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Inhaled nitric oxide to control platelet hyper-reactivity in patients with acute submassive pulmonary embolism.
Nitric Oxide ( IF 3.2 ) Pub Date : 2020-01-12 , DOI: 10.1016/j.niox.2020.01.004 Jeffrey A Kline 1 , Michael A Puskarich 2 , Jonathan W Pike 1 , John Zagorski 1 , Nathan J Alves 1
Nitric Oxide ( IF 3.2 ) Pub Date : 2020-01-12 , DOI: 10.1016/j.niox.2020.01.004 Jeffrey A Kline 1 , Michael A Puskarich 2 , Jonathan W Pike 1 , John Zagorski 1 , Nathan J Alves 1
Affiliation
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BACKGROUND
We test if inhaled nitric oxide (NO) attenuates platelet functional and metabolic hyper-reactivity in subjects with submassive pulmonary embolism (PE).
METHODS
Participants with PE were randomized to either 50 ppm NO + O2 or O2 only for 24 h with blood sampling at enrollment and after treatment; results were compared with healthy controls. Platelet metabolic activity was assessed by oxygen consumption (basal and uncoupled) and reactivity was assessed with agonist-stimulated thromboelastography (TEG) and fluorometric measurement of agonist-stimulated cytosolic [Ca++] without and with pharmacological soluble guanylate (sGC) modulation.
RESULTS
Participants (N = 38 per group) were well-matched at enrollment for PE severity, comorbidities as well as TEG parameters and platelet O2 consumption. NO treatment doubled the mean plasma [NO3-] (P < 0.001) indicating successful delivery, but placebo treatment produced no change. After 24 h, neither TEG nor O2 consumption parameters differed significantly between treatment groups. Platelet cytosolic [Ca++] was elevated with PE versus controls, and was decreased by treatment with cinaciguat (an sGC activator), but not riociguat (an sGC stimulator). Stimulated platelet lysate sGC activity was increased with PE compared with controls.
CONCLUSIONS
In patients with acute submassive PE, despite evidence of adequate drug delivery, inhaled NO had no major effect on platelet O2 consumption or agonist-stimulated parameters on TEG. Pharmacological activation, but not stimulation, of sGC effectively decreased platelet cytosolic [Ca++], and platelet sGC activity was increased with PE, confirming the viability of sGC as a therapeutic target.
中文翻译：
吸入一氧化氮可控制急性亚大规模肺栓塞患者的血小板反应过度。
背景技术我们测试吸入性一氧化氮（NO）是否会减弱亚大规模肺栓塞（PE）患者的血小板功能和代谢反应过度。方法PE参与者在入选时和治疗后均随机抽取50 ppm NO + O2或O2进行24 h随机抽血。将结果与健康对照进行比较。血小板代谢活性通过耗氧量（基础的和非耦合的）进行评估，反应性通过激动剂刺激的血栓弹力描记术（TEG）进行评估，并在无药理可溶性鸟苷酸（sGC）调节的情况下，通过荧光测量激动剂刺激的胞浆[Ca ++]进行测定。结果参加者（每组N = 38）在PE严重程度，合并症，TEG参数和血小板O2摄入量方面完全匹配。NO治疗使平均血浆[NO3-]倍增（P <0.001），表明分娩成功，但安慰剂治疗无变化。24小时后，治疗组之间的TEG和O2消耗参数均无显着差异。与对照组相比，PE可使血小板胞浆[Ca ++]升高，而西那西瓜（一种sGC激活剂）治疗可降低血小板胞浆[Ca ++]，而利阿西瓜（一种sGC刺激剂）则不会治疗。与对照组相比，PE刺激的血小板裂解物sGC活性增加。结论尽管有充分药物递送的证据，但在急性亚大规模PE患者中，吸入NO对TEG的血小板O 2消耗或激动剂刺激参数没有重大影响。sGC的药理激活而非刺激作用有效地降低了血小板胞浆[Ca ++]的含量，PE增强了血小板sGC的活性，
更新日期：2020-01-13
中文翻译：
吸入一氧化氮可控制急性亚大规模肺栓塞患者的血小板反应过度。
背景技术我们测试吸入性一氧化氮（NO）是否会减弱亚大规模肺栓塞（PE）患者的血小板功能和代谢反应过度。方法PE参与者在入选时和治疗后均随机抽取50 ppm NO + O2或O2进行24 h随机抽血。将结果与健康对照进行比较。血小板代谢活性通过耗氧量（基础的和非耦合的）进行评估，反应性通过激动剂刺激的血栓弹力描记术（TEG）进行评估，并在无药理可溶性鸟苷酸（sGC）调节的情况下，通过荧光测量激动剂刺激的胞浆[Ca ++]进行测定。结果参加者（每组N = 38）在PE严重程度，合并症，TEG参数和血小板O2摄入量方面完全匹配。NO治疗使平均血浆[NO3-]倍增（P <0.001），表明分娩成功，但安慰剂治疗无变化。24小时后，治疗组之间的TEG和O2消耗参数均无显着差异。与对照组相比，PE可使血小板胞浆[Ca ++]升高，而西那西瓜（一种sGC激活剂）治疗可降低血小板胞浆[Ca ++]，而利阿西瓜（一种sGC刺激剂）则不会治疗。与对照组相比，PE刺激的血小板裂解物sGC活性增加。结论尽管有充分药物递送的证据，但在急性亚大规模PE患者中，吸入NO对TEG的血小板O 2消耗或激动剂刺激参数没有重大影响。sGC的药理激活而非刺激作用有效地降低了血小板胞浆[Ca ++]的含量，PE增强了血小板sGC的活性，
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