A chronic physical activity treatment in obese rats normalizes the contributions of ET-1 and NO to insulin-mediated posterior cerebral artery vasodilation.
A chronic physical activity treatment in obese rats normalizes the contributions of ET-1 and NO to insulin-mediated posterior cerebral artery vasodilation.
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肥胖大鼠的长期体力活动治疗使 ET-1 和 NO 对胰岛素介导的大脑后动脉血管舒张的贡献正常化。
DOI：
10.1152/japplphysiol.00811.2016
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发表时间：
2017
期刊：
影响因子：
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通讯作者：
Laughlin,MHarold
中科院分区：
文献类型：
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作者：
Olver,TDylan;McDonald,MatthewW;Klakotskaia,Diana;Richardson,RachelA;Jasperse,JeffreyL;Melling,CWJames;Schachtman,ToddR;Yang,HsiaoT;Emter,CraigA;Laughlin,MHarold
这项研究测试了这样的假设：肥胖引起的胰岛素刺激的脑血管舒张减少可以通过急性内皮素-1a受体拮抗作用而正常化，并且体力活动干预治疗可以通过增强一氧化氮合酶（NOS）依赖性扩张来恢复对胰岛素的血管反应性。 Otsuka Long-Evans Tokushima 脂肪大鼠被分为以下组：20周龄食物对照组（CON-20）； 20周龄免费获得食物（肥胖模型，OB-20）； 40 周龄食品受控 (CON-40)； 40周龄免费食物获取（OB-40）；以及 40 周免费食物访问+RUN（RUN-40；20 至 40 周的轮式运行访问）。大鼠接受巴恩斯迷宫测试和正常血糖高胰岛素钳夹（EHC）。在 40 周队列中，检查了小脑和海马血流 (BF)（微球输注）。在未治疗、内皮素-1a 受体拮抗和大脑后动脉 NOS 抑制条件下评估胰岛素的血管舒缩反应（加压肌动描记）。与 CON 和 RUN 组相比，OB 组中胰岛素刺激的血管舒张作用减弱（P≤0.04）。 OB 组中内皮素-1a 受体拮抗作用使胰岛素扩张正常化（组间，P≥0.56），并且 RUN-40 组与 OB-40 组相比，胰岛素刺激的 NOS 介导的扩张更大（P<0.01）。 40 周龄时，OB-40 组 EHC 期间小脑 BF 下降（P=0.02），但 CON 或 RUN 组则没有下降（P≥0.36）。 Barnes 迷宫测试显示，与 CON 和 OB 组相比，RUN-40 组的输入错误和延迟增加（P < 0.01）。这些发现表明，肥胖引起的胰岛素血管反应性受损涉及内皮素-1 增加和一氧化氮信号传导减少。疾病发作后开始的慢性自发体力活动，可逆转胰岛素血管舒张受损和巴恩斯迷宫表现下降，这可能是由于探索行为的增加。新的值得注意的新发现是：1) 在啮齿类动物中，肥胖相关的胰岛素介导的血管舒张缺陷与胰岛素刺激的 ET-1 的影响增加和胰岛素刺激的 NOS 的影响减弱有关，2) 疾病发作后开始的体力活动干预可恢复胰岛素介导的血管舒张功能血管舒张，可能是通过使胰岛素刺激的 ET-1 和 NOS 平衡正常化来实现的。这些数据表明，长期运动对胰岛素介导的血管舒张的治疗作用超出了活跃的骨骼肌血管系统，还包括脑血管系统。
This study tested the hypotheses that obesity-induced decrements in insulin-stimulated cerebrovascular vasodilation would be normalized with acute endothelin-1a receptor antagonism and that treatment with a physical activity intervention restores vasoreactivity to insulin through augmented nitric oxide synthase (NOS)-dependent dilation. Otsuka Long-Evans Tokushima Fatty rats were divided into the following groups: 20 wk old food controlled (CON-20); 20 wk old free food access (model of obesity, OB-20); 40 wk old food controlled (CON-40); 40 wk old free food access (OB-40); and 40 wk old free food access+RUN (RUN-40; wheel-running access from 20 to 40 wk). Rats underwent Barnes maze testing and a euglycemic hyperinsulinemic clamp (EHC). In the 40-wk cohort, cerebellum and hippocampus blood flow (BF) were examined (microsphere infusion). Vasomotor responses (pressurized myography) to insulin were assessed in untreated, endothelin-1a receptor antagonism, and NOS inhibition conditions in posterior cerebral arteries. Insulin-stimulated vasodilation was attenuated in the OB vs. CON and RUN groups (P≤ 0.04). Dilation to insulin was normalized with endothelin-1a receptor antagonism in the OB groups (between groups,P≥ 0.56), and insulin-stimulated NOS-mediated dilation was greater in the RUN-40 vs. OB-40 group (P< 0.01). At 40 wk of age, cerebellum BF decreased during EHC in the OB-40 group (P= 0.02) but not CON or RUN groups (P≥ 0.36). Barnes maze testing revealed increased entry errors and latencies in the RUN-40 vs. CON and OB groups (P< 0.01). These findings indicate that obesity-induced impairments in vasoreactivity to insulin involve increased endothelin-1 and decreased nitric oxide signaling. Chronic spontaneous physical activity, initiated after disease onset, reversed impaired vasodilation to insulin and decreased Barnes maze performance, possibly because of increased exploratory behavior.NEW & NOTEWORTHYThe new and noteworthy findings are that1) in rodents, obesity-related deficits in insulin-mediated vasodilation are associated with increased influence of insulin-stimulated ET-1 and depressed influence of insulin-stimulated NOS and2) a physical activity intervention, initiated after the onset of disease, restores insulin-mediated vasodilation, likely by normalizing insulin-stimulated ET-1 and NOS balance. These data demonstrate that the treatment effects of chronic exercise on insulin-mediated vasodilation extend beyond active skeletal muscle vasculature and include the cerebrovasculature.