Tawfik Huda E, Cena Jonathan, Schulz Richard, Kaufman Susan
Faculty of Medicine and Dentistry, Department of Physiology, University of Alberta, Edmonton, Alberta, Canada.
Am J Physiol Heart Circ Physiol. 2008 Oct;295(4):H1736-42. doi: 10.1152/ajpheart.87.2008. Epub 2008 Aug 29.
Multiparity is associated with increased risk of cardiovascular disease. We tested whether multiparity induces oxidative stress in rat vascular tissue. Coronary arteries and thoracic aorta were isolated from multiparous and age-matched virgin rats. Relaxation to ACh and sodium nitroprusside (SNP) was measured by wire myography. We also tested the effect of the superoxide dismutase mimetic MnTE2PyP (30 microM), the NADPH oxidase inhibitor apocynin (10 microM), and the peroxynitrite scavenger FeTPPs (10 microM) on ACh-mediated relaxation in coronary arteries. Vascular superoxide anion was measured using the luminol derivative L-012 and nitric oxide (NO) generation by the Griess reaction. Multiparity reduced maximal response and sensitivity to ACh in coronary arteries [maximal relaxation (E(max)): multiparous 49+/-3% vs. virgins 95%+/-3%; EC(50): multiparous 135+/-1 nM vs. virgins 60+/-1 nM], and in aortic rings (E(max): multiparous 38+/-3% vs. virgins 79+/-4%; EC(50): multiparous 160+/-2 nM vs. virgins 90+/-3 nM). Coronary arteries from the two groups relaxed similarly to SNP. Superoxide anions formation was significantly higher in both coronary arteries (2.8-fold increase) and aorta (4.1-fold increase) from multiparous rats compared with virgins. In multiparous rats, incubation with MnTE2PyP, apocynin, and FeTPPs improved maximal relaxation to ACh (MnTE2PyP: 74+/-5%; vehicle: 41+/-5%; apocynin: 73+/-3% vs. vehicle: 41+/-3%; FeTPPs: 72+/-3% vs. vehicle: 46+/-3%) and increased sensitivity (EC(50): MnTE2PyP: 61+/-0.5 nM vs. vehicle: 91+/-1 nM; apocynin: 45+/-3 nM vs. vehicle: 91+/-6 nM; FeTPP: 131 +/- 2 nM vs. vehicle: 185+/-1 nM). Multiparity also reduced total nitrate/nitrite levels (multiparous: 2.5+/-2 micromol/mg protein vs. virgins: 7+/-1 micromol/mg protein) and endothelial nitric oxide synthase protein levels (multiparous: 0.53+/-0.1 protein/actin vs. virgins: 1.0+/-0.14 protein/actin). These data suggest that multiparity induces endothelial dysfunction through decreased NO bioavailability and increased reactive oxygen species formation.
多胎妊娠与心血管疾病风险增加有关。我们测试了多胎妊娠是否会在大鼠血管组织中诱导氧化应激。从经产大鼠和年龄匹配的未孕大鼠中分离出冠状动脉和胸主动脉。通过线肌张力测定法测量对乙酰胆碱（ACh）和硝普钠（SNP）的舒张反应。我们还测试了超氧化物歧化酶模拟物MnTE2PyP（30微摩尔）、NADPH氧化酶抑制剂夹竹桃麻素（10微摩尔）和过氧亚硝酸盐清除剂FeTPPs（10微摩尔）对冠状动脉中ACh介导的舒张反应的影响。使用鲁米诺衍生物L - 012测量血管超氧阴离子，并通过格里斯反应测量一氧化氮（NO）生成。多胎妊娠降低了冠状动脉中对ACh的最大反应和敏感性[最大舒张（E(max)）：经产大鼠为49±3%，未孕大鼠为95%±3%；半数有效浓度（EC(50)）：经产大鼠为135±1纳摩尔，未孕大鼠为60±1纳摩尔]，以及主动脉环中的情况（E(max)：经产大鼠为38±3%，未孕大鼠为79±4%；EC(50)：经产大鼠为160±2纳摩尔，未孕大鼠为90±3纳摩尔）。两组的冠状动脉对SNP的舒张反应相似。与未孕大鼠相比，经产大鼠的冠状动脉（增加2.8倍）和主动脉（增加4.1倍）中超氧阴离子的形成均显著更高。在经产大鼠中，用MnTE2PyP、夹竹桃麻素和FeTPPs孵育可改善对ACh的最大舒张（MnTE2PyP：74±5%；溶媒：41±5%；夹竹桃麻素：73±3%，溶媒：41±3%；FeTPPs：72±3%，溶媒：46±3%）并提高敏感性（EC(50)：MnTE2PyP：61±0.5纳摩尔，溶媒：91±1纳摩尔；夹竹桃麻素：45±3纳摩尔，溶媒：91±6纳摩尔；FeTPP：131±2纳摩尔，溶媒：185±1纳摩尔）。多胎妊娠还降低了总硝酸盐/亚硝酸盐水平（经产大鼠：2.5±2微摩尔/毫克蛋白质，未孕大鼠：7±1微摩尔/毫克蛋白质）和内皮型一氧化氮合酶蛋白水平（经产大鼠：0.53±0.1蛋白/肌动蛋白，未孕大鼠：1.0±0.14蛋白/肌动蛋白）。这些数据表明，多胎妊娠通过降低NO生物利用度和增加活性氧形成来诱导内皮功能障碍。
