Sustained release nitrite therapy results in myocardial protection in a porcine model of metabolic syndrome with peripheral vascular disease
Sustained release nitrite therapy results in myocardial protection in a porcine model of metabolic syndrome with peripheral vascular disease
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DOI：
10.1152/ajpheart.00163.2015
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发表时间：
2015-07-15
影响因子：
4.8
通讯作者：
Lefer, David J.
中科院分区：
文献类型：
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作者：
Bradley, Jessica M.;Islam, Kazi N.;Lefer, David J.
代谢综合征（MetS）降低内皮一氧化氮（NO）的生物利用度，并加剧血管功能障碍的患者既往存在的血管疾病。亚硝酸盐是一氧化氮的一种储存形式，在内源性一氧化氮减少的病理状态下可以调节血管功能。本研究的目的是在肥胖Ossabaw猪（OS）模型中表征严重MetS和肥胖对血脂异常、心肌氧化应激和内皮NO合成酶（eNOS）调节的影响，并研究一种新型缓释亚硝酸钠（sr -亚硝酸钠）对重度肢体缺血（CLI）肥胖osabaw猪冠状动脉反应性和心肌氧化还原状态的影响。在6个月的致动脉粥样硬化饮食后，肥胖OS表现出MetS表型。肥胖的OS降低了eNOS功能和NO的生物利用度。此外，肥胖的OS表现出氧化应激增加和抗氧化酶显著降低。研究了sr -亚硝酸盐治疗肥胖OS的疗效。处理3周后，sr -亚硝酸盐（80 mg.kg(-1)）。day(1) bid po)增加心肌亚硝酸盐水平和eNOS功能。sr -亚硝酸盐处理可降低心肌氧化应激，提高心肌抗氧化能力。体外对左冠状动脉前降段血管反应性的评估显示，与安慰剂治疗的动物相比，sr -亚硝酸盐治疗的动物对硝普钠的血管反应性有明显改善，但对P物质和缓激肽的血管反应性没有改善。总之，在临床相关的MetS和CLI大动物模型中，sr -亚硝酸盐治疗可增强心肌NO生物利用度，减轻氧化应激，改善体外冠状动脉血管舒张。
Metabolic syndrome (MetS) reduces endothelial nitric oxide (NO) bioavailability and exacerbates vascular dysfunction in patients with preexisting vascular diseases. Nitrite, a storage form of NO, can mediate vascular function during pathological conditions when endogenous NO is reduced. The aims of the present study were to characterize the effects of severe MetS and obesity on dyslipidemia, myocardial oxidative stress, and endothelial NO synthase (eNOS) regulation in the obese Ossabaw swine (OS) model and to examine the effects of a novel, sustained-release formulation of sodium nitrite (SR-nitrite) on coronary vascular reactivity and myocardial redox status in obese OS subjected to critical limb ischemia (CLI). After 6 mo of an atherogenic diet, obese OS displayed a MetS phenotype. Obese OS had decreased eNOS functionality and NO bioavailability. In addition, obese OS exhibited increased oxidative stress and a significant reduction in antioxidant enzymes. The efficacy of SR-nitrite therapy was examined in obese OS subjected to CLI. After 3 wk of treatment, SR-nitrite (80 mg.kg(-1).day(-1) bid po) increased myocardial nitrite levels and eNOS function. Treatment with SR-nitrite reduced myocardial oxidative stress while increasing myocardial antioxidant capacity. Ex vivo assessment of vascular reactivity of left anterior descending coronary artery segments demonstrated marked improvement in vasoreactivity to sodium nitroprusside but not to substance P and bradykinin in SR-nitrite-treated animals compared with placebo-treated animals. In conclusion, in a clinically relevant, large-animal model of MetS and CLI, treatment with SR-nitrite enhanced myocardial NO bioavailability, attenuated oxidative stress, and improved ex vivo coronary artery vasorelaxation.