Cabrales Pedro, Caroen Scott, Oronsky Arnold, Carter Corey, Trepel Jane, Summers Thomas, Reid Tony, Oronsky Neil, Lybeck Michelle, Oronsky Bryan
a Department of Bioengineering , University of California San Diego (UCSD) , La Jolla , CA , USA.
b EpicentRx , Mountain View , CA , USA.
Expert Rev Hematol. 2017 Jun;10(6):575-582. doi: 10.1080/17474086.2017.1324779. Epub 2017 May 22.
RRx-001, a clinical macrophage-stimulating anti-cancer agent that also produces nitric oxide (NO) was studied in a model of ischemia-reperfusion injury.
The production of NO is dependent on the oxygen tension because nitric oxide synthases convert l-arginine to NO and l-citrulline in the presence of O. Since the P450 enzymes, which metabolize nitrate esters such as nitroglycerin are dependent on oxygen, the generation of 'exogenous' NO is also sensitive to alterations in tissue PO. I/R injury was studied in a hamster chamber window, with compression of the periphery of the window for 1 h to induce ischemia. Animals received RRx-001 (5 mg/kg) 24 h before ischemia and sodium nitrite (10 nmols/kg) was supplemented 10 min after the start of reperfusion. Vessel diameter, blood flow, adherent leukocytes, and functional capillary density were assessed by intravital microscopy at 0.5, 2, and 24 h following the release of the ischemia.
The results demonstrated that, compared to control, RRx-001 preconditioning increased blood flow and functional capillary density, and preserved tissue viability in the absence of side effects over a sustained time period.
Thus, RRx-001 may serve as a long-lived protective agent during postsurgical restoration of flow and other ischemia-reperfusion associated conditions, increasing blood flow and functional capillary density as well as preserving tissue viability in the absence of side effects.
RRx-001是一种具有临床应用价值的巨噬细胞刺激抗癌剂，同时也能产生一氧化氮（NO），本研究在缺血再灌注损伤模型中对其进行了研究。
NO的产生取决于氧张力，因为一氧化氮合酶在有氧的情况下将L-精氨酸转化为NO和L-瓜氨酸。由于代谢硝酸酯类（如硝酸甘油）的P450酶依赖于氧，“外源性”NO的生成也对组织氧分压的变化敏感。在仓鼠室窗模型中研究缺血再灌注损伤，通过对窗周进行1小时的压迫来诱导缺血。动物在缺血前24小时接受RRx-001（5毫克/千克），再灌注开始10分钟后补充亚硝酸钠（10纳摩尔/千克）。在解除缺血后的0.5、2和24小时，通过活体显微镜评估血管直径、血流量、黏附白细胞和功能性毛细血管密度。
结果表明，与对照组相比，RRx-001预处理可增加血流量和功能性毛细血管密度，并在较长时间内维持组织活力且无副作用。
因此，RRx-001在术后血流恢复及其他缺血再灌注相关情况下，可能作为一种长效保护剂，增加血流量和功能性毛细血管密度，同时在无副作用的情况下维持组织活力。
