Introduction

Cardiovascular diseases are coupled to decreased nitric oxide (NO) bioavailability, and there is a constant search for novel and better NO-donors. Here we synthesized and characterized the cardiovascular effects of the new organic nitrate 2-nitrate-1,3-dioctanoxypropan (NDOP).

Methods

A combination of in vitro and in vivo experiments was performed in C57BL/6 mice and Wistar rats. Thus, the ability of NDOP in donating NO in a cell-free system and in vascular smooth muscles cells (VSMC) and its ability to induce vasorelaxation in aortic rings from mice were evaluated. In addition, changes in blood pressure and heart rate to different doses of NDOP were evaluated in conscious rats. Finally, acute pre-clinical toxicity to oral administration of NDOP was assessed in mice.

Results

In cell-free system, NDOP increased NO levels, which was dependent on xanthine oxidoreductase (XOR). NDOP also increased NO levels in VSMC, which was not influenced by endothelial NO synthase. Furthermore, incubation with the XOR inhibitor febuxostat blunted the vasorelaxation in aortic ring preparations. In conscious rats, NDOP elicited dose-dependent reduction in blood pressure accompanied with increased heart rate. In vessel preparations, NDOP (10⁻⁸-10⁻³ mol/L) induced endothelium-independent vasorelaxation, which was inhibited by the NO scavengers 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide and hydroxocobalamin or by inhibition of soluble guanylyl cyclase using H- [1,2,4] oxadiazolo [4,3-a]quinoxalin-1-one. To investigate if NDOP acts through potassium channels, selective blockers were used. Inhibition of BK_Ca, K_v or K_ATP subtypes of potassium channels had no effect, but inhibition of inward-rectifier potassium channels (K_IR) significantly reduced NDOP-mediated vasorelaxation. Lastly, NDOP showed low toxicity (LD₅₀ ~5000 mg/kg).

Conclusion

Bioactivation of NDOP involves functional XOR, and this new organic nitrate elicits vasorelaxation via NO-cGMP-PKG signaling and activation of K_IR channels. Future studies should further characterize the underlying mechanism and evaluate the therapeutic benefits of chronic NDOP treatment in relevant cardiovascular disease models.

中文翻译：

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新型有机硝酸盐2-硝酸盐-1,3-二辛氧基丙烷（NDOP）通过激活内向整流器钾通道（K _IR）诱导一氧化氮的产生和血管舒张。

介绍

心血管疾病与一氧化氮（NO）的生物利用度降低相关，因此人们一直在寻找新颖，更好的NO供体。在这里，我们合成并表征了新型有机硝酸盐2-硝酸盐-1,3-二辛烷氧基丙烷（NDOP）的心血管作用。

方法

在C57BL / 6小鼠和Wistar大鼠中进行了体外和体内实验的组合。因此，评估了NDOP在无细胞系统和血管平滑肌细胞（VSMC）中捐献NO的能力及其在小鼠主动脉环中诱导血管舒张的能力。此外，在清醒大鼠中评估了不同剂量的NDOP引起的血压和心率变化。最后，在小鼠中评估了对口服NDOP的急性临床前毒性。

结果

在无细胞系统中，NDOP增加了NO水平，这取决于黄嘌呤氧化还原酶（XOR）。NDOP还增加了VSMC中的NO水平，不受内皮NO合酶的影响。此外，与XOR抑制剂非布索坦一起温育使主动脉环制剂中的血管舒张减弱。在清醒的大鼠中，NDOP引起血压的剂量依赖性降低，并伴有心律加快。在容器准备中，NDOP（10 ^-8 -10 ^-3 （mol / L）诱导内皮依赖性血管舒张，其被NO清除剂2-苯基-4,4,5,5-四甲基咪唑啉-1-氧基-3-氧化物和羟考拉巴宁抑制，或通过使用H-抑制可溶性胍基环化酶来抑制[1,2,4]恶二唑[4,3-a]喹喔啉-1-酮。为了研究NDOP是否通过钾通道起作用，使用了选择性阻滞剂。抑制钾离子通道的BK _Ca，K _v或K _ATP亚型没有作用，但是抑制内向整流钾离子通道（K _IR）则明显减少了NDOP介导的血管舒张。最后，NDOP显示低毒性（LD ₅₀〜5000毫克/千克）。

结论

NDOP的生物活化涉及功能性XOR，这种新的有机硝酸盐通过NO-cGMP-PKG信号传导和K _IR通道活化引发血管舒张。未来的研究应进一步表征其潜在机制，并评估慢性NDOP治疗在相关心血管疾病模型中的治疗效果。