Kirkby Nicholas S, Tesfai Abel, Ahmetaj-Shala Blerina, Gashaw Hime H, Sampaio Walkyria, Etelvino Gisele, Leão Nádia Miricéia, Santos Robson A, Mitchell Jane A
Vascular Biology Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom; and
Vascular Biology Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom; and.
FASEB J. 2016 Dec;30(12):4172-4179. doi: 10.1096/fj.201600647R. Epub 2016 Sep 6.
Nonsteroidal antiinflammatory drugs, including ibuprofen, are among the most commonly used medications and produce their antiinflammatory effects by blocking cyclooxygenase (COX)-2. Their use is associated with increased risk of heart attacks caused by blocking COX-2 in the vasculature and/or kidney, with our recent work implicating the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA), a cardiotoxic hormone whose effects can be prevented by l-arginine. The ibuprofen salt ibuprofen arginate (Spididol) was created to increase solubility but we suggest that it could also augment the NO pathway through codelivery of arginine. Here we investigated the idea that ibuprofen arginate can act to simultaneously inhibit COX-2 and preserve the NO pathway. Ibuprofen arginate functioned similarly to ibuprofen sodium for inhibition of mouse/human COX-2, but only ibuprofen arginate served as a substrate for NOS. Ibuprofen arginate but not ibuprofen sodium also reversed the inhibitory effects of ADMA and N-nitro-l-arginine methyl ester on inducible NOS (macrophages) and endothelial NOS in vitro (aorta) and in vivo (blood pressure). These observations show that ibuprofen arginate provides, in one preparation, a COX-2 inhibitor and NOS substrate that could act to negate the harmful cardiovascular consequences mediated by blocking renal COX-2 and increased ADMA. While remarkably simple, our findings are potentially game-changing in the nonsteroidal antiinflammatory drug arena.-Kirkby, N. S., Tesfai, A., Ahmetaj-Shala, B., Gashaw, H. H., Sampaio, W., Etelvino, G., Leão, N. M., Santos, R. A., Mitchell, J. A. Ibuprofen arginate retains eNOS substrate activity and reverses endothelial dysfunction: implications for the COX-2/ADMA axis.
包括布洛芬在内的非甾体抗炎药是最常用的药物之一，它们通过阻断环氧化酶（COX）-2发挥抗炎作用。其使用与因阻断血管和/或肾脏中的COX-2而导致心脏病发作的风险增加有关，我们最近的研究表明内源性一氧化氮合酶抑制剂不对称二甲基精氨酸（ADMA）是一种心脏毒性激素，其作用可被L-精氨酸预防。布洛芬盐精氨酸布洛芬（Spididol）的产生是为了提高溶解度，但我们认为它也可以通过精氨酸的共递送增强一氧化氮途径。在这里，我们研究了精氨酸布洛芬可以同时抑制COX-2并保留一氧化氮途径的想法。精氨酸布洛芬在抑制小鼠/人COX-2方面的作用与布洛芬钠相似，但只有精氨酸布洛芬可作为一氧化氮合酶的底物。精氨酸布洛芬而非布洛芬钠还能在体外（主动脉）和体内（血压）逆转ADMA和N-硝基-L-精氨酸甲酯对诱导型一氧化氮合酶（巨噬细胞）和内皮型一氧化氮合酶的抑制作用。这些观察结果表明，精氨酸布洛芬在一种制剂中提供了一种COX-2抑制剂和一氧化氮合酶底物，它们可以消除因阻断肾脏COX-2和ADMA增加而介导的有害心血管后果。虽然非常简单，但我们的发现可能会在非甾体抗炎药领域引发变革。-柯克比，N.S.，特斯法伊，A.，阿赫梅塔伊-沙拉，B.，加肖，H.H.，桑帕约，W.，埃特尔维诺，G.，莱昂，N.M.，桑托斯，R.A.，米切尔，J.A.精氨酸布洛芬保留内皮型一氧化氮合酶底物活性并逆转内皮功能障碍：对COX-2/ADMA轴的影响
