ENDOTHELIUM-DEPENDENT REGULATION OF CEREBROVASCULAR TONE BY EXTRACELLULAR AND INTRACELLULAR ATP

ATP receptors and ATP-sensitive potassium channels (K-ATP) are express ed in vascular smooth muscle (VSM) and endothelial cells (EC). In isol ated penetrating vessels, ATP caused a dilatation when applied intralu minally but not extraluminally. The actions of ATP were blocked by the nitric oxide (NO) synthesis inhibitor N-omega-nitro-L-arginine (0.1 m u M) but were only reduced by N-monomethyl-L-arginine (0.1 mM); respon ses to intraluminal ATP were also prevented by thapsigargin. The K-ATP Opener (KCO) nicorandil (1 mu M) caused an NO-independent vasodilatat ion when applied extraluminally and an NO-dependent response when appl ied intraluminally. Both responses were blocked by glibenclamide. EC-m ediated responses to nicorandil were prevented by blockade of guanylat e cyclase by LY-83583 (10 mu M). The effects of nicorandil were mimick ed by pinacidil (1-10 mu M). Exposure of the endothelium to 500 mu M c yanide and 0 mM glucose (''in vitro ischemia'') caused a vasodilatatio n that was reduced by exposure to glibenclamide (5 mu M). Blockade of NO synthase produced similar effects, suggesting that the ischemic dil ation is mediated by K-ATP and NO. Our results suggest that both VSM a nd EC mediate the vascular responses induced by KCOs, whereas the dila tation induced by intraluminal ATP is mediated by the endothelium. The endothelium-dependent component of the in vitro ischemic vasodilatati on is mediated by opening of endothelial K-ATP and subsequent release of NO.