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Deletion of pannexin-1 (Panx-1) leads not only to a reduction in endothelium-derived hyperpolarization but also to an increase in NO-mediated vasodilation. Therefore, we evaluated the participation of Panx-1-formed channels in the control of membrane potential and [Ca 2+ ] i  of endothelial cells. Changes in NO-mediated vasodilation, membrane potential, superoxide anion (O 2  ·– ) formation, and endothelial cell [Ca 2+ ] i  were analyzed in rat isolated mesenteric arterial beds and primary cultures of mesenteric endothelial cells. Inhibition of Panx-1 channels with probenecid (1 mM) or the Panx-1 blocking peptide  10 Panx (60  μ M) evoked an increase in the ACh (100 nM)-induced vasodilation of KCl-contracted mesenteries and in the phosphorylation level of endothelial NO synthase (eNOS) at serine 1177 (P-eNOS S1177 ) and Akt at serine 473 (P-Akt S473 ). In addition, probenecid or  10 Panx application activated a rapid, tetrodotoxin (TTX, 300 nM)-sensitive, membrane potential depolarization and [Ca 2+ ] i  increase in endothelial cells. Interestingly, the endothelial cell depolarization was converted into a transient spike after removing Ca 2+  ions from the buffer solution and in the presence of 100  μ M mibefradil or 10  μ M Ni 2+ . As expected, Ni 2+  also abolished the increment in [Ca 2+ ] i . Expression of Na v 1.2, Na v 1.6, and Ca v 3.2 isoforms of voltage-dependent Na +  and Ca 2+  channels was confirmed by immunocytochemistry. Furthermore, the Panx-1 channel blockade was associated with an increase in O 2  ·–  production. Treatment with 10  μ M TEMPOL or 100  μ M apocynin prevented the increase in O 2  ·–  formation, ACh-induced vasodilation, P-eNOS S1177 , and P-Akt S473  observed in response to Panx-1 inhibition. These findings indicate that the Panx-1 channel blockade triggers a novel complex signaling pathway initiated by the sequential activation of TTX-sensitive Na v  channels and Ca v 3.2 channels, leading to an increase in NO-mediated vasodilation through a NADPH oxidase-dependent P-eNOS S1177 , which suggests that Panx-1 may be involved in the endothelium-dependent control of arterial blood pressure.

Novel Pannexin-1-Coupled Signaling Cascade Involved in the Control of Endothelial Cell Function and NO-Dependent Relaxation