In vivo interaction of prostacyclin with an inhibitor of cyclic nucleotide phosphodiesterase, HL 725.

Prostacyclin (PGI2) inactivates platelets by stimulation of adenylate cyclase, and its effect can be potentiated in vitro by simultaneous inhibition of cyclic AMP phosphodiesterase. The interaction of synthetic PGI2 and the potent phosphodiesterase inhibitor HL 725 was studied in a model of systemic platelet activation by intravenous injection of collagen. Platelet aggregate formation was evaluated by continuous on-line measurement of the circulating platelet count. Collagen injection in rabbits receiving vehicle caused a 30 +/- 3% decrease in the circulating platelet count. Infusion of PGI2 (0.05, 0.1 and 0.75 micrograms kg-1 min-1) dose-dependently inhibited this decrease. HL 725 (0.5, 1 and 3 micrograms kg-1 min-1) caused a slight but significant effect. Combinations of PGI2 and HL 725, respectively, at 0.25 + 1.0 and 0.1 + 0.5 micrograms kg-1 min-1 inhibited platelet aggregate formation to a greater extent than when either substance was used alone and produced a comparable inhibition to PGI2 at 0.75 micrograms kg-1 min-1. Collagen induced an acute fall in the mean arterial blood pressure (MABP) which also was inhibited by PGI2, HL 725 and their combinations. The infusion of a combination of PGI2 and HL 725 before collagen produced a decrease in the MABP which was greater than when either compound was used on its own. Thus, PGI2 and the phosphodiesterase inhibitor HL 725 interact in vivo to inhibit platelet aggregation and lower MABP.