Novel endothelium-derived relaxing factors - Identification of factors andcellular targets

Nitric oxide (NO), together with prostacyclin (PGI(2)), mediates shear stre ss and endothelium-dependent vasodilator-mediated vasorelaxation. In the pr esence of inhibition of NO synthase (NOS) with nitroarginine analogues. suc h as of N-W-nitro-L-arginine methyl ester (L-NAME) and N-W-nitro-L-arginine (L-NNA), and indomethacin, to inhibit cyclooxygenase (COX) and the synthes is of PGI(2), many blood vessels still respond with an endothelium-dependen t relaxation to either chemical [i.e. acetylcholine (ACh)] or mechanical (s hear stress) activation. This non-NO and non-PGI(2) vasorelaxation appears to be mediated by hyperpolarization of the vascular smooth muscle cell (VSM C). Although NO can hyperpolarize VSMC, a novel mediator, the endothelium-d erived hyperpolarizing factor (EDHF), which opens a VSMC K+ channel(s) nota bly in resistance vessels, has been proposed. Little agreement exists as to the nature of this putative factor. but several candidate molecules have b een proposed and evidence. notably from the microcirculation, suggests that endothelium-dependent hyperpolarization (EDH) may be mediated via low elec trical resistance coupling ria myoendothelial gap junctions. We describe a number of techniques that are being used to identify EDHF and present data that address the contribution of a small increase in extracellular K+ as an EDHF. (C) 2001 Elsevier Science Inc. All rights reserved.