Novel endothelium-derived relaxing factors. Identification of factors and cellular targets.
Nitric oxide (NO), together with prostacyclin (PGI2), mediates shear stress and endothelium-dependent vasodilator-mediated vasorelaxation. In the presence of inhibition of NO synthase (NOS) with nitroarginine analogues, such 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 synthesis of PGI2, many blood vessels still respond with an endothelium-dependent relaxation to either chemical [i.e. acetylcholine (ACh)] or mechanical (shear stress) activation. This non-NO and non-PGI2 vasorelaxation appears to be mediated by hyperpolarization of the vascular smooth muscle cell (VSMC). Although NO can hyperpolarize VSMC, a novel mediator, the endothelium-derived hyperpolarizing factor (EDHF), which opens a VSMC K(+) channel(s) notably in resistance vessels, has been proposed. Little agreement exists as to the nature of this putative factor, but several candidate molecules have been proposed and evidence, notably from the microcirculation, suggests that endothelium-dependent hyperpolarization (EDH) may be mediated via low electrical resistance coupling via 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.
Ding
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Department of Pharmacology and Therapeutics and the Smooth Muscle Research Group, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada. hding@ucalgary.ca
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D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001685:Biological Factors / Q000502:physiology*; D004730:Endothelium, Vascular / Q000502:physiology*; D011464:Epoprostenol / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000502:physiology; D011188:Potassium / Q000378:metabolism*
D001685:Biological Factors; C067410:endothelium-dependent hyperpolarization factor; D016718:Arachidonic Acid; D009569:Nitric Oxide; D011464:Epoprostenol; D011188:Potassium