Stroes E S, Koomans H A, de Bruin T W, Rabelink T J
Department of Nephrology, University Hospital Utrecht, The Netherlands.
Lancet. 1995 Aug 19;346(8973):467-71. doi: 10.1016/s0140-6736(95)91322-x.
To study whether vascular dysfunction in hypercholesterolaemia is reversible, we investigated patients without overt arterial disease who were taking maintenance treatment for hypercholesterolaemia. Medication was stopped for 2 weeks, reinstituted for 12 weeks, and again stopped for 6 weeks. During both maintenance treatment and the 12 weeks of step-up medication the lipid profile was improved but did not return to normal. Dose-response curves for serotonin-induced vasodilatation, an index of nitric oxide-dependent vasodilatation, showed a comparable and significant rightward shift after a medication-free period of 2 and 6 weeks compared with control subjects, indicating endothelial dysfunction, which was already maximum after 2 weeks. After 12 weeks of lipid-lowering medication, the difference in endothelial function between controls and patients had disappeared. Co-infusion of L-arginine, the substrate for nitric oxide synthase, returned the impaired serotonin response during hypercholesterolaemia to normal, but had no effect on this response in controls or in patients while on lipid-lowering medication. Neither endothelium-independent vasorelaxation, assessed by sodium nitroprusside infusion, nor vasoconstriction induced by the nitric oxide blocker L-NMMA, were different between controls and patients, whether the latter were on or off lipid-lowering medication. Our results show an L-arginine-sensitive, impaired nitric-oxide-mediated vascular relaxation of forearm resistance vessels in hypercholesterolaemia which is reproducible, and reversible after short-term lipid-lowering therapy. Demonstration of such changes in this readily accessible vascular bed will allow larger trials assessing vascular function during lipid-lowering therapy to be done.
为研究高胆固醇血症时血管功能障碍是否可逆，我们对正在接受高胆固醇血症维持治疗且无明显动脉疾病的患者进行了调查。药物停用2周，重新用药12周，然后再次停药6周。在维持治疗期间以及逐步增加用药的12周内，血脂谱均有所改善，但未恢复正常。血清素诱导的血管舒张（一氧化氮依赖性血管舒张的指标）的剂量反应曲线显示，与对照组相比，在停药2周和6周后的无药期后出现了可比且显著的右移，表明存在内皮功能障碍，且在2周后已达到最大值。在进行12周的降脂药物治疗后，对照组与患者之间的内皮功能差异消失。同时输注一氧化氮合酶的底物L-精氨酸可使高胆固醇血症期间受损的血清素反应恢复正常，但对对照组或正在接受降脂药物治疗的患者的这种反应没有影响。无论是通过输注硝普钠评估的非内皮依赖性血管舒张，还是一氧化氮阻滞剂L-NMMA诱导的血管收缩，在对照组与患者之间均无差异，无论患者是否正在接受降脂药物治疗。我们的结果表明，高胆固醇血症时前臂阻力血管存在L-精氨酸敏感的、一氧化氮介导的血管舒张受损，这种情况是可重复的，并且在短期降脂治疗后是可逆的。在这种易于接近的血管床中证明此类变化将有助于开展更大规模的评估降脂治疗期间血管功能的试验。
