Modulation of human platelet aggregation by the phosphodiesterase type 5 inhibitor sildenafil.
The aim of this study was to investigate if the phospodiesterase type 5 inhibitor sildenafil inhibits collagen- or ADP-induced human platelet aggregation and bleeding time. To investigate this, two studies were designed. In the first, a single oral dose of sildenafil, 100 mg, was administered to healthy men. Bleeding time was determined and agonist (ADP and collagen)-induced platelet aggregation (ex vivo in platelet rich plasma) was measured 0, 1, and 4 h after application. In the second, a single oral dose of sildenafil, 50 mg, was administered and, in addition to the parameters in the first study, we also determined the platelet aggregation after 24 h and measured the effect of a nitric oxide donor (S-nitroso-N-acetylpenicillamine [SNAP]) in combination to mimic a physiologic nitric oxide release from the endothelium. The bleeding time of 1 h after sildenafil medication (100 mg) was significantly prolonged but recovered toward control values after 4 h, whereas application of sildenafil at a lower dose (50 mg) did not alter the bleeding time. Sildenafil (100 and 50 mg) did not inhibit the ADP-induced aggregation, whereas the collagen-induced aggregation (100 mg) was markedly reduced after 1 h and significantly inhibited 4 h after application. This inhibitory effect was overcome by higher concentrations of collagen. SNAP (0.5 microM) induced an inhibition of platelet aggregation that was potentiated after taking sildenafil (50 mg, 1 and 4 h afterward) and abrogated after 24 h. These data indicates that sildenafil may inhibit collagen-induced platelet aggregation ex vivo. After co-administration of nitric oxide, collagen- and ADP-induced platelet aggregation was significantly inhibited, which may reflect physiologic conditions of an in vivo system.
Berkels
R
R
Department of Pharmacology, University of Cologne, Germany. Reinhard.Berkels@medizin.uni-koeln.de
Klotz
T
T
Sticht
G
G
Englemann
U
U
Klaus
W
W
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000328:Adult; D006801:Humans; D008297:Male; D008875:Middle Aged; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects*; D011687:Purines; D000068677:Sildenafil Citrate; D013450:Sulfones; D013997:Time Factors
D020030:Nitric Oxide Donors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; C110881:S-nitro-N-acetylpenicillamine; D013450:Sulfones; D000244:Adenosine Diphosphate; D000068677:Sildenafil Citrate; D010396:Penicillamine