Effect of a Prostaglandin E1 Derivative (OP-1206) and Acetylsalicylic Acid on Electrically Induced Thrombosis in Guinea-Pig Mesenteric Artery and Its Modification by an Inhibitor of Prostaglandin I2 Synthetase, Tranylcypromine

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Abstract
The antithrombotic effect of a prostaglandin E1 derivative, OP-1206 (17S-20-dimethyl-trans-.DELTA.2-PGE1).cntdot..alpha.-cyclodextrin clathrate (OP-1206.cntdot..alpha.-CD), was compared with that of acetylsalicylic acid (ASA) in a electrically induced thrombosis model of guinea-pig mesenteric arteries using intact animals and animals subjected to the superfusion of tranylcypromine (TC, 15 mM) over their mesentery. The drug-effect was assessed by the change of the threshold voltage for the thrombus formation. TC (1.5-15 mM) lowered the threshold voltage, and the effect was comparable to its inhibitory effect on PGI2 formation in vitro, suggesting that PGI2 generated in mesenteric arteries acts to prevent thrombus formation. In intact animals, OP-1206-.alpha.-CD at doses of 0.01-0.3 mg/kg, p.o. (as OP-1206), significantly and dose-dependently elevated the threshold voltage. ASA (30-1000 mg/kg, p.o.) significantly elevated the threshold voltage, but the effect reached to its maximum at 100 mg/kg and lessened with further increase of ASA. In TC-treated animals, OP-1206.cntdot..alpha.-CD elevated the threshold voltage dose-dependently, but the elevation of threshold voltage by ASA reached to its plateau level which was significantly lower than that obtained with OP-1206.cntdot..alpha.-CD at 0.3 mg/kg, indicating that the antithrombotic effect of ASA is incomplete in this model. Threshold voltages in TC-treated animals given OP-1206.cntdot..alpha.-CD was significantly lower than those in intact animals at all doses tested but threshold voltages in TC-treated and intact animals given ASA at 300-1000 mg/kg were not different, suggesting that high doses of ASA inhibits PGI2 formation in vivo. Thus, the antithrombotic effect of ASA was restricted by its inhibitor effect on PGI2 formation and its incomplete inhibition on thrombus formation, while such differences were not observed in OP-1206.cntdot..alpha.-CD.