The effect of Sildenafil on human platelet secretory function is controlled by a complex interplay between phosphodiesterases 2, 3 and 5.
Human platelets contain the cyclic nucleotide-hydrolyzing phosphodiesterases (PDEs) 2, 3 and 5. The cGMP-PDE5 inhibitors Sildenafil and Zaprinast have been demonstrated to potentiate the anti-platelet aggregatory effect of NO donors like sodium nitroprusside (SNP) in vitro but the mechanisms of Sildenafil's action on the secretory function of human platelets have not been analysed in detail. In the present paper, we show (1) that both compounds potentiate the SNP-induced increase in cGMP in human platelets concentration-dependently. (2) However, whereas Sildenafil plus SNP treatment only partially inhibits thrombin-induced release of serotonin, the less selective Zaprinast plus SNP cause a complete inhibition. (3) The inhibition mediated by Sildenafil plus SNP is limited to low compound concentrations at which cAMP levels are increased, probably due to cGMP-mediated inhibition of PDE3. (4) High concentrations of Sildenafil (plus SNP) neither affect cAMP levels, likely due to the activation of PDE2, nor inhibits the release of serotonin. Thus, increases in both cyclic nucleotides seem to control platelet function. (5) Accordingly, treatment with increasing concentrations of Sildenafil plus SNP and a selective PDE2 inhibitor, which by its own has no effect, induced a concentration-dependent increase in cAMP and complete inhibition of platelet activation. In summary, our data indicate that Sildenafil inhibits secretory function of human platelets at least in part due to the cGMP-mediated effects on intracellular cAMP and that entire inhibition of serotonin release from thrombin-activated platelets is controlled by both cyclic nucleotides.
Dunkern
Torsten R
TR
Department of Biochemistry Inflammation, ALTANA Pharma AG, Byk-Gulden-Str.2, Konstanz 78467, Germany. torsten.dunkern@altanapharma.com
Hatzelmann
Armin
A
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000502:physiology*; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D000242:Cyclic AMP / Q000096:biosynthesis; D006152:Cyclic GMP / Q000096:biosynthesis; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006801:Humans; D066298:In Vitro Techniques; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D043264:Phosphodiesterase I / Q000502:physiology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000502:physiology*; D010879:Piperazines / Q000494:pharmacology*; D015539:Platelet Activation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011687:Purines; D011688:Purinones / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism; D000068677:Sildenafil Citrate; D013450:Sulfones
D020030:Nitric Oxide Donors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D011687:Purines; D011688:Purinones; D011724:Pyridazines; D013450:Sulfones; D009599:Nitroprusside; D012701:Serotonin; D000068677:Sildenafil Citrate; C051270:motapizone; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D043264:Phosphodiesterase I; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human; C011145:zaprinast; D006152:Cyclic GMP