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

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 mu M) 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 I-2 metabolites, especially 6-keto-prostaglandin 1 alpha, 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.

Automated summary

This study found that high doses of omeprazole may suppress store-operated Ca2+ channels and the G protein-coupled receptor/phospholipase C/inositol 1,4,5-triphosphate pathway, leading to decreased phosphorylation of eNOS and impaired EDRF production. These results provide new insights into the impact of omeprazole on vascular biology.