Impaired nitric oxide-mediated vasodilation in transgenic sickle mouse
Impaired nitric oxide-mediated vasodilation in transgenic sickle mouse
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DOI：
10.1152/ajpheart.2000.278.6.h1799
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发表时间：
2000-06-01
影响因子：
4.8
通讯作者：
Nagel, RL
中科院分区：
文献类型：
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作者：
Kaul, DK;Liu, XD;Nagel, RL
表达人β(S)-和β(S-Antilles)-球蛋白的转基因镰状小鼠表现出血管内镰状化、红细胞粘附和对氧气反应的小动脉收缩减弱。我们假设这些异常和可能的内皮损伤（在镰状细胞性贫血中也有报道）改变了该小鼠模型中一氧化氮（NO）介导的微血管反应和血流动力学。与对照组相比，转基因小鼠的平均动脉压（MAP）较低（90 +/- 7 vs. 113 +/- 8 mmHg，P < 0.00001），同时内皮一氧化氮合酶（eNOS）表达增加。 N-G-硝基-L-精氨酸甲酯（L-NAME）是 NOS 的非选择性抑制剂，在对照和转基因小鼠中，MAP 增加了约 30%，提睾肌小动脉（分支顺序：A2 和 A3）直径减少了约 40%，证实了 NOS 活性；施用 L-精氨酸后，这些变化是可逆的。氨基胍（一种诱导型 NOS 抑制剂）没有效果。转基因小鼠对 NO 介导的血管扩张剂（即乙酰胆碱和硝普钠 (SNP)）的反应显示小动脉扩张减少 (P, 0.02-0.01)。吲哚美辛不会改变对 ACh 和 SNP 的反应。 Forskolin 是一种 cAMP 激活剂，在两组小鼠中引起 A2 和 A3 血管的类似扩张（分别为 44% 和 70%）。因此，在转基因小鼠中，eNOS/NO 活性增加会导致血压降低，并减弱小动脉对 NO 介导的血管扩张剂的反应。虽然NOS/NO活性增加可以补偿血流异常，但它也可能导致血管张力的病理生理改变。
Transgenic sickle mice expressing human beta(S)- and beta(S-Antilles)-globins show intravascular sickling, red blood cell adhesion, and attenuated arteriolar constriction in response to oxygen. We hypothesize that these abnormalities and the likely endothelial damage, also reported in sickle cell anemia, alter nitric oxide (NO)-mediated microvascular responses and hemodynamics in this mouse model. Transgenic mice showed a lower mean arterial pressure (MAP) compared with control groups (90 +/- 7 vs. 113 +/- 8 mmHg, P < 0.00001), accompanied by increased endothelial nitric oxide synthase (eNOS) expression. N-G-nitro-L-arginine methyl ester (L-NAME), a nonselective inhibitor of NOS, caused an similar to 30% increase in MAP and similar to 40% decrease in the diameters of cremaster muscle arterioles (branching orders: A2 and A3) in both control and transgenic mice, confirming NOS activity; these changes were reversible after L-arginine administration. Aminoguanidine, an inhibitor of inducible NOS, had no effect. Transgenic mice showed a decreased (P, 0.02-0.01) arteriolar dilation in response to NO-mediated vasodilators, i.e., ACh and sodium nitroprusside (SNP). Indomethacin did not alter the responses to ACh and SNP. Forskolin, a cAMP-activating agent, caused a comparable dilation of A2 and A3 vessels (similar to 44 and 70%) in both groups of mice. Thus in transgenic mice, an increased eNOS/NO activity results in lower blood pressure and diminished arteriolar responses to NO-mediated vasodilators. Although the increased NOS/NO activity may compensate for flow abnormalities, it may also cause pathophysiological alterations in vascular tone.