β-blockade prevents coronary macro- and microvascular dysfunction induced by a high salt diet and insulin resistance in the Goto?Kakizaki rat
β-blockade prevents coronary macro- and microvascular dysfunction induced by a high salt diet and insulin resistance in the Goto?Kakizaki rat
复制标题
β-阻断可预防 Goto?Kakizaki 大鼠由高盐饮食和胰岛素抵抗引起的冠状动脉大血管和微血管功能障碍
DOI：
10.1042/cs20201441
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发表时间：
2021
期刊：
影响因子：
6
通讯作者：
Pearson James T. et al
中科院分区：
文献类型：
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作者：
Pearson James T. et al
高盐摄入会加剧胰岛素抵抗，引起全身血管周围炎症、氧化-亚硝化应激和内皮功能障碍引起的高血压。血管紧张素转换酶抑制剂（ACEi）和血管紧张素受体阻滞剂（ARB）已被证明可以消除炎症和氧化还原应激，但只能部分恢复肠系膜血管的内皮功能。我们研究了当高盐摄入与胰岛素抵抗相结合时，交感-肾上腺过度激活是否会引起雄性Goto-Kakizaki（GK）和Wistar大鼠的冠状动脉血管功能障碍，这些大鼠接受了两种不同类型的β受体阻滞剂或载体，利用体内同步加速器微血管造影术。此外，我们研究了长期卡维地洛（CAR）治疗是否比美托洛尔（MET）更能保护一氧化氮（NO）介导的冠状动脉扩张。高盐饮食（6%NaCl w/w）加重了冠状动脉微血管内皮功能障碍和NO-抵抗的车辆治疗GK大鼠，而Wistar大鼠表现出适度的损害。微血管功能障碍与心肌内皮素、诱导型一氧化氮合酶（NOS）蛋白和3-硝基酪氨酸（3-NT）表达升高有关。CAR和MET均降低了基础冠状动脉灌注，但恢复了微血管内皮依赖性和非依赖性扩张，表明在溶剂处理的大鼠中交感-肾上腺过度激活的作用。虽然MET治疗降低了心肌硝酸盐，但只有MET治疗在不存在NO和前列腺素（联合抑制）的情况下完全恢复了多巴酚丁胺（DOB）刺激的微血管扩张，表明MET恢复了归因于内皮源性超极化（EDH）的冠状动脉血流储备。总之，高盐摄入和胰岛素抵抗引起的交感-肾上腺过度激活诱发冠状动脉微血管内皮功能障碍和NO敏感性降低，MET和CAR治疗恢复，尽管持续的炎症和氧化-亚硝化应激可能是由不受抑制的肾素-血管紧张素-醛固酮系统（RAAS）过度激活引起的。
A high salt intake exacerbates insulin resistance, evoking hypertension due to systemic perivascular inflammation, oxidative-nitrosative stress and endothelial dysfunction. Angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blockers (ARBs) have been shown to abolish inflammation and redox stress but only partially restore endothelial function in mesenteric vessels. We investigated whether sympatho-adrenal overactivation evokes coronary vascular dysfunction when a high salt intake is combined with insulin resistance in male Goto–Kakizaki (GK) and Wistar rats treated with two different classes of β-blocker or vehicle, utilising synchrotron-based microangiographyin vivo. Further, we examined if chronic carvedilol (CAR) treatment preserves nitric oxide (NO)-mediated coronary dilation more than metoprolol (MET). A high salt diet (6% NaCl w/w) exacerbated coronary microvessel endothelial dysfunction and NO-resistance in vehicle-treated GK rats while Wistar rats showed modest impairment. Microvascular dysfunction was associated with elevated expression of myocardial endothelin, inducible NO synthase (NOS) protein and 3-nitrotyrosine (3-NT). Both CAR and MET reduced basal coronary perfusion but restored microvessel endothelium-dependent and -independent dilation indicating a role for sympatho-adrenal overactivation in vehicle-treated rats. While MET treatment reduced myocardial nitrates, only MET treatment completely restored microvessel dilation to dobutamine (DOB) stimulation in the absence of NO and prostanoids (combined inhibition), indicating that MET restored the coronary flow reserve attributable to endothelium-derived hyperpolarisation (EDH). In conclusion, sympatho-adrenal overactivation caused by high salt intake and insulin resistance evoked coronary microvessel endothelial dysfunction and diminished NO sensitivity, which were restored by MET and CAR treatment in spite of ongoing inflammation and oxidative-nitrosative stress presumably caused by uninhibited renin–angiotensin–aldosterone system (RAAS) overactivation.