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

Harald Darius, Allan M. Lefer, István Leprán, J. Bryan Smith

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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 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. 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. 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. 1985 British Pharmacological Society

Original languageEnglish
Pages (from-to)735-741
Number of pages7
JournalBritish journal of pharmacology
Issue number3
Publication statusPublished - Mar 1985

ASJC Scopus subject areas

  • Pharmacology

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