Tsiountsioura Melina, Cvirn Gerhard, Schlagenhauf Axel, Haidl Harald, Zischmeier Kathrin, Janschitz Nicole, Koestenberger Martin, Wonisch Willibald, Paar Margret, Wagner Thomas, Weiss Eva-Christine, Hallström Seth
Division of Physiological Chemistry, Otto Loewi Research Center, Medical University of Graz, 8010 Graz, Austria.
Division of General Paediatrics, Department of Paediatrics and Adolescent Medicine, Medical University of Graz, 8036 Graz, Austria.
Biomedicines. 2022 Mar 11;10(3):649. doi: 10.3390/biomedicines10030649.
Nitric oxide donors (NO-donors) have been shown to have therapeutic potential (e.g., ischemia/reperfusion injury). However, due to their release rate/antiplatelet properties, they may cause bleeding in patients. We therefore studied the antiplatelet effects of the two different NO-donors, i.e., S-NO-Human Serum Albumin (S-NO-HSA) and Diethylammonium (Z)-1-(,-diethylamino)diazen-1-ium-1,2-diolate (DEA-NONOate) in whole blood (WB) samples. WB samples were spiked with S-NO-HSA or DEA-NONOate (100 µmol/L or 200 µmol/L), and the NO release rate (nitrite/nitrate levels via HPLC) and antiplatelet efficacy (impedance aggregometry, platelet function analyzer, Cone-and-platelet analyzer, thrombelastometry) were assessed. S-NO-HSA had a significantly lower NO release compared to equimolar concentrations of DEA-NONOate. Virtually no antiplatelet action of S-NO-HSA was observed in WB samples, whereas DEA-NONOate significantly attenuated platelet function in WB. Impedance aggregometry measurements revealed that Amplitudes (slope: -0.04022 ± 0.01045 ohm/µmol/L, = 0.008) and Lag times (slope: 0.6389 ± 0.2075 s/µmol/L, = 0.0051) were dose-dependently decreased and prolonged by DEA-NONOate. Closure times (Cone-and-platelet analyzer) were dose-dependently prolonged (slope: 0.3738 ± 0.1403 s/µmol/L, = 0.0174 with collagen/ADP coating; slope: -0.5340 ± 0.1473 s/µmol/L, = 0.0019 with collagen/epinephrine coating) by DEA-NONOate. These results in WB further support the pharmacological potential of S-NO-HSA as an NO-donor due to its ability to presumably prevent bleeding events even at high concentrations up to 200 µmol/L.
一氧化氮供体（NO供体）已被证明具有治疗潜力（例如，缺血/再灌注损伤）。然而，由于它们的释放速率/抗血小板特性，它们可能会导致患者出血。因此，我们研究了两种不同的NO供体，即S-NO-人血清白蛋白（S-NO-HSA）和二乙铵（Z）-1-（，-二乙氨基）重氮-1,2-二醇盐（DEA-NONOate）在全血（WB）样本中的抗血小板作用。将WB样本与S-NO-HSA或DEA-NONOate（100 µmol/L或200 µmol/L）混合，并评估NO释放速率（通过HPLC测定亚硝酸盐/硝酸盐水平）和抗血小板功效（阻抗聚集法、血小板功能分析仪、锥板血小板分析仪、血栓弹力图）。与等摩尔浓度的DEA-NONOate相比，S-NO-HSA的NO释放明显更低。在WB样本中几乎未观察到S-NO-HSA的抗血小板作用，而DEA-NONOate显著减弱了WB中的血小板功能。阻抗聚集法测量显示，DEA-NONOate使幅度（斜率：-0.04022±0.01045欧姆/µmol/L，P = 0.008）和延迟时间（斜率：0.6389±0.2075秒/µmol/L，P = 0.0051）呈剂量依赖性降低和延长。DEA-NONOate使封闭时间（锥板血小板分析仪）呈剂量依赖性延长（斜率：0.3738±0.1403秒/µmol/L，胶原蛋白/ADP包被时P = 0.0174；斜率：-0.5340±0.1473秒/µmol/L，胶原蛋白/肾上腺素包被时P = 0.0019）。WB中的这些结果进一步支持了S-NO-HSA作为NO供体的药理学潜力，因为即使在高达200 µmol/L的高浓度下，它也可能具有预防出血事件的能力。
