Taner C B, Severson S R, Best P J, Lerman A, Miller V M
Department of Surgery, Division of Cardiovascular Diseases, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
J Appl Physiol (1985). 2001 Mar;90(3):816-20. doi: 10.1152/jappl.2001.90.3.816.
In experimental hypercholesterolemia, endothelium-dependent relaxations decrease, as does endothelial immunoreactivity for nitric oxide (NO) synthase (NOS; eNOS) in coronary arteries. Systemic levels of NO also decrease with concomitant elevations in systemic circulating levels of endothelin (ET)-1. Chronic treatment of hypercholesterolemic pigs with ET-receptor antagonists increases circulating NO and improves endothelium-dependent relaxations. Mechanisms causing these increases are not known. Therefore, experiments were designed to test the hypothesis that chronic administration of ET-receptor antagonists to hypercholesterolemic pigs increases NO production through increases in NOS activity. Female juvenile pigs were fed a 2% cholesterol atherogenic diet and were randomly allocated to receive no treatment (controls), a selective ET(A)-receptor antagonist (ABT-624), or a combined ET(A) + ET(B)-receptor antagonist (RO-48-5695) daily for 12 wk. After 12 wk, endothelial cells from thoracic aorta were prepared for measurement of eNOS mRNA or eNOS activity. Total cholesterol, low-density-lipoprotein cholesterol, and concentrations of ET-1 were significantly higher in all three groups at 12 wk compared with baseline levels. Circulating plasma-oxidized products of NO (NOx) increased with ET-receptor blockade. NOS mRNA was similar among groups. Total and Ca-dependent NOS activity was significantly higher in aortic endothelial cells from the ET(A) + ET(B)-treated pigs compared with those treated with ET(A) antagonist alone. These results suggest that changes in systemic NOx after chronic inhibition of ET(A) + ET(B) receptors in hypercholesterolemia may result from posttranscriptional changes in NOS.
在实验性高胆固醇血症中，内皮依赖性舒张功能降低，冠状动脉中一氧化氮（NO）合酶（NOS；内皮型NOS）的内皮免疫反应性也降低。随着内皮素（ET）-1全身循环水平的升高，NO的全身水平也降低。用ET受体拮抗剂长期治疗高胆固醇血症猪可增加循环中的NO并改善内皮依赖性舒张功能。导致这些增加的机制尚不清楚。因此，设计实验来检验以下假设：对高胆固醇血症猪长期给予ET受体拮抗剂可通过增加NOS活性来增加NO的产生。雌性幼猪喂食含2%胆固醇的致动脉粥样化饮食，并随机分配为不接受治疗（对照组）、每日接受选择性ET(A)受体拮抗剂（ABT-624）或ET(A)+ET(B)受体联合拮抗剂（RO-48-5695），持续12周。12周后，制备胸主动脉内皮细胞以测量内皮型NOS mRNA或内皮型NOS活性。与基线水平相比，所有三组在12周时总胆固醇、低密度脂蛋白胆固醇和ET-1浓度均显著升高。随着ET受体阻断，循环血浆中NO的氧化产物（NOx）增加。各组之间NOS mRNA相似。与单独用ET(A)拮抗剂治疗的猪相比，用ET(A)+ET(B)治疗的猪主动脉内皮细胞中总NOS活性和钙依赖性NOS活性显著更高。这些结果表明，高胆固醇血症中慢性抑制ET(A)+ET(B)受体后全身NOx的变化可能是由NOS的转录后变化引起的。
