Summary
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. Despite the effect on platelets, plasma cyclic GMP levels did not increase. These results suggest that the nitric oxide-containing SIN 1 inhibits platelet aggregation not only in vitro but also in vivo and that this property can be a beneficial effect in antianginal therapy.
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Abbreviations
- Cyclic GMP:
-
guanosine 3′∶5′-cyclic monophosphate
- NO:
-
nitric oxide
- PAF:
-
platelet-activating factor
- PRP:
-
platelet-rich plasma
- SIN 1:
-
3-morpholino-sydnonimine
References
Basista M, Grodzinska L, Swies J (1985) The influence of molsidomine and its active metabolite SIN 1 on fibrinolysis and platelet aggregation. Thromb Haemostas 54:746–749
Böhme E, Graf H, Schultz G (1978) Effects of sodium nitroprusside and other smooth muscle relaxants on cyclic GMP formation in smooth muscle and platelets. Adv Cyclic Nucleotide Res 9:131–143
Böhme E, Grossmann G, Spies C (1983) Effects of molsidomine and other NO-containing vasodilators on cyclic GMP formation. Eur Heart J 4:19–24
Diamond J, Holmes TG (1975) Effects of potassium chloride and smooth muscle relaxants on tension and cyclic nucleotide levels in rat myometrium. Can J Physiol Pharmacol 53:1099–1107
Gerzer R, Hofmann F, Schultz G (1981) Purification of a soluble, sodium nitroprusside-stimulated guanylate cyclase from bovine lung. Eur J Biochem 116:479–486
Gerzer R, Tremblay J, Pang S, De Lean A, Hamet P (1985) Atrial natriuretic factor activates mammalian particulate guanylate cyclase. Fed Proc 44:698
Gerzer R, Witzgall H, Tremblay J, Gutkowska J, Hamet P (1985) Rapid increase in plasma and urinary cyclic GMP after bolus injection of atrial natriuretic factor in man. J Clin Endocrinol Metab 61:1217–1219
Gerzer R, Karrenbrock B, Siess W, Heim JM (1988) Direct comparison of the effects of nitroprusside, SIN 1, and various nitrates on platelet aggregation and soluble guanylate cyclase activity. Thromb Res 52:11–21
Hanahan DJ (1986) Platelet activating factor: a biologically active phosphoglyceride. Annu Rev Biochem 55:483–509
Heim JM, Gottmann K, Weil J, Haufe MC, Gerzer R (1988) Is cyclic GMP a clinically useful marker for ANF action? Z Kardiol 77 [Suppl 2]:41–46
Hogan JC, Lewis MJ, Henderson AH (1988) In vivo EDRF activity influences platelet function. Br J Pharmacol 94:1020–1022
Ignarro LJ, Kadowitz PJ (1985) The pharmacological and physiological role of cyclic GMP in vascular smooth muscle relaxation. Annu Rev Pharmacol Toxicol 25:171–191
Karrenbrock B, Grewe R, Loeschke K, Gerzer R (1987) Comparaison des effets du SIN 1 du nitrorussiate de sodium et des dérivés nitrés sur l'inhibition de l'agrégation plaquettaire et l'activation de la guanylate-cyclase soluble plaquettaire. Pathol Biol 35:251–254
Levin RI, Weksler BB, Jaffe EA (1982) The interaction of sodium nitroprusside with human endothelial cells and platelets: nitroprusside and prostacyclin synergistically inhibit platelet function. Circulation 66:1299–1307
Matsuoka I, Nakanishi H (1985) An analysis of inhibitory effect of cyclic GMP on arachidonic acid- or collagen-induced aggregation in rabbit platelets. Thromb Res 37:185–193
Moncada S, Radomski MW, Palmer RMJ (1988) Endothelium-derived relaxing factor — identification as nitric oxide and role in the control of vascular tone and platelet function. Biochem Pharmacol 37:2495–2501
Ostrowski J (1976) Cassella Internal Report 1976
Scholtholt J (1985) Molsidomine. Handb Exp Pharmacol 76:365–383
Siess W (1989) Molecular mechanisms of platelet activation. Physiol Rev 69:58–177
Tremblay J, Gerzer R, Hamet P (1988) Cyclic GMP in cell function. Adv Sec Mess Phosphoprotein Res 22:319–382
Waldman SA, Murad F (1987) Cyclic GMP synthesis and function. Pharmacol Rev 39:163–196
Yamakado T, Nishikawa M, Hidaka H (1982) Stimulation of human platelet guanylate cyclase by nitrous compounds. Thromb Res 26:135–141
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Karrenbrock, B., Heim, J.M. & Gerzer, R. Effect of molsidomine on ex vivo platelet aggregation and plasma guanosine 3′∶5′-cyclic monophosphate levels in healthy volunteers. Klin Wochenschr 68, 213–217 (1990). https://doi.org/10.1007/BF01662718
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DOI: https://doi.org/10.1007/BF01662718