Rationale

Development and progression of cardiovascular diseases, including hypertension, are often associated with impaired nitric oxide synthase (NOS) function and nitric oxide (NO) deficiency. Current treatment strategies to restore NO bioavailability with organic nitrates are hampered by undesirable side effects and development of tolerance. In this study, we evaluated NO release capability and cardiovascular effects of the newly synthesized organic nitrate 1, 3-bis (hexyloxy) propan-2-yl nitrate (NDHP).

Methods

A combination of in vitro and in vivo approaches was utilized to assess acute effects of NDHP on NO release, vascular reactivity and blood pressure. The therapeutic value of chronic NDHP treatment was assessed in an experimental model of angiotensin II-induced hypertension in combination with NOS inhibition.

Results

NDHP mediates NO formation in both cell-free system and small resistance arteries, a process which is catalyzed by xanthine oxidoreductase. NDHP-induced vasorelaxation is endothelium independent and mediated by NO release and modulation of potassium channels. Reduction of blood pressure following acute intravenous infusion of NDHP was more pronounced in hypertensive rats (two-kidney-one-clip model) than in normotensive sham-operated rats. Toxicological tests did not reveal any harmful effects following treatment with high doses of NDHP. Finally, chronic treatment with NDHP significantly attenuated the development of hypertension and endothelial dysfunction in rats with chronic NOS inhibition and angiotensin II infusion.

Conclusion

Acute treatment with the novel organic nitrate NDHP increases NO formation, which is associated with vasorelaxation and a significant reduction of blood pressure in hypertensive animals. Chronic NDHP treatment attenuates the progression of hypertension and endothelial dysfunction, suggesting a potential for therapeutic applications in cardiovascular disease.

中文翻译：

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新型有机单硝酸盐NDHP可减轻高血压大鼠的高血压和内皮功能障碍

基本原理

心血管疾病（包括高血压）的发生和发展通常与一氧化氮合酶（NOS）功能受损和一氧化氮（NO）缺乏有关。不良的副作用和耐受性的发展阻碍了目前用有机硝酸盐恢复NO生物利用度的治疗策略。在这项研究中，我们评估了新合成的有机硝酸盐1、3-双（己氧基）丙-2-基硝酸盐（NDHP）的NO释放能力和心血管作用。

方法

利用体外和体内方法的组合来评估NDHP对NO释放，血管反应性和血压的急性影响。在血管紧张素II诱发的高血压与NOS抑制相结合的实验模型中评估了慢性NDHP治疗的治疗价值。

结果

NDHP介导无细胞系统和小的阻力动脉中NO的形成，该过程由黄嘌呤氧化还原酶催化。NDHP诱导的血管舒张是内皮独立的，并由NO释放和钾通道的调节介导。在高血压大鼠（两肾一夹模型）中，急性静脉内注射NDHP后的血压降低比正常血压的假手术大鼠更明显。毒理学测试未显示大剂量NDHP治疗后有任何有害作用。最后，用NDHP进行慢性治疗可显着减轻患有慢性NOS抑制和血管紧张素II输注的大鼠的高血压和内皮功能障碍。

结论

用新型有机硝酸盐NDHP进行的急性治疗会增加NO的形成，这与血管舒张和高血压动物血压的显着降低有关。慢性NDHP治疗可减轻高血压和内皮功能障碍的进展，提示其在心血管疾病中的治疗应用潜力。