Departments of Cardiac Physiology and Advanced Medical Research in Pulmonary Hypertension, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan.
Monash Biomedicine Institute and Department of Physiology, Monash University, Melbourne, Australia.
Clin Sci (Lond). 2021 Jan 29;135(2):327-346. doi: 10.1042/CS20201441.
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 microangiography in 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.
高盐摄入加剧胰岛素抵抗，通过全身血管周围炎症、氧化应激和内皮功能障碍引起高血压。血管紧张素转换酶抑制剂（ACEi）和血管紧张素受体阻滞剂（ARB）已被证明可消除炎症和氧化应激，但仅部分恢复肠系膜血管内皮功能。我们研究了当高盐摄入与胰岛素抵抗结合时，交感肾上腺过度激活是否会引起冠状动脉血管功能障碍，在接受两种不同类型β受体阻滞剂或载体治疗的雄性 Goto-Kakizaki（GK）和 Wistar 大鼠中，利用基于同步加速器的活体微血管成像技术进行研究。此外，我们还研究了慢性卡维地洛（CAR）治疗是否比美托洛尔（MET）更能维持一氧化氮（NO）介导的冠状动脉扩张。高盐饮食（6% NaCl w/w）加剧了载体治疗的 GK 大鼠冠状动脉微血管内皮功能障碍和 NO 抵抗，而 Wistar 大鼠则表现出适度的损害。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）的表达升高有关。CAR 和 MET 均降低基础冠状动脉灌注，但恢复了微血管内皮依赖性和非依赖性扩张，表明交感肾上腺过度激活在载体治疗的大鼠中起作用。虽然 MET 治疗降低了心肌硝酸盐，但只有 MET 治疗完全恢复了微脉管舒张对多巴酚丁胺（DOB）的刺激，而没有 NO 和前列腺素（联合抑制），表明 MET 恢复了归因于内皮衍生超极化（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引起冠状动脉微血管内皮功能障碍和 NO 敏感性降低，尽管肾素-血管紧张素-醛固酮系统（RAAS）过度激活导致持续的炎症和氧化应激，MET 和 CAR 治疗仍可恢复这些功能。
