Pueyo M E, Arnal J F, Rami J, Michel J B
Institut National de la Santé et de la Recherche Médicale U460, Paris, France.
Am J Physiol. 1998 Jan;274(1):C214-20. doi: 10.1152/ajpcell.1998.274.1.C214.
Angiotensin II (ANG II) produces vasoconstriction by a direct action on smooth muscle cells via AT1 receptors. These receptors are also present in the endothelium, but their function is poorly understood. This study was therefore undertaken to determine whether ANG II elicits the release of nitric oxide (NO) from cultured rat aortic endothelial cells. NO production, measured by the accumulation of nitrite and nitrate, was enhanced by 10(-7) M ANG II. The biological activity of the NO released by ANG II action was evaluated by measuring its guanylate cyclase-stimulating activity in smooth muscle cells. The guanosine 3',5'-cyclic monophosphate (cGMP) content of smooth muscle cells was significantly increased by exposure of supernatant from ANG II-stimulated endothelial cells. These effects resulted from the activation of NO synthase, as they were inhibited by the L-arginine analogs. These ANG II actions were mediated by the AT1 receptor, as shown by their inhibition by the AT1 antagonist losartan. The cGMP production by reporter cells was inhibited by the calmodulin antagonist W-7, suggesting that ANG II activates endothelial calmodulin-dependent NO synthase. This hypothesis is also supported by the increase of intracellular free calcium induced by ANG II in endothelial cells. ANG II also stimulated luminol-enhanced chemiluminescence in endothelial cells. This effect was inhibited by N omega-monomethyl-L-arginine and superoxide dismutase, suggesting that this luminol-enhanced chemiluminescence reflected an increase in peroxynitrite production. Thus ANG II stimulates NO release from macrovascular endothelium, which may modulate the direct vasoconstrictor effect of ANG II on smooth muscle cells. However, this beneficial effect may be counteracted by the simultaneous production of peroxynitrite, which could contribute to several pathological processes in the vascular wall.
血管紧张素II（ANG II）通过AT1受体直接作用于平滑肌细胞，从而产生血管收缩作用。这些受体也存在于内皮细胞中，但其功能尚不清楚。因此，本研究旨在确定ANG II是否能诱导培养的大鼠主动脉内皮细胞释放一氧化氮（NO）。通过亚硝酸盐和硝酸盐的积累来测量，10（-7）M的ANG II可增强NO的生成。通过测量其在平滑肌细胞中刺激鸟苷酸环化酶的活性，评估ANG II作用释放的NO的生物活性。用ANG II刺激的内皮细胞的上清液处理后，平滑肌细胞的鸟苷3'，5'-环磷酸（cGMP）含量显著增加。这些作用是由NO合酶的激活引起的，因为它们被L-精氨酸类似物抑制。这些ANG II的作用是由AT1受体介导的，AT1拮抗剂氯沙坦可抑制这些作用表明了这一点。钙调蛋白拮抗剂W-7可抑制报告细胞产生cGMP，这表明ANG II激活了内皮细胞中钙调蛋白依赖性NO合酶。ANG II诱导内皮细胞内游离钙增加也支持了这一假设。ANG II还刺激内皮细胞中鲁米诺增强的化学发光。Nω-单甲基-L-精氨酸和超氧化物歧化酶可抑制这种作用，这表明这种鲁米诺增强的化学发光反映了过氧亚硝酸盐生成的增加。因此，ANG II刺激大血管内皮细胞释放NO，这可能会调节ANG II对平滑肌细胞的直接血管收缩作用。然而，这种有益作用可能会被同时产生的过氧亚硝酸盐抵消，而过氧亚硝酸盐可能会导致血管壁的几种病理过程。
