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The role of intracellular free Ca2+ concentration ([Ca2+]i) in cellular regulation of endothelin-1 (ET-1) secretion was investigated in cultured porcine aortic endothelial cells of first passage. Intracellular Ca2+ concentrations were adjusted between 50 nM and 1 microM using EGTA and thapsigargin, respectively. ET-1 secretion was maximal at [Ca2+]i of 190-470 nM, and reduced at low (50 and 110 nM) and high (> 470 nM) [Ca2+]i. The Ca2+ ionophores A23187 and ionomycin (each 1 microM), both of which raise [Ca2+]i above 1 microM, also potently inhibited ET-1 secretion under basal and stimulated conditions. The A23187-induced reduction in ET-1 secretion was not affected by NG-nitro-L-arginine (0.1 mM). Our results provide evidence that basal ET-1 secretion is regulated by Ca2+ and that Ca2+ ionophores reduce ET-1 secretion due to the inhibitory effect of high [Ca2+]i.