Omeprazole suppresses endothelial calcium response and eNOS Ser1177 phosphorylation in porcine aortic endothelial cells

Abstract

Background: Although high doses of proton pump inhibitors can elicit an anticancer effect, this strategy may impair vascular biology. In particular, their effects on endothelial Ca²⁺ signaling and production of endothelium-derived relaxing factor (EDRF) are unknown. To this end, we investigated the effects of high dosages of omeprazole on endothelial Ca²⁺ responses and EDRF production in primary cultured porcine aortic endothelial cells.

Methods and results: Omeprazole (10-1000 μM) suppressed both bradykinin (BK)- and thapsigargin-induced endothelial Ca²⁺ response in a dose-dependent manner. Furthermore, omeprazole slightly attenuated Ca²⁺ mobilization from the endoplasmic reticulum, whereas no inhibitory effects on endoplasmic reticulum Ca²⁺-ATPase were observed. Omeprazole decreased BK-induced phosphorylation of endothelial nitric oxide synthase (eNOS) at Ser1177 and tended to decrease BK-induced nitric oxide production. Production of prostaglandin I₂ metabolites, especially 6-keto-prostaglandin 1α, also tended to be reduced by omeprazole.

Conclusion: Our results are the first to indicate that high doses of omeprazole may suppress both store-operated Ca²⁺ channels and partially the G protein-coupled receptor/phospholipase C/inositol 1,4,5-triphosphate pathway, and decreased BK-induced, Ca²⁺-dependent phosphorylation of eNOS(Ser1177). Thus, high dosages of omeprazole impaired EDRF production by attenuating intracellular Ca²⁺ signaling.

Keywords: Calcium; Endothelial cells; Endothelium-dependent relaxing factors; Nitric oxide synthase; Omeprazole.