, of EDHF. Is it just the poor cousin of NO, stepping into the breech when the latter is compromised, especially under conditions of enhanced oxidative stress? Then a beacon of light shone out from Japan, with the demonstration that EDHF assumed greater importance as vessel diameter decreased.2 This was a key observation, supporting the importance of EDHF in the region of the vascular system where resistance is primarily determined. This was hotly followed by the revelation that EDHF may be targeted in diseases, diabetes,3–5 hypertension,6 and apolipoprotein E-deficient mice.7 Thus, EDHF, suggested to provide vasodilation when NO was compromised, was also under attack in disease. Despite its Cinderella status, investigation into the nature of EDHF has continued with breakneck intensity, with the conviction that …