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Acetylcholine\u2010evoked NO release was reduced by 68% in high K<jats:sup>+<\/jats:sup> (80\u2003mM) and by 85% in the presence of apamin plus charybdotoxin. In noradrenaline\u2010contracted arteries, asymmetric dimethylarginine (ADMA), an inhibitor of NO synthase inhibited acetylcholine\u2010evoked NO release and relaxation. However, only further addition of oxyhaemoglobin or apamin plus charybdotoxin eliminated the residual acetylcholine\u2010evoked NO release and relaxation. Removal of extracellular calcium or an inhibitor of calcium influx channels, SKF96365, abolished acetylcholine\u2010evoked increase in NO concentration and [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>. Cyclopiazonic acid (CPA, 30\u2003\u03bcM), an inhibitor of sarcoplasmic Ca<jats:sup>2+<\/jats:sup>\u2010ATPase, caused a sustained NO release in the presence, but only a transient increase in the absence, of extracellular calcium. Incubation with apamin and charybdotoxin did not change acetylcholine or CPA\u2010induced increases in [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>, but inhibited the sustained NO release induced by CPA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications:<\/jats:title><jats:p>Acetylcholine increases endothelial cell [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> by release of stored calcium and calcium influx resulting in activation of apamin and charybdotoxin\u2010sensitive K channels, hyperpolarization and release of NO in the rat superior mesenteric artery.<\/jats:p><jats:p><jats:italic>British Journal of Pharmacology<\/jats:italic> (2006) <jats:bold>149<\/jats:bold>, 560\u2013572. doi:<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" 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