Anti‐platelet therapy: phosphodiesterase inhibitors

Abstract

Inhibition of platelet aggregation can be achieved either by the blockade of membrane receptors or by interaction with intracellular signalling pathways. Cyclic adenosine 3′,5′-monophosphate (cAMP) and cyclic guanosine 3′,5′-monophosphate (cGMP) are two critical intracellular second messengers provided with strong inhibitory activity on fundamental platelet functions. Phosphodiesterases (PDEs), by catalysing the hydrolysis of cAMP and cGMP, limit the intracellular levels of cyclic nucleotides, thus regulating platelet function. The inhibition of PDEs may therefore exert a strong platelet inhibitory effect. Platelets possess three PDE isoforms (PDE2, PDE3 and PDE5), with different selectivity for cAMP and cGMP. Several nonselective or isoenzyme-selective PDE inhibitors have been developed, and some of them have entered clinical use as antiplatelet agents. This review focuses on the effect of PDE2, PDE3 and PDE5 inhibitors on platelet function and on the evidence for an antithrombotic action of some of them, and in particular of dipyridamole and cilostazol.

Effects of high flavanol dark chocolate on cardiovascular function and platelet aggregation

“…Nevertheless, it augmented the effect of prostacyclin, confirming that theobromine promotes cAMP-dependent decreases in platelet aggregation via PDE inhibition. The inhibitory profile of theobromine is very similar to the nonselective PDE inhibitor pentoxifylline and the selective PDE3 inhibitor cilostazol, which have limited effect alone, yet show markedly increased inhibition of platelet aggregation in the presence of prostacyclin [29].…”

“…Platelet aggregation responses after consuming HFDC for 6 weeks were not significantly Both chocolates contained similar levels of theobromine and caffeine (Table 1), which can act as phosphodiesterase (PDE) inhibitors [21], a well-established mechanism for inhibiting platelet aggregation [29]. Theobromine plasma levels were comparable after HFDC and LFDC, and significantly greater than baseline (Table 5).…”

“…Hence PDE inhibitors, including methylxanthines, reduce ADP and PAR1 responses and are potent suppressors of platelet aggregation [29]. As HFDC and LFDC contained comparable levels of theobromine, it seemed likely that PDE inhibition accounted for the decrease in platelet responses.…”

Cyclic nucleotide‐dependent inhibitory signaling interweaves with activating pathways to determine platelet responses

“…The clinical relevance of crosstalk between activating and cyclic nucleotide‐dependent inhibitory pathways is further highlighted by the success of drugs targeting either the Gi‐coupled P2Y12 receptor or PDEs 3A and 5A,12, 104, 105 which prevent the blockade of cyclic nucleotide production or degradation, respectively 106. Stimulators of the cGMP pathway are commonly used to treat vascular disease due to their ability to lower vascular tone by acting on smooth muscle cells, however, simultaneous platelet inhibition might contribute to their beneficial effects.…”

Effects of Chronic Treatment With Cilostazol, a Phosphodiesterase 3 Inhibitor, on Female Rat Bladder in a Partial Bladder Outlet Obstruction Model

“…PDEs consist of 11 broad families (PDE1-PDE11), and their distribution and function differ according to species [24]. In addition, PDE family is known to regulate the concentration by balancing the enzyme activity and to play an important role in signal transduction.…”