In vitro evidence of an endothelial cell-dependent antiplatelet activity for isosorbide dinitrate, but not for its 2- and 5-mononitrate metabolites.
In an experimental model in which cultured endothelial cells (EC) and platelets were incubated with autologous plasma, we investigated the pharmacological modulations by isosorbide nitrates (ISN) [isosorbide dinitrate (ISDN) + 2-isosorbide mononitrate (2-ISMN) + 5-ISMN] of the EC-induced inhibition of platelet aggregation; and the associated changes in prostanoid profile of these mixed EC-platelet suspensions. ISDN antiplatelet activities were found to be magnified profoundly by EC, being dependent upon both ISDN concentration and EC number, e.g., 5.10(-5) M ISDN in the presence of 2.10(4) cells, fully arrested ADP-induced aggregation, whereas the same ISDN concentration induced 30% inhibition in control platelet activities. In contrast, there were no significant changes in 2- and 5-ISMN antiaggregating properties, whether incubated in the presence or absence of EC. Thromboxane B2 accumulated noticeably after aggregation, whereas 6-keto-prostaglandin (PG) F1 alpha and PGE2 accumulated poorly in the medium. In the presence of EC, thromboxane B2 accumulation fell in parallel to the extent of aggregation, whereas 6-keto-PGF2 alpha and PGE2 accumulated in the medium. Aspirin-treated, washed ECs still inhibited platelet aggregation. ISDN was the only ISN capable of inducing PG-accumulation profile changes. These results demonstrate the existence of an endothelium-dependent ISDN antiplatelet activity. Furthermore, this effect is specific to ISDN not being shown by its mononitrate metabolites. These results suggest that PG accumulation changes may be a consequence rather than a cause of the inhibition of platelet activity by (ISDN-stimulated) EC.
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000328:Adult; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D002457:Cell Extracts / Q000494:pharmacology*; D002478:Cells, Cultured; D015232:Dinoprostone; D004727:Endothelium / Q000166:cytology* / Q000187:drug effects; D005260:Female; D006801:Humans; D007548:Isosorbide Dinitrate / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects*; D011458:Prostaglandins E / Q000378:metabolism; D013929:Thromboxane B2 / Q000378:metabolism; D014020:Tissue Extracts / Q000494:pharmacology*
D001095:Arachidonic Acids; D002457:Cell Extracts; D011458:Prostaglandins E; D014020:Tissue Extracts; C030398:isosorbide-2-mononitrate; D016718:Arachidonic Acid; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D000244:Adenosine Diphosphate; D007548:Isosorbide Dinitrate; D015232:Dinoprostone; C030397:isosorbide-5-mononitrate