Pharmacological characterization of cinnamophilin, a novel dual inhibitor of thromboxane synthase and thromboxane A2 receptor.

1. The pharmacological effects of cinnamophilin, a new lignan, isolated from Cinnamomum philippinense, was determined in vitro in human platelet, rat isolated aorta and guinea-pig isolated trachea and in vivo in mice and guinea-pigs. 2. Cinnamophilin inhibited dose-dependently human platelet-rich plasma (PRP) aggregation induced by arachidonic acid (AA), collagen and U-46619 with IC50 of 5.0 +/- 0.4, 5.6 +/- 0.6 and 3.0 +/- 0.4 microM, respectively. The second wave of ADP- or adrenaline-induced platelet aggregation was inhibited by cinnamophilin, while the first wave was only slightly inhibited by cinnamophilin above 30 microM. 3. Cinnamophilin was found to be a thromboxane A2 (TXA2) receptor blocking agent in human platelet, rat aorta and guinea-pig trachea as revealed by its competitive antagonism of U-46619-induced aggregation of human-PRP, contraction of rat aortic rings and guinea-pig tracheal rings with pA2 values of 7.3 +/- 0.2, 6.3 +/- 0.1 and 5.2 +/- 0.2, respectively. 4. [3H]-inositol monophosphate formation and the rise of intracellular Ca2+ caused by U-46619 in human platelet was suppressed by cinnamophilin (10 microM). 5. Cinnamophilin induced a dose-dependent inhibition of thromboxane B2 (TXB2) formation, while the prostaglandin E2 (PGE2) formation was increased. Cinnamophilin did not affect unstimulated platelet adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels. When the platelets were challenged with AA, a dose-dependent rise in cyclic AMP was observed. Dazoxiben (a pure TX synthase inhibitor) and SQ 29548 (a pure TXA2 receptor antagonist) did not affect cyclic AMP levels in AA-treated platelets. 6. A high concentration of cinnamophilin (100 MicroM), failed to attenuate the contractile response of rat aorta to endothelin-l, angiotensin II, 5-hydroxytryptamine or noradrenaline. Contraction of tracheal rings induced by histamine, carbachol or KCl was also not inhibited by cinnamophilin (100 MicroM).7. Thirty min after intraperitoneal (i.p.) administration of cinnamophilin (100 microg kg-1), tail bleeding time of mice was prolonged more markedly than with indomethacin, dazoxiben or SQ 29548.8. Intravenous administration of AA (50 microg kg-1) to guinea-pig induced bronchoconstriction. Cinnamophilin(0.1 mg kg-1, i.v.) was administered 1 min before AA, the bronchoconstriction response to AA was abolished.9. It is concluded that cinnamophilin is a novel dual TX synthase inhibitor and TXA2 receptor antagonist and that it may be a useful tool for the investigation and treatment of diseases involving TXA2 disorders.