[Selective inhibition of CI-914 on the production of TXA2 and HHT].
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 TXA2 synthetase, was found to be inhibited by the agent in a dose-dependent manner, with IC50 value of 78.6 mumol/L. Only at higher concentration (500 mumol/L) of CI-914, was the production of 12-HETE (measured by HPLC), a lipoxygenase product in platelets, shown to be inhibited. These indicate that CI-914 mainly inhibits the metabolism of AA via cyclooxygenase and TXA2 synthetase rather than via lipoxygenase. In rat platelets and A23187-stimulated pleural neutrophils, CI-914 caused a dose-related decrease of TXA2 production (measured by RIA), with IC50 values of 28.6 and 51.3 mumol/L, respectively. Meanwhile, significant increases of PGE2 synthesis in the platelets and 6-keto-PGF1 alpha 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 TXA2 synthetase in rat platelets and pleural neutrophils.
Chen
X S
XS
Department of Pharmacology, College of Pharmacy, Second Military Medical University, Shanghai.
Long
K
K
Yue
T L
TL
Jiang
Y Y
YY
Wan
W Q
WQ
D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis*; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D002316:Cardiotonic Agents; D008297:Male; D009504:Neutrophils / Q000378:metabolism; D011724:Pyridazines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013929:Thromboxane B2 / Q000096:biosynthesis*
D002316:Cardiotonic Agents; D011724:Pyridazines; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; C042527:imazodan