Specific inhibitory effects of the NO donor MAHMA/NONOate on human platelets

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• 作者：Anna Kobsar¹ ; ^{Kobsar_A@ukw.de" class="auth_mail} ; Sandra Simonis¹ ; ^{sandra.simonis@gmail.com" class="auth_mail} ; Erdwine Klinker ^{Klinker_E@ukw.de" class="auth_mail} ; Angela Koessler ^{Koessler_A@ukw.de" class="auth_mail} ; Sabine Kuhn ^{Kuhn_S1@ukw.de" class="auth_mail} ; Markus Boeck ^{Boeck_M@ukw.de" class="auth_mail} ; Juergen Koessler ; ^{Koessler_J@ukw.de" class="auth_mail}
• 关键词：MAHMA/NONOate (PubChem CID ; 188926)
• 刊名：European Journal of Pharmacology
• 出版年：15 July 2014
• 年：2014
• 卷：735
• 期：Complete
• 页码：169-176
• 全文大小：512 K

文摘

Nitric oxide (NO) is a physiological inhibitor of platelet function and has vaso-dilating effects. Therefore, synthesized NO releasing agents are used e.g. in cardiovascular medicine. The aim of this study was to characterise specific effects of the short living agent MAHMA/NONOate, a NO donor of the diazeniumdiolate class, on human platelets.

Whole blood was obtained from healthy volunteers. In washed human platelets, the MAHMA/NONOate induced phosphorylation of the vasodilator-stimulated phosphoprotein (VASP) and cyclic nucleotide production were studied by Western Blot and by enzyme immunoassay kits. Agonist induced aggregation was measured in platelet rich plasma. Paired Student壮s t-test was used for statistical analysis.

MAHMA/NONOate significantly stimulated platelet VASP phosphorylation in a concentration dependent manner and increased intracellular cGMP, but not cAMP levels, transiently. ODQ, a specific inhibitor of the soluble guanylyl cyclase, completely prevented VASP phosphorylation induced by low MAHMA/NONOate concentrations (5 nM–15 nM). The effects of higher concentrations (30–200 nM) were only partially inhibited by ODQ. MAHMA/NONOate reduced platelet aggregation induced by low doses of agonists (2 µM ADP, 0.5 µg/mL collagen, 5 µM TRAP-6) in a concentration dependent manner.

MAHMA/NONOate leads to a rapid and transient activation of platelet inhibitory systems, accompanied by decreased platelet aggregation induced by low dose agonists. At low MAHMA/NONOate concentrations, the effects are cGMP dependent and at higher concentrations additionally cGMP independent. The substance could be of interest for clinical situations requiring transient and subtotal inhibition of platelet function.