Mechanisms for the in vivo antiplatelet effects of isosorbide dinitrate.
We investigated two possible reasons for the greater antiplatelet efficacy of isosorbide dinitrate (ISDN) in vivo as compared to in vitro. ISDN and its two main hepatic metabolites, isosorbide-2-mononitrate (IS-2-MN) and isosorbide-5-mononitrate (IS-5-MN) were compared for their ability to inhibit platelet aggregation and thromboxane B2 generation in vitro in response to threshold concentrations of ADP, adrenaline, collagen, thrombin and arachidonic acid. We also determined the concentration of prostacyclin required to inhibit by 50% platelet aggregation (IC50) in response to supra-threshold doses of aggregating agents. Out of the three nitrates tested, IS-2-MN was more effective than ISDN in inhibition of platelet aggregation and thromboxane B2 formation after ADP (minimum effective concentration: 10(-7) M) and adrenaline (minimum effective concentration: 10(-6) M). In addition, ISDN 10(-4)-10(-6) M decreased IC50 for prostacyclin from 2.7 +/- 1.2 to 0.36 +/- 0.2 nM. Generation of a platelet-active species, IS-2-MN, and synergism with prostacyclin are novel properties of ISDN and may account for in vivo-in vitro differences in antiaggregatory properties and in vivo mechanism of action.
De Caterina
R
R
CNR Institute of Clinical Physiology, Pisa, Italy.
Giannessi
D
D
Mazzone
A
A
Bernini
W
W
D000328:Adult; D011464:Epoprostenol / Q000494:pharmacology; D005260:Female; D006801:Humans; D016285:Iloprost; D066298:In Vitro Techniques; D007548:Isosorbide Dinitrate / Q000031:analogs & derivatives / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors; D013929:Thromboxane B2 / Q000096:biosynthesis
D010975:Platelet Aggregation Inhibitors; C030398:isosorbide-2-mononitrate; D013929:Thromboxane B2; D011464:Epoprostenol; D007548:Isosorbide Dinitrate; D016285:Iloprost; C030397:isosorbide-5-mononitrate