Antiplatelet effects of dietary nitrate in healthy volunteers: involvement of cGMP and influence of sex.

Free radical biology & medicine Pub Date : 2013-12-01 Epub Date: 2013-06-24 DOI:10.1016/j.freeradbiomed.2013.06.031
Shanti Velmurugan, Vikas Kapil, Suborno M Ghosh, Sheridan Davies, Andrew McKnight, Zainab Aboud, Rayomand S Khambata, Andrew J Webb, Alastair Poole, Amrita Ahluwalia
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Abstract

Ingestion of vegetables rich in inorganic nitrate has emerged as an effective method, via the formation of a nitrite intermediate, for acutely elevating vascular NO levels. As such a number of beneficial effects of dietary nitrate ingestion have been demonstrated including the suggestion that platelet reactivity is reduced. In this study we investigated whether inorganic nitrate supplementation might also reduce platelet reactivity in healthy volunteers and have determined the mechanisms involved in the effects seen. We conducted two randomised crossover studies each in 24 (12 of each sex) healthy subjects assessing the acute effects of dietary nitrate (250 ml beetroot juice) or potassium nitrate capsules (KNO3, 8 mmol) vs placebo control on platelet reactivity. Inorganic nitrate ingested either from a dietary source or via supplementation raised circulating nitrate and nitrite levels in both sexes and attenuated ex vivo platelet aggregation responses to ADP and, albeit to a lesser extent, collagen but not epinephrine in male but not female volunteers. These inhibitory effects were associated with a reduced platelet P-selectin expression and elevated platelet cGMP levels. In addition, we show that nitrite reduction to NO occurs at the level of the erythrocyte and not the platelet. In summary, our results demonstrate that inorganic nitrate ingestion, whether via the diet or through supplementation, causes a modest decrease in platelet reactivity in healthy males but not females. Our studies provide strong support for further clinical trials investigating the potential of dietary nitrate as an adjunct to current antiplatelet therapies to prevent atherothrombotic complications. Moreover, our observations highlight a previously unknown sexual dimorphism in platelet reactivity to NO and intimate a greater dependence of males on the NO-soluble guanylate cyclase pathway in limiting thrombotic potential.

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健康志愿者膳食硝酸盐的抗血小板作用:cGMP的参与和性别的影响
摄入富含无机硝酸盐的蔬菜已成为一种有效的方法,通过形成亚硝酸盐中间体,急剧升高血管NO水平。因此,饮食中摄入硝酸盐的许多有益影响已被证明,包括血小板反应性降低的建议。在这项研究中,我们调查了无机硝酸盐补充剂是否也可能降低健康志愿者的血小板反应性,并确定了所见效果的机制。我们进行了两项随机交叉研究,每项研究在24名(男女各12名)健康受试者中进行,评估膳食硝酸盐(250毫升甜菜根汁)或硝酸钾胶囊(kno3,8 mmol)与安慰剂对照对血小板反应性的急性影响。从饮食来源或通过补充摄入的无机硝酸盐提高了两性中循环硝酸盐和亚硝酸盐的水平,并减弱了体外血小板聚集对ADP的反应,尽管程度较小,但在男性志愿者中胶原蛋白的反应减弱,而在女性志愿者中肾上腺素的反应没有减弱。这些抑制作用与血小板p选择素表达降低和血小板cGMP水平升高有关。此外,我们发现亚硝酸盐还原为NO发生在红细胞水平,而不是血小板水平。总之,我们的研究结果表明,无论是通过饮食还是通过补充剂摄入无机硝酸盐,都会导致健康男性血小板反应性适度降低,而女性则不会。我们的研究为进一步的临床试验提供了强有力的支持,研究膳食硝酸盐作为当前抗血小板治疗的辅助疗法,预防动脉粥样硬化血栓并发症的潜力。此外,我们的观察结果强调了先前未知的血小板对NO的反应性的性别二态性,并表明男性在限制血栓形成潜力方面更依赖NO可溶性鸟苷酸环化酶途径。
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