Flow activates an endothelial potassium channel to release an endogenous nitrovasodilator.
Flow-mediated vasodilation is endothelium dependent. We hypothesized that flow activates a potassium channel on the endothelium, and that activation of this channel leads to the release of the endogenous nitrovasodilator, nitric oxide. To test this hypothesis, rabbit iliac arteries were perfused at varying flow rates, at a constant pressure of 60 mm Hg. Increments in flow induced proportional increases in vessel diameter, which were abolished by L,N-mono-methylarginine (the antagonist of nitric-oxide synthesis). Barium chloride, depolarizing solutions of potassium, verapamil, calcium-free medium, and antagonists of the KCa channel (charybdotoxin, iberiotoxin) also blocked flow-mediated vasodilation. Conversely, responses to other agonists of endothelium-dependent and independent vasodilation were unaffected by charybdotoxin or iberiotoxin. To confirm that flow activated a specific potassium channel to induce the release of nitric oxide, endothelial cells cultured on micro-carrier beads were added to a flow chamber containing a vascular ring without endothelium. Flow-stimulated endothelial cells released a diffusible vasodilator; the degree of vasorelaxation was dependent upon the flow rate. Relaxation was abrogated by barium, tetraethylammonium ion, or charybdotoxin, but was not affected by apamin, glybenclamide, tetrodotoxin, or ouabain. The data suggest that transmission of a hyperpolarizing current from endothelium to the vascular smooth muscle is not necessary for flow-mediated vasodilation. Flow activates a potassium channel (possibly the KCa channel) on the endothelial cell membrane that leads to the release of nitric oxide.
Cooke
J P
JP
Division of Cardiovascular Medicine, Stanford University School of Medicine, California 94305.
Rossitch
E
E
Andon
N A
NA
Loscalzo
J
J
Dzau
V J
VJ
D000818:Animals; D018999:Charybdotoxin; D004730:Endothelium, Vascular / Q000502:physiology*; D005260:Female; D066298:In Vitro Techniques; D009569:Nitric Oxide / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology*; D011817:Rabbits; D012039:Regional Blood Flow; D012604:Scorpion Venoms / Q000494:pharmacology; D014664:Vasodilation; D014665:Vasodilator Agents / Q000378:metabolism*; D014700:Verapamil / Q000494:pharmacology
D015221:Potassium Channels; D012604:Scorpion Venoms; D014665:Vasodilator Agents; D018999:Charybdotoxin; D009569:Nitric Oxide; D014700:Verapamil; D009638:Norepinephrine