The in vitro and ex vivo effect of therapeutic levels of papaverine on human platelet aggregation induced by 3-5 microM adenosine-5'-diphosphate (ADP) was evaluated in platelet-rich plasma (PRP) by photometric and impedance aggregometry, and in whole blood by impedance aggregometry. 2. Platelet aggregation induced by 3-5 microM ADP in whole blood was significantly inhibited by 5.32 and 10.64 microM papaverine in vitro. This effect was also observed in PRP enriched with erythrocytes but not in PRP alone or enriched with leukocytes. 3. Papaverine (5.32 microM) significantly enhanced the antiplatelet activity of adenosine (0.75 microM) in human whole blood, an effect that was not observed in PRP. 4. A single oral dose of 100 mg papaverine hydrochloride, given to eight healthy human volunteers 1 h before the platelet aggregation evaluation, significantly inhibited the platelet aggregation induced by 3-5 microM ADP in whole blood. This effect was not observed in PRP. 5. Oral administration of the same dose at 8-h intervals (10 times) to seven additional healthy human volunteers led to a significant negative correlation (r = -0.55, P < 0.01) between the slope of platelet aggregation in whole blood and plasma papaverine levels (0.12-0.75 microM). 6. Papaverine and adenosine, alone or together, had no in vitro effect on whole blood platelet aggregation of male Wistar rats measured by impedance aggregometry. 7. These results suggest that papaverine inhibits human platelet aggregation in whole blood by an interaction with red blood cells.
