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Therefore, we evaluated the participation of Panx\u20101\u2010formed channels in the control of membrane potential and [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> of endothelial cells. Changes in NO\u2010mediated vasodilation, membrane potential, superoxide anion (O<jats:sub>2<\/jats:sub><jats:sup>\u22c5\u2013<\/jats:sup>) formation, and endothelial cell [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> were analyzed in rat isolated mesenteric arterial beds and primary cultures of mesenteric endothelial cells. Inhibition of Panx\u20101 channels with probenecid (1\u2009mM) or the Panx\u20101 blocking peptide <jats:sup>10<\/jats:sup>Panx (60\u2009<jats:italic>\u03bc<\/jats:italic>M) evoked an increase in the ACh (100\u2009nM)\u2010induced vasodilation of KCl\u2010contracted mesenteries and in the phosphorylation level of endothelial NO synthase (eNOS) at serine 1177 (P\u2010eNOS<jats:sup>S1177<\/jats:sup>) and Akt at serine 473 (P\u2010Akt<jats:sup>S473<\/jats:sup>). In addition, probenecid or <jats:sup>10<\/jats:sup>Panx application activated a rapid, tetrodotoxin (TTX, 300\u2009nM)\u2010sensitive, membrane potential depolarization and [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> increase in endothelial cells. Interestingly, the endothelial cell depolarization was converted into a transient spike after removing Ca<jats:sup>2+<\/jats:sup> ions from the buffer solution and in the presence of 100\u2009<jats:italic>\u03bc<\/jats:italic>M mibefradil or 10\u2009<jats:italic>\u03bc<\/jats:italic>M Ni<jats:sup>2+<\/jats:sup>. As expected, Ni<jats:sup>2+<\/jats:sup> also abolished the increment in [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>. Expression of Na<jats:sub>v<\/jats:sub>1.2, Na<jats:sub>v<\/jats:sub>1.6, and Ca<jats:sub>v<\/jats:sub>3.2 isoforms of voltage\u2010dependent Na<jats:sup>+<\/jats:sup> and Ca<jats:sup>2+<\/jats:sup> channels was confirmed by immunocytochemistry. Furthermore, the Panx\u20101 channel blockade was associated with an increase in O<jats:sub>2<\/jats:sub><jats:sup>\u22c5\u2013<\/jats:sup> production. Treatment with 10\u2009<jats:italic>\u03bc<\/jats:italic>M TEMPOL or 100\u2009<jats:italic>\u03bc<\/jats:italic>M apocynin prevented the increase in O<jats:sub>2<\/jats:sub><jats:sup>\u22c5\u2013<\/jats:sup> formation, ACh\u2010induced vasodilation, P\u2010eNOS<jats:sup>S1177<\/jats:sup>, and P\u2010Akt<jats:sup>S473<\/jats:sup> observed in response to Panx\u20101 inhibition. These findings indicate that the Panx\u20101 channel blockade triggers a novel complex signaling pathway initiated by the sequential activation of TTX\u2010sensitive Na<jats:sub>v<\/jats:sub> channels and Ca<jats:sub>v<\/jats:sub>3.2 channels, leading to an increase in NO\u2010mediated vasodilation through a NADPH oxidase\u2010dependent P\u2010eNOS<jats:sup>S1177<\/jats:sup>, which suggests that Panx\u20101 may be involved in the endothelium\u2010dependent control of arterial blood pressure.<\/jats:p>","DOI":"10.1155\/2021\/2678134","type":"journal-article","created":{"date-parts":[[2021,2,21]],"date-time":"2021-02-21T04:05:10Z","timestamp":1613880310000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Novel Pannexin\u20101\u2010Coupled Signaling Cascade Involved in the Control of Endothelial Cell Function and NO\u2010Dependent 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