Böger R H, Bode-Böger S M, Phivthong-ngam L, Brandes R P, Schwedhelm E, Mügge A, Böhme M, Tsikas D, Frölich J C
Institute of Clinical Pharmacology, Hannover Medical School, Germany.
Atherosclerosis. 1998 Nov;141(1):31-43. doi: 10.1016/s0021-9150(98)00145-2.
Vascular oxidative stress brought about by superoxide radicals and oxidized low-density lipoproteins (oxLDL) is a major factor contributing to decreased NO-dependent vasodilator function in hypercholesterolemia and atherosclerosis. We investigated whether chronic administration of L-arginine (2% in drinking water) or of alpha-tocopherol (300 mg/day) improves endothelium-dependent vasodilator function and systemic NO production, reduces vascular oxidative stress, and reduces the progression of atherosclerosis in cholesterol-fed rabbits with pre-existing hypercholesterolemia. Systemic NO production was assessed as urinary nitrate excretion; oxidative stress was measured by urinary 8-iso-PGF2alpha excretion in vivo, by lucigenin-enhanced chemiluminescence of isolated aortic rings ex vivo, and by copper-mediated LDL oxidation in vitro. Endothelium-dependent relaxation was almost completely abrogated in cholesterol-fed rabbits. Urinary nitrate excretion was reduced by 46+/-10%, and 8-iso-PGF2alpha excretion was increased by 61+/-18% as compared to controls (each P <0.05). Vascular superoxide radical release stimulated by PMA ex vivo was increased by 273+/-93% in this group, and the lag time of LDL oxidation was reduced by 35+/-6% (each P <0.05). Treatment with L-arginine and alpha-tocopherol reduced intimal lesion formation (by 68+/-6 and 4+/-11%, respectively; P <0.05) and improved endothelium-dependent relaxation. Both treatments also normalized urinary 8-iso-PGF2alpha excretion. L-Arginine increased urinary nitrate excretion by 43+/-13% (P <0.05) and reduced superoxide radical release by isolated aortic rings to control levels, which was unaffected by vitamin E treatment. By contrast, vitamin E dramatically increased the resistance of isolated LDL to copper-mediated oxidation in vitro by 178+/-7% (P <0.05), which was only marginally prolonged by L-arginine. Intimal thickening was reduced by both treatments. We conclude that both L-arginine and alpha-tocopherol reduce the progression of atherosclerotic plaques in cholesterol-fed rabbits. However, while L-arginine increases NO formation and reduces superoxide release, alpha-tocopherol antagonizes mainly oxLDL-related events in atherogenesis. Thus, both treatments reduce urinary isoprostane excretion and improve endothelium-dependent vasodilation via different mechanisms.
由超氧自由基和氧化型低密度脂蛋白（oxLDL）引起的血管氧化应激是导致高胆固醇血症和动脉粥样硬化中一氧化氮（NO）依赖性血管舒张功能降低的主要因素。我们研究了长期给予L-精氨酸（饮用水中含2%）或α-生育酚（300毫克/天）是否能改善内皮依赖性血管舒张功能和全身NO生成，降低血管氧化应激，并减缓已有高胆固醇血症的胆固醇喂养兔的动脉粥样硬化进展。全身NO生成通过尿硝酸盐排泄进行评估；氧化应激通过体内尿8-异前列腺素F2α排泄、离体主动脉环的光泽精增强化学发光以及体外铜介导的LDL氧化来测量。在胆固醇喂养的兔中，内皮依赖性舒张几乎完全被消除。与对照组相比，尿硝酸盐排泄减少了46±10%，8-异前列腺素F2α排泄增加了61±18%（均P<0.05）。在该组中，离体主动脉环受佛波酯（PMA）刺激后血管超氧自由基释放增加了273±93%，LDL氧化的延迟时间缩短了35±6%（均P<0.05）。用L-精氨酸和α-生育酚治疗可减少内膜病变形成（分别减少68±6%和4±11%；P<0.05）并改善内皮依赖性舒张。两种治疗还使尿8-异前列腺素F2α排泄恢复正常。L-精氨酸使尿硝酸盐排泄增加了43±13%（P<0.05），并将离体主动脉环的超氧自由基释放降低至对照水平，而维生素E治疗对此无影响。相比之下，维生素E在体外显著增加了离体LDL对铜介导氧化的抵抗力，增加了178±7%（P<0.05），L-精氨酸仅使其稍有延长。两种治疗均减少了内膜增厚。我们得出结论，L-精氨酸和α-生育酚均可减缓胆固醇喂养兔动脉粥样硬化斑块的进展。然而，L-精氨酸增加NO生成并减少超氧自由基释放，而α-生育酚主要拮抗动脉粥样硬化发生中与oxLDL相关的事件。因此，两种治疗均通过不同机制减少尿异前列腺素排泄并改善内皮依赖性血管舒张。
