Denniss Steven G, Ford Rebecca J, Smith Christopher S, Jeffery Andrew J, Rush James W E
Integrative Vascular Biology Laboratory, Department of Kinesiology, Faculty of Applied Health Sciences, University of Waterloo, Waterloo, Ontario, Canada.
Integrative Vascular Biology Laboratory, Department of Kinesiology, Faculty of Applied Health Sciences, University of Waterloo, Waterloo, Ontario, Canada
J Appl Physiol (1985). 2016 May 15;120(10):1141-50. doi: 10.1152/japplphysiol.00675.2015. Epub 2016 Feb 25.
Exaggerated cyclooxygenase (COX) and thromboxane-prostanoid (TP) receptor-mediated endothelium-dependent contraction can contribute to endothelial dysfunction. This study examined the effect of resveratrol (RSV) on endothelium-dependent contraction and cell signaling in the common carotid artery (CCA) from spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY). Acetylcholine (Ach)-stimulated endothelium-dependent nitric oxide synthase (NOS)-mediated relaxation in precontracted SHR CCA was impaired (maximum 73 ± 6% vs. 87 ± 5% in WKY) (P < 0.05) by competitive COX-mediated contraction. Chronic (28-day) treatment in vivo (drinking water) with a ∼0.075 mg·kg(-1)·day(-1) RSV dose affected neither endothelium-dependent relaxation nor endothelium-dependent contraction and associated prostaglandin (PG) production evaluated in non-precontracted NOS-blocked CCA. In contrast, a chronic ∼7.5 mg·kg(-1)·day(-1) RSV dose improved endothelium-dependent relaxation (94 ± 6%) and attenuated endothelium-dependent contraction (58 ± 4% vs. 73 ± 5% in No-RSV) and PG production (183 ± 43 vs. 519 ± 93 pg/ml) in SHR CCA, while U46619-stimulated TP receptor-mediated contraction was unaffected. In separate acute in vitro experiments, 20-μM RSV preincubation attenuated endothelium-dependent contraction (6 ± 4% vs. 62 ± 2% in No Drug) and PG production (121 ± 15 vs. 491 ± 93 pg/ml) and attenuated U46619-stimulated contraction (134 ± 5% vs. 171 ± 4%) in non-precontracted NOS-blocked SHR CCA. Compound C, a known AMP-activated protein kinase (AMPK) inhibitor, did not prevent the RSV attenuating effect on Ach- and U46619-stimulated contraction but did prevent the RSV attenuating effect on PG production (414 ± 58 pg/ml). These data demonstrate that RSV can attenuate endothelium-dependent contraction both by suppressing arterial wall PG production, which may be partially mediated by AMPK, and by TP receptor hyporesponsiveness, which does not appear to be mediated by AMPK.
环氧合酶（COX）和血栓素-前列腺素（TP）受体介导的内皮依赖性收缩反应过度可导致内皮功能障碍。本研究检测了白藜芦醇（RSV）对自发性高血压大鼠（SHR）和Wistar Kyoto大鼠（WKY）颈总动脉（CCA）内皮依赖性收缩及细胞信号传导的影响。在预收缩的SHR CCA中，乙酰胆碱（Ach）刺激的内皮依赖性一氧化氮合酶（NOS）介导的舒张功能受损（最大舒张率73±6%，而WKY为87±5%）（P<0.05），这是由竞争性COX介导的收缩所致。体内（饮用水）给予约0.075 mg·kg⁻¹·d⁻¹的RSV进行慢性（28天）治疗，对未预收缩的NOS阻断的CCA中评估的内皮依赖性舒张、内皮依赖性收缩及相关前列腺素（PG）生成均无影响。相反，约7.5 mg·kg⁻¹·d⁻¹的RSV慢性给药剂量可改善SHR CCA的内皮依赖性舒张（94±6%），减弱内皮依赖性收缩（58±4%，无RSV组为73±5%）及PG生成（183±43对519±93 pg/ml），而U46619刺激的TP受体介导的收缩不受影响。在单独的急性体外实验中，20 μM RSV预孵育可减弱未预收缩的NOS阻断的SHR CCA中的内皮依赖性收缩（6±4%，无药物组为62±2%）及PG生成（121±15对491±93 pg/ml），并减弱U46619刺激的收缩（134±5%，无药物组为171±4%）。已知的AMP激活蛋白激酶（AMPK）抑制剂化合物C不能阻止RSV对Ach和U46619刺激的收缩的减弱作用，但能阻止RSV对PG生成的减弱作用（414±58 pg/ml）。这些数据表明，RSV可通过抑制动脉壁PG生成（可能部分由AMPK介导）和TP受体低反应性来减弱内皮依赖性收缩，而TP受体低反应性似乎不是由AMPK介导的。
