Matsumoto Takayuki, Kakami Mika, Noguchi Eri, Kobayashi Tsuneo, Kamata Katsuo
Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan.
Am J Physiol Heart Circ Physiol. 2007 Sep;293(3):H1480-90. doi: 10.1152/ajpheart.00229.2007. Epub 2007 May 18.
We investigated whether the balance between endothelium-derived relaxing factors (EDRFs) and endothelium-derived contracting factors (EDCFs) might be altered in mesenteric arteries from aged Otsuka Long-Evans Tokushima Fatty (OLETF) rats (a Type 2 diabetic model) [vs. age-matched control Long-Evans Tokushima Otsuka (LETO) rats]. ACh-induced relaxation was impaired in the OLETF group, and a tendency for the relaxation to reverse at high ACh concentrations was observed in both groups. This tendency was abolished by indomethacin. Nitric oxide- and/or endothelium-derived hypolarizing factor-mediated relaxation and the protein expressions of phospho-endothelial nitric oxide synthase (Ser1177) and extracellular superoxide dismutase were also reduced in OLETF. An ACh-induced contraction was observed at higher ACh concentrations in the presence of N(G)-nitro-L-arginine (L-NNA) but was greater in OLETF rats. This contraction in OLETF rats was reduced by cyclooxygenase (COX) inhibitors and by prostanoid-receptor antagonists. The ACh-induced productions of thromboxane A(2) and PGE(2) were greater in OLETF than LETO rats, as were the mesenteric artery COX-1 and COX-2 protein expressions. Moreover, tert-butyl hydroperoxide (t-BOOH) (membrane-permeant oxidant) induced a concentration-dependent contraction that was greater in OLETF rats. The t-BOOH-mediated contraction was increased both by L-NNA and by endothelium removal in LETO but not OLETF rats, suggesting that a negative modulatory role of the endothelium was lost in OLETF rats. These results suggest that an imbalance between EDRFs and EDCFs may be implicated in the endothelial dysfunction seen in aged OLETF mesenteric arteries, and may be attributable to increased oxidative stress.
我们研究了在老年大冢长- Evans 德岛肥胖（OLETF）大鼠（2 型糖尿病模型）的肠系膜动脉中，内皮源性舒张因子（EDRFs）和内皮源性收缩因子（EDCFs）之间的平衡是否会发生改变[与年龄匹配的对照长- Evans 德岛大冢（LETO）大鼠相比]。OLETF 组中乙酰胆碱（ACh）诱导的舒张功能受损，并且在两组中均观察到在高 ACh 浓度下舒张有逆转的趋势。吲哚美辛消除了这种趋势。OLETF 中一氧化氮和/或内皮源性超极化因子介导的舒张以及磷酸化内皮型一氧化氮合酶（Ser1177）和细胞外超氧化物歧化酶的蛋白表达也降低。在存在 N(G)-硝基-L-精氨酸（L-NNA）的情况下，在较高 ACh 浓度时观察到 ACh 诱导的收缩，但在 OLETF 大鼠中更大。OLETF 大鼠中的这种收缩被环氧化酶（COX）抑制剂和前列腺素受体拮抗剂降低。OLETF 大鼠中 ACh 诱导的血栓素 A(2)和前列腺素 E(2)的产生比 LETO 大鼠更大，肠系膜动脉 COX-1 和 COX-2 的蛋白表达也是如此。此外，叔丁基过氧化氢（t-BOOH）（膜通透性氧化剂）诱导浓度依赖性收缩，在 OLETF 大鼠中更大。t-BOOH 介导的收缩在 LETO 大鼠中被 L-NNA 和去除内皮增加，但在 OLETF 大鼠中没有，这表明 OLETF 大鼠中内皮的负调节作用丧失。这些结果表明，EDRFs 和 EDCFs 之间的失衡可能与老年 OLETF 肠系膜动脉中所见的内皮功能障碍有关，并且可能归因于氧化应激增加。
