Potentiation of anti-aggregating activity of PGI2 by 7-ethoxycarbonyl-6,8-dimethyl-4-hydroxymethyl-1(2H)-phthalazinone (EG-626) in rabbit platelets in vitro.
Anti-aggregating activity of 7-ethoxycarbonyl-6,8-dimethyl-4-hydroxymethyl-1(2H)-phthalazinone (EG 626) was tested using rabbit platelets in vitro. EG-626 alone, when added before, prevented platelet aggregation induced by ADP, as did PGI2, papaverine and dipyridamole. Spontaneous disaggregation was also accelerated when EG-626 was added after the maximal aggregation induced by ADP. EG-626 alone also inhibited platelet aggregation induced by collagen and arachidonic acid. ID50s of these agents in ADP-induced aggregation were 7-9 nM for PGI2, 223 microM for EG-626, 266 microM for papaverine and 957 microM for dipyridamole. When EG-626 was used in combination with PGI2, a threshold dose (50 microM) of EG-626 potentiated the antiaggregation effect of subthreshold dose (3 nM) of PGI2 upto 100% inhibition in collagen-induced platelet aggregation. The marked potentiating effect of EG-626 was accompanied by an accumulation of cyclic AMP in the platelets. These effects might be due to inhibition of phosphodiesterase. Papaverine and dipyridamole, other phosphodiesterase inhibitors, also potentiated the anti-aggregating activity of PGI2. The activity of papaverine, however, was one eighth of EG-626 and that of dipyridamole was much less. The most effective combination of PGI2 and EG-626 to induce 50% inhibition was obtained with 20% of ID50 of each agent, whereas that of PGI2 and papaverine or dipyridamole was 39 or 41%, respectively.
D000818:Animals; D004176:Dipyridamole / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D011464:Epoprostenol / Q000494:pharmacology*; D010208:Papaverine / Q000494:pharmacology; D010793:Phthalazines / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects*; D011453:Prostaglandins / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology*; D011817:Rabbits
D010793:Phthalazines; D011453:Prostaglandins; D011724:Pyridazines; C011329:phthalazinol; D004176:Dipyridamole; D010208:Papaverine; D011464:Epoprostenol