Phosphodiesterase inhibitors piroximone and enoximone inhibit platelet aggregation in vivo and in vitro.

摘要

The phosphodiesterase type III inhibitors piroximone (PIR) and enoximone (ENO) exert positive inotropic and vasodilating effects in patients with severe heart failure. PIR and ENO raise cyclic AMP levels in cardiac and vascular smooth muscle cells. Platelet activity is also regulated by intracellular levels of cyclic AMP. In this study we have investigated the effects of PIR and ENO on platelet activity in vivo and in vitro. PIR and ENO inhibited ADP induced platelet aggregation in a time- and concentration-dependent manner with IC50-values of 67 +/- 14 mumol/l and 129 +/- 6 mumol/l, respectively. Coincubation of PIR with the adenylate cyclase activator iloprost resulted in a synergistic potentiation of the platelet inhibitory effect. In anesthetized rats PIR and ENO (2 mg/kg bw) exerted an effective inhibition of collagen induced reduction in peripheral platelet count (vehicle 49 +/- 7%, PIR 22 +/- 8%, ENO 30 +/- 6%; P < 0.01). In washed human platelets incubation with PIR and ENO resulted in a time- and concentration-dependent increase of the intracellular second messenger cyclic AMP. In Fura-2 AM loaded platelets PIR and ENO diminished PAF induced Ca2+ mobilization concentration dependently. Thus, the observed antiplatelet effects following PIR and ENO might exert beneficial effects in patients with cardiovascular disease.