Cyclopiazonic Acid-Induced Ca Store Depletion Initiates Endothelium-Dependent Hyperpolarization-Mediated Vasorelaxation of Mesenteric Arteries in Healthy and Colitis Mice.

: Since the role of store-operated calcium entry (SOCE) in endothelium-dependent hyperpolarization (EDH)-mediated vasorelaxation of mesenteric arteries in health and colitis is not fully understood, cyclopiazonic acid (CPA), a specific inhibitor of the sarco(endo) plasmic reticulum calcium-ATPases (SERCA), was used as a SOCE activator to investigate its role in normal mice and its alteration in colitis mice. : The changes in Ca signaling in vascular endothelial cells (VEC) were examined by single cell Ca imaging and tension of mesenteric arteries in response to CPA were examined using Danish DMT520A microvascular measuring system. : CPA activated the SOCE through depletion of the endoplasmic reticulum (ER) Ca in endothelial cells. CPA had a concentration-dependent vasorelaxing effect in endothelium-intact mesenteric arteries, which was lost after endothelial removal. Both nitric oxide (NO) and prostacyclin (PGI) inhibitors did not affect CPA-induced vasorelaxation; however, after both NO and PGI were inhibited, K channel blocker [10 mM tetraethylammonium chloride (TEA)] inhibited CPA-induced vasorelaxation while K channel activator (0.3 μM SKA-31) promoted it. Two SOCE blockers [30 μM SKF96365 and 100 μM flufenamic acid (FFA)], and an Orai channel blocker (30 μM GSK-7975A) inhibited this vasorelaxation. The inhibition of both Na/K-ATPase (NKA) and Na/Ca-exchange (NCX) also inhibited CPA-induced vasorelaxation. Finally, the CPA involved in EDH-induced vasorelaxation by the depletion of ER Ca of mesenteric arteries was impaired in colitis mice. : Depletion of ER Ca by CPA induces a vasorelaxation of mesenteric arteries that is mediated through EDH mechanism and invokes the activation of SOCE. The CPA-induced endothelium-dependent dilation is impaired in colitis which may limit blood perfusion to the intestinal mucosa.