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Upon inhibition of the Na,K\u2010ATPase with ouabain, cSrc activation is shown to occur in many cell types. This study tests the hypothesis that acute potentiation of agonist\u2010induced contraction by ouabain is mediated through Na,K\u2010ATPase\u2010cSrc signalling\u2010dependent sensitization of vascular smooth muscle cells to Ca<jats:sup>2+<\/jats:sup>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Agonist\u2010induced rat mesenteric small artery contraction was examined in vitro under isometric conditions and in vivo in anaesthetized rats. Arterial wall tension and [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> in vascular smooth muscle cells were measured simultaneously. Changes in cSrc and myosin phosphatase targeting protein 1 (MYPT1) phosphorylation were analysed by Western blot. Protein expression was examined with immunohistochemistry. The \u03b11 and \u03b12 isoforms of the Na,K\u2010ATPase were transiently downregulated by siRNA transfection in vivo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Ten micromolar ouabain, but not digoxin, potentiated contraction to noradrenaline. This effect was not endothelium\u2010dependent. Ouabain sensitized smooth muscle cells to Ca<jats:sup>2+<\/jats:sup>, and this was associated with increased phosphorylation of cSrc and MYPT1. Inhibition of tyrosine kinase by genistein, PP2 or pNaKtide abolished the potentiating effect of ouabain on arterial contraction and Ca<jats:sup>2+<\/jats:sup> sensitization. Downregulation of the Na,K\u2010ATPase \u03b12 isoform made arterial contraction insensitive to ouabain and tyrosine kinase inhibition.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Data suggest that micromolar ouabain potentiates agonist\u2010induced contraction of rat mesenteric small artery via Na,K\u2010ATPase\u2010dependent cSrc activation, which increases Ca<jats:sup>2+<\/jats:sup> sensitization of vascular smooth muscle cells by MYPT1 phosphorylation. This mechanism may be critical for acute control of vascular tone.<\/jats:p><\/jats:sec>","DOI":"10.1111\/apha.13059","type":"journal-article","created":{"date-parts":[[2018,2,26]],"date-time":"2018-02-26T16:11:33Z","timestamp":1519661493000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["The \u03b12 isoform Na,K\u2010ATPase modulates contraction of rat mesenteric small artery via cSrc\u2010dependent Ca<sup>2+<\/sup> sensitization"],"prefix":"10.1111","volume":"224","author":[{"given":"E. 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