Antagonism of platelet-activating factor-induced increase in cytosolic free calcium concentration in human endothelial cells.

The effects of platelet-activating factor (PAF) antagonists on the agonist-induced increase in cytosolic free calcium concentration, [Ca2+]i, in human vascular endothelial cells grown in monolayer were investigated by a continuous superfusion technique using a calcium fluorescent probe, fura-2. PAF caused a small but dose-dependent increase in [Ca2+]i. Seven structurally dissimilar PAF antagonists dose-dependently suppressed the peak response, among which WEB 2086 was the most potent, followed by WEB 2170 greater than FR 900452 not equal to ONO 6240 greater than BN 52021 not equal to kadsurenone not equal to CV 3988. These antagonists except for CV 3988 were specific for PAF, since they had no effects on calcium mobilization induced by thrombin or histamine, while CV 3988 had a non-specific effect. PAF in the same range of concentration increased prostacyclin release from human endothelial cells. WEB 2086 also inhibited the PAF-induced prostacyclin release, while it had not effect on the release induced by histamine and thrombin. These results demonstrate the specificity and dose-response characteristics of PAF antagonists in cultured human endothelial cells and suggest that a PAF antagonist could be a valuable therapeutic agent in certain human diseases where PAF activation of endothelial cells may have a critical role.