Abstract:
The effects of CI-914, a novel cardiotonic agent, on AA metabolism in rat neutrophils and platelets in vitro were investigated. Using washed rat platelets, the formation of HHT (measured by HPLC), a product of AA metabolism via cyclooxygenase and TXA
2 synthetase, was found to be inhibited by the agent in a dose-dependent manner, with IC
50 value of 78.6μmol/L. Only at higher concentration (500μmol/L) of CI-914, was the production of 12-HETE (measured by HP LC), a lipoxygenase product in platelets, shown to be inhibited. These indicate that CI-914. mainly inhibits the metabolism of AA via cyclooxygenase and TXA
2 synthetase rather than via lipoxygenase. In rat platelets and A
23187stimulated pleural neutrophils, CI-914 caused a dose-related decrease of TXA
2 production (measured by RIA), with IC
50 values of 28.6 and 51.3μmol/L , respectively. Meanwhile, significant increases of PGE
2 synthesis in the platelets and 6-keto-PGF
1α synthesis in the pleural neutrophils were observed when CI-914 was preincubated with these cells. It is suggested that CI-914 might selectively inhibit the activity of TXA
2 synthetase in rat platelets and pleural neutrophils.