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Aldosterone is a mineralocorticoid hormone that plays an important role in regulating electrolyte balance and blood pressure and also participates in endothelial dysfunction. We evaluated the direct effect of aldosterone on human umbilical vein cells (HUVEC). Levels of eNOS phosphorylation by vascular endothelial growth factor were diminished, and the amount of NO produced in response to vascular endothelial growth factor measured as NO2+NO3 was significantly decreased in cells previously incubated with aldosterone. Incubation with aldosterone for 24 h dose-dependently increased Nox4 mRNA expression in HUVEC. Although NF-kappaB was not apparently activated by aldosterone, mRNA levels of vascular cell adhesion molecule-1, E-selectin, monocyte chemotactic protein-1, and intercellular adhesion molecule-1 in HUVEC were significantly increased after incubation with aldosterone. Thus, aldosterone directly causes the dysregulation of endothelial cell function, which may be partly responsible for high blood pressure and atherosclerosis.

We examined the role of receptor-operated Ca 2+ influx in endothelin-1 (ET-1)- or sarafotoxin S6c (S6c)-induced contraction of the muscularis mucosae. Responses of the esophageal muscularis mucosae isolated from guinea-pigs were recorded by an isotonic transducer and a polygraph. ET-1 and S6c produced contraction of the esophageal muscularis mucosae in a concentration-dependent manner. The contractile responses to ETs were abolished in a Ca 2+ -free EGTA-containing medium, weakly inhibited by nicardipine. and markedly inhibited by SK&F96365. In addition, both H-7 and U-73122 strongly inhibited the ET-induced contractions. but U-73343 weakly inhibited these responses. These results indicate that the esophageal muscularis mucosae of guinea pigs has ET receptors that are coupled mainly to receptor-operated Ca 2+ influx and linked with the phospholipase C-protein kinase C pathway.