Dick Gregory M, Katz Paige S, Farias Martin, Morris Michael, James Jeremy, Knudson Jarrod D, Tune Johnathan D
Dept. of Physiology, Louisiana State University Health Sciences Center, New Orleans, USA.
Am J Physiol Heart Circ Physiol. 2006 Dec;291(6):H2997-3002. doi: 10.1152/ajpheart.01035.2005. Epub 2006 Aug 11.
Elevated plasma levels of fat-derived signaling molecules are associated with obesity, vascular endothelial dysfunction, and coronary heart disease; however, little is known about their direct coronary vascular effects. Accordingly, we examined mechanisms by which one adipokine, resistin, affects coronary vascular tone and endothelial function. Studies were conducted in anesthetized dogs and isolated coronary artery rings. Resistin did not change coronary blood flow, mean arterial pressure, or heart rate. Resistin had no effect on acetylcholine-induced relaxation of artery rings; however, resistin did impair bradykinin-induced relaxation. Selective impairment was also observed in vivo, as resistin attenuated vasodilation to bradykinin but not to acetylcholine. Resistin had no effect on dihydroethidium fluorescence, an indicator of superoxide (O(2)(-)) production, and the inhibitory effect of resistin on bradykinin-induced relaxation persisted in the presence of Tempol, a superoxide dismutase mimetic. To determine whether resistin impaired production of and/or responses to nitric oxide (NO) or prostaglandins (e.g., prostacyclin; PGI(2)), we performed experiments with N(omega)-nitro-L-arginine methyl ester (L-NAME) and indomethacin. The effect of resistin to attenuate bradykinin-induced vasodilation persisted in the presence of L-NAME or indomethacin, suggesting resistin may act at a cell signaling point upstream of NO or PGI(2) production. Resistin-induced endothelial dysfunction is not generalized, and it is not consistent with effects mediated by O(2)(-) or interference with NO or PGI(2) signaling. The site of the resistin-induced impairment is unknown but may be at the bradykinin receptor or a closely associated signal transduction machinery proximal to NO synthase or cyclooxygenase.
脂肪衍生信号分子的血浆水平升高与肥胖、血管内皮功能障碍和冠心病相关；然而，关于它们对冠状动脉的直接作用却知之甚少。因此，我们研究了一种脂肪因子——抵抗素影响冠状动脉张力和内皮功能的机制。研究在麻醉犬和离体冠状动脉环上进行。抵抗素不改变冠状动脉血流量、平均动脉压或心率。抵抗素对乙酰胆碱诱导的动脉环舒张无影响；然而，抵抗素确实损害了缓激肽诱导的舒张。在体内也观察到了选择性损害，因为抵抗素减弱了对缓激肽的血管舒张作用，但对乙酰胆碱无此作用。抵抗素对二氢乙锭荧光（超氧化物（O(2)(-)）产生的指标）无影响，并且在超氧化物歧化酶模拟物Tempol存在的情况下，抵抗素对缓激肽诱导的舒张的抑制作用仍然存在。为了确定抵抗素是否损害一氧化氮（NO）或前列腺素（例如前列环素；PGI(2)）的产生和/或反应，我们用N(ω)-硝基-L-精氨酸甲酯（L-NAME）和吲哚美辛进行了实验。在L-NAME或吲哚美辛存在的情况下，抵抗素减弱缓激肽诱导的血管舒张的作用仍然存在，这表明抵抗素可能作用于NO或PGI(2)产生上游的细胞信号点。抵抗素诱导的内皮功能障碍并非普遍存在，并且与由O(2)(-)介导的作用或对NO或PGI(2)信号传导的干扰不一致。抵抗素诱导损害的位点尚不清楚，但可能在缓激肽受体或与一氧化氮合酶或环氧化酶近端紧密相关的信号转导机制处。
