Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan.
Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan.
Eur J Pharmacol. 2017 Jul 15;807:151-158. doi: 10.1016/j.ejphar.2017.03.062. Epub 2017 Apr 19.
Endothelium-derived hyperpolarization (EDH) is an important signaling mechanism of endothelium-dependent vasorelaxation, and little attention has been paid to the EDH-type responses in female metabolic syndrome such as that observed with type-2 diabetes. We previously reported that EDH-type relaxation was impaired in superior mesenteric arteries from male Otsuka Long-Evans Tokushima Fatty (OLETF) rat, a model of type-2 diabetes, however, the response was unclear in female OLETF rat. Thus, the aim of this study was to examine if EDH-type relaxation was altered in superior mesenteric arteries isolated from female OLETF rats compared to age-matched, control female Long-Evans Tokushima Otsuka (LETO) rats at age 50-59 weeks. We investigated concentration-relaxation curves for acetylcholine (at age 50-53 weeks), NS309 (an activator of small- and intermediate-conductance calcium-activated potassium channels) (at age 50-53 weeks), and GSK1016790A (an agonist of transient receptor potential vanilloid type 4, TRPV4) (at age 58 or 59 weeks) in the presence of the nitric oxide synthase inhibitor N-nitro-L-arginine and the cyclooxygenase inhibitor indomethacin to investigate EDH-type responses in the superior mesenteric artery. Obesity, mild hyperglycemia, hyperinsulinemia, and hyperlipidemia (i.e., increased total cholesterol, triglyceride, and non-esterified fatty acids) were more frequent in OLETF rats than in age-matched LETO rats at age 50-53 weeks. Acetylcholine-, NS309-, and GSK1016790A-induced relaxations in arteries from OLETF rats were all significantly reduced compared to those in LETO rats. These results indicated that EDH-type relaxations were impaired in female OLETF rats. This novel experimental model may provide new insights into vascular dysfunction in metabolic syndrome in females.
内皮细胞衍生的超极化（EDH）是内皮依赖性血管舒张的重要信号机制，但对于女性代谢综合征（如 2 型糖尿病）中的 EDH 型反应，关注甚少。我们之前曾报道过，2 型糖尿病模型 Otsuka Long-Evans Tokushima Fatty（OLETF）雄性大鼠肠系膜上动脉的 EDH 型舒张受损，然而，在雌性 OLETF 大鼠中，这种反应尚不清楚。因此，本研究旨在探讨与年龄匹配的雌性 Long-Evans Tokushima Otsuka（LETO）大鼠相比，50-59 周龄雌性 OLETF 大鼠肠系膜上动脉的 EDH 型舒张是否发生改变。我们在存在一氧化氮合酶抑制剂 N-硝基-L-精氨酸和环氧化酶抑制剂吲哚美辛的情况下，研究了乙酰胆碱（50-53 周龄）、NS309（小和中等电导钙激活钾通道激活剂）（50-53 周龄）和 GSK1016790A（瞬时受体电位香草酸 4，TRPV4 激动剂）（58 或 59 周龄）的浓度-舒张曲线，以研究肠系膜上动脉的 EDH 型反应。肥胖、轻度高血糖、高胰岛素血症和高脂血症（即总胆固醇、甘油三酯和非酯化脂肪酸增加）在 50-53 周龄时在 OLETF 大鼠中比在年龄匹配的 LETO 大鼠中更为常见。与 LETO 大鼠相比，OLETF 大鼠的乙酰胆碱、NS309 和 GSK1016790A 诱导的动脉舒张均显著降低。这些结果表明，EDH 型舒张在雌性 OLETF 大鼠中受损。这种新的实验模型可能为女性代谢综合征中的血管功能障碍提供新的见解。
