Organic nitrates: direct antiplatelet effects and synergism with prostacyclin. Antiplatelet effects of organic nitrates.
Isosorbide dinitrate inhibits platelet function in vivo at concentrations about 10 times lower than in vitro (10(-7)-10(-6) vs. 10(-6)-10(-5) M). We investigated two possible reasons for this difference. Isosorbide dinitrate and its in vivo longer-lived metabolites, isosorbide-2- and isosorbide-5-mononitrate were incubated for 5 min with human platelet-rich plasma or washed platelets; irreversible aggregation was induced with threshold doses of ADP, adrenaline, collagen, arachidonic acid and thrombin, and thromboxane (TX) B2 production was measured by radioimmunoassay. Moreover, the concentration of exogenous prostacyclin required to inhibit platelet aggregation by 50% (IC50) after preincubation with isosorbide dinitrate or vehicle was determined. At 10(-7) M, only isosorbide-2-mononitrate inhibited aggregation (-12%, p less than 0.05) and TX production (-36%, p less than 0.01) by ADP. At 10(-6) M isosorbide-2-mononitrate inhibited aggregation by adrenaline more than the dinitrate (-41% vs. -25%, p less than 0.05). In addition, at supra-threshold doses of all the aggregating agents, isosorbide dinitrate decreased IC50 of prostacyclin from 2.7 +/- 1.2 to 0.36 +/- 0.2 nM. Generation of a platelet-active metabolite and synergism with prostacyclin are new properties of isosorbide dinitrate that may account for antiplatelet effects in vivo.
De Caterina
R
R
CNR Institute of Clinical Physiology, University of Pisa, Italy.
Giannessi
D
D
Bernini
W
W
Mazzone
A
A
D000328:Adult; D001792:Blood Platelets / Q000187:drug effects* / Q000502:physiology; D004357:Drug Synergism; D011464:Epoprostenol / Q000494:pharmacology*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007548:Isosorbide Dinitrate / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D009566:Nitrates / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D013929:Thromboxane B2 / Q000097:blood
D009566:Nitrates; C030398:isosorbide-2-mononitrate; D013929:Thromboxane B2; D011464:Epoprostenol; D007548:Isosorbide Dinitrate; C030397:isosorbide-5-mononitrate