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

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Abstract
1 Prostacyclin (PGI2) inactivates platelets by stimulation of adenylate cyclase, and its effect can be potentiated in vitro by simultaneous inhibition of cyclic AMP phosphodiesterase. 2 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. 3 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 μg kg−1 min−1) dose-dependently inhibited this decrease. HL 725 (0.5, 1 and 3 μg kg−1 min−1) caused a slight but significant effect. 4 Combinations of PGI2 and HL 725, respectively, at 0.25 + 1.0 and 0.1 + 0.5 μg 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 μg kg−1 min−1. 5 Collagen induced an acute fall in the mean arterial blood pressure (MABP) which also was inhibited by PGI2, HL 725 and their combinations. 6 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. 7 Thus, PGI2 and the phosphodiesterase inhibitor HL 725 interact in vivo to inhibit platelet aggregation and lower MABP.