Yada Toyotaka, Shimokawa Hiroaki, Tachibana Hiroyuki
Department of Biochemistry, Kawasaki Medical School, Kurashiki, Japan.
Department of Medical Engineering, Kawasaki University of Medical Welfare, Kurashiki, Japan.
Microcirculation. 2018 Jul;25(5):e12456. doi: 10.1111/micc.12456. Epub 2018 May 18.
It has been previously demonstrated that endothelial caveolin-1 plays crucial roles to produce an endothelium-derived hyperpolarizing factor in mouse mesenteric arteries. We examined whether this mechanism is involved in the endothelium-dependent hyperpolarization-mediated responses to compensate reduced NO-mediated responses in diabetes mellitus during coronary occlusion in dogs in vivo.
Canine subepicardial collateral coronary small arteries (≥100 μm) and arterioles (<100 μm) were observed by an intravital microscope. Experiments were performed during occlusion of the left anterior descending coronary artery (90 minutes) under the following conditions (n = 6 each); (i) control, (ii) diabetes mellitus, and (iii) diabetes mellitus+L-NMMA+K channel blockade. Vascular and myocardial levels of caveolin-1, eNOS, and caspase-3 were measured by ELISA.
Caveolin-1 levels in the ischemic area were greater in coronary microvessels than in conduit arteries in the control group. NO-mediated coronary vasodilatations of small arteries to bradykinin did not increase in diabetes mellitus associated with decreased eNOS phosphorylation at Ser1177 compared with baseline of controls and were restored by compensation of endothelium-dependent hyperpolarization and were suppressed by K channel blockade.
NO-mediated vasodilatations of small coronary arteries during coronary occlusion are impaired in diabetes mellitus and are compensated by endothelium-dependent hyperpolarization of arterioles in dogs in vivo.
先前已证明，内皮小窝蛋白-1在小鼠肠系膜动脉中产生内皮源性超极化因子方面发挥关键作用。我们研究了在犬体内冠状动脉闭塞期间，该机制是否参与了内皮依赖性超极化介导的反应，以补偿糖尿病中一氧化氮（NO）介导反应的减少。
用活体显微镜观察犬的心外膜下冠状动脉小动脉（≥100μm）和小动脉（<100μm）。在以下条件下（每组n = 6），于左前降支冠状动脉闭塞期间（90分钟）进行实验：（i）对照，（ii）糖尿病，（iii）糖尿病+L-NMMA+钾通道阻断。通过酶联免疫吸附测定法（ELISA）测量小窝蛋白-1、内皮型一氧化氮合酶（eNOS）和半胱天冬酶-3的血管和心肌水平。
在对照组中，缺血区域中小冠状动脉微血管的小窝蛋白-1水平高于传导动脉。与对照组基线相比，糖尿病时小动脉对缓激肽的NO介导的冠状动脉舒张未增加，这与Ser1177位点eNOS磷酸化降低有关，且通过内皮依赖性超极化的补偿得以恢复，并被钾通道阻断所抑制。
在犬体内，糖尿病时冠状动脉闭塞期间小冠状动脉的NO介导的舒张受损，并通过小动脉的内皮依赖性超极化得到补偿。
