[Inhibition of platelet aggregation by endothelium-derived relaxing factor-like agents].
In the last years, an inhibition of aggregation by organic nitrates or by similar drugs has been demonstrated by some authors, but has also been ruled out by other authors. The present work was thus performed to study a possible inhibition of platelet aggregation by the respective drugs in comparison with the molecular mechanism of action of these drugs, that is activation of soluble guanylate cyclase. We found that in vitro, organic nitrates activate soluble guanylate cyclase and inhibit platelet aggregation only in millimolar concentrations, while sodium nitroprusside and SIN-1, the active metabolite of molsidomine, influence these parameters in micromolar concentrations. This difference between the actions of the O-NO2-containing nitrates and the NO-containing compounds nitroprusside and SIN-1 is, however, not apparent ex vivo. Ex vivo, not only molsidomine, that is converted in the liver to SIN-1, but also isosorbide-5-mononitrate inhibited platelet aggregation. Thus, it appears that organic nitrates can in vivo release nitric oxide in a tissue other than platelets in amounts that are high enough to inhibit platelet aggregation. These studies suggest, that an antiaggregatory effect may participate in the clinical actions not only of drugs that directly resemble EDRF, such as SIN-1, but also by the organic nitrates. However, since nitrates cannot be activated directly by the platelets, it appears that also the antiaggregatory effects of nitrates, but not of molsidomine, underlie the mechanisms of tolerance development.
Medizinische Klinik Innenstadt, Universität München.
R
R
Gerzer
B
B
Karrenbrock
C
C
Drummer
J M
JM
Heim
D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects*; D006801:Humans; D007548:Isosorbide Dinitrate / Q000031:analogs & derivatives / Q000627:therapeutic use; D008981:Molsidomine / Q000031:analogs & derivatives / Q000627:therapeutic use*; D009569:Nitric Oxide / Q000502:physiology*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D014665:Vasodilator Agents / Q000627:therapeutic use
D010975:Platelet Aggregation Inhibitors; D014665:Vasodilator Agents; D009569:Nitric Oxide; C002385:linsidomine; D008981:Molsidomine; D007548:Isosorbide Dinitrate; C030397:isosorbide-5-mononitrate
Hemmung der Thrombozytenaggregation durch EDRF-ähnliche Wirkstoffe.