Comparison of anti-platelet properties of molsidomine, isosorbide-5-mononitrate and placebo in healthy volunteers.

The purpose of the present work was to investigate the ex vivo platelet-inhibiting properties of the nitric oxide-containing vasodilator, molsidomine, and the organic nitrate, isosorbide-5-mononitrate, in comparison with placebo. Ex vivo platelet aggregation in 11 healthy volunteers was measured before, as well as 30 and 60 min after, the intake of either 4 mg molsidomine, 20 mg isosorbide-5-mononitrate (ISMN) or placebo in a randomized double-blind fashion. The release of thromboxane was also determined.

[Platelet aggregation with SIN 1: comparison with isosorbide-5-mononitrate and acetylsalicylic acid].

SIN 1, the bioactive metabolite of molsidomine, not only appears to lack the problem of inducing nitrate tolerance, but also exerts antiaggregatory and fibrinolytic properties. These effects, which either are not or only in part shared by the drug isosorbide-5-mononitrate, might be beneficial in the prevention of thromboembolic complications in cardiovascular disease. In contrast to the effects of acetylsalicylic acid, SIN 1 already inhibits aggregation during the first phase of aggregation, and it inhibits aggregations induced by agonists that are not or only marginally influenced by acetylsalicylic acid (such as the aggregation induced by platelet activating factor).

Effect of molsidomine on ex vivo platelet aggregation and plasma guanosine 3':5'-cyclic monophosphate levels in healthy volunteers.

To find out whether 3-morpholino-sydnonimine (SIN 1), the active metabolite of molsidomine, exerts its antiaggregatory effects not only in vitro but also in vivo, we tested ex vivo aggregation before and after intravenous application of molsidomine in healthy volunteers. We also measured plasma levels of guanosine 3':5'-cyclic monophosphate (cyclic GMP) as SIN 1, the bioactive metabolite of molsidomine, becomes effective via activation of soluble guanylate cyclase. In eight out of ten subjects molsidomine had an inhibitory effect on platelet aggregation and a higher threshold concentration of platelet-activating factor was required after molsidomine application to induce irreversible aggregation.

[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.

Inhibition of platelet activating factor-induced platelet aggregation by molsidomine, SIN-1, and nitrates in vitro and ex vivo.

We compared in vitro the effects of molsidomine, its active metabolite SIN-1, sodium nitroprusside, and the organic nitrates nitroglycerin, isosorbide-5-mononitrate, and isosorbide-2,5-dinitrate on platelet aggregation induced by platelet activating factor and on the activity of soluble guanylate cyclase. In addition, the effects of molsidomine and of isosorbide-5-mononitrate on ex vivo platelet function were studied. In vitro, SIN-1 and sodium nitroprusside were about 100-fold more potent activators of platelet guanylate cyclase and inhibitors of platelet activating factor-induced aggregation than the other agents.