EDHF: an update.
The endothelium controls vascular tone not only by releasing NO and prostacyclin, but also by other pathways causing hyperpolarization of the underlying smooth muscle cells. This characteristic was at the origin of the term 'endothelium-derived hyperpolarizing factor' (EDHF). However, this acronym includes different mechanisms. Arachidonic acid metabolites derived from the cyclo-oxygenases, lipoxygenases and cytochrome P450 pathways, H(2)O(2), CO, H(2)S and various peptides can be released by endothelial cells. These factors activate different families of K(+) channels and hyperpolarization of the vascular smooth muscle cells contribute to the mechanisms leading to their relaxation. Additionally, another pathway associated with the hyperpolarization of both endothelial and vascular smooth muscle cells contributes also to endothelium-dependent relaxations (EDHF-mediated responses). These responses involve an increase in the intracellular Ca(2+) concentration of the endothelial cells, followed by the opening of SK(Ca) and IK(Ca) channels (small and intermediate conductance Ca(2+)-activated K(+) channels respectively). These channels have a distinct subcellular distribution: SK(Ca) are widely distributed over the plasma membrane, whereas IK(Ca) are preferentially expressed in the endothelial projections toward the smooth muscle cells. Following SK(Ca) activation, smooth muscle hyperpolarization is preferentially evoked by electrical coupling through myoendothelial gap junctions, whereas, following IK(Ca) activation, K(+) efflux can activate smooth muscle Kir2.1 and/or Na(+)/K(+)-ATPase. EDHF-mediated responses are altered by aging and various pathologies. Therapeutic interventions can restore these responses, suggesting that the improvement in the EDHF pathway contributes to their beneficial effect. A better characterization of EDHF-mediated responses should allow the determination of whether or not new drugable targets can be identified for the treatment of cardiovascular diseases.
Félétou
Michel
M
Department of Angiology, Institut de Recherches Servier, Suresnes, France. michel.feletou@fr.netgrs.com
Vanhoutte
Paul M
PM
D016718:Arachidonic Acid / Q000378:metabolism; D001685:Biological Factors / Q000502:physiology*; D002318:Cardiovascular Diseases / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000502:physiology* / Q000503:physiopathology; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000502:physiology
D001685:Biological Factors; C067410:endothelium-dependent hyperpolarization factor; D016718:Arachidonic Acid