Biotechnology Center, Federal University of Paraíba, João Pessoa, PB, Brazil; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Redox Biol. 2018 May;15:182-191. doi: 10.1016/j.redox.2017.12.004. Epub 2017 Dec 11.
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).
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.
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.
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.
心血管疾病（包括高血压）的发展和进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。目前，使用有机硝酸盐恢复 NO 生物利用度的治疗策略受到不良副作用和耐受性发展的阻碍。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 释放能力和心血管效应。
采用体外和体内相结合的方法评估 NDHP 对 NO 释放、血管反应性和血压的急性影响。结合 NOS 抑制，在血管紧张素 II 诱导的高血压实验模型中评估慢性 NDHP 治疗的治疗价值。
NDHP 在无细胞体系和小阻力动脉中均介导 NO 的形成，这一过程由黄嘌呤氧化还原酶催化。NDHP 诱导的血管舒张不受内皮影响，由 NO 释放和钾通道调节介导。与正常血压假手术大鼠相比，急性静脉输注 NDHP 后降低高血压大鼠（双肾一夹模型）的血压更为明显。毒性试验未显示高剂量 NDHP 治疗后有任何有害影响。最后，慢性 NDHP 治疗显著减轻了慢性 NOS 抑制和血管紧张素 II 输注大鼠高血压和内皮功能障碍的发展。
新型有机硝酸盐 NDHP 的急性治疗可增加 NO 的形成，这与高血压动物的血管舒张和血压显著降低有关。慢性 NDHP 治疗可减轻高血压和内皮功能障碍的进展，表明其在心血管疾病治疗中有潜在应用。
