Effects of Atorvastatin, Amlodipine, and Their Combination on Vascular Dysfunction in Insulin-Resistant Rats
Effects of Atorvastatin, Amlodipine, and Their Combination on Vascular Dysfunction in Insulin-Resistant Rats
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DOI：
10.1254/jphs.13178fp
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发表时间：
2014-01-01
影响因子：
3.5
通讯作者：
Imamura, Takeshi
中科院分区：
文献类型：
--
作者：
Okamura, Tomio;Tawa, Masashi;Imamura, Takeshi
血管组织中四氢生物蝶呤（BH 4）的缺乏通过在胰岛素抵抗状态下降低eNOS活性和增加超氧阴离子（O-2（-））产生而导致内皮功能障碍。我们研究了阿托伐他汀，一种3-羟基-3-甲基戊二酰辅酶A（HMG CoA）还原酶抑制剂，钙拮抗剂，以及它们的组合对高果糖喂养大鼠动脉粥样硬化的血压，动脉舒张和收缩，血管氧化应激的影响。口服阿托伐他汀8周并没有显著降低血压，但正常化血管紧张素II诱导的血管收缩和内皮功能的果糖喂养的大鼠。阿托伐他汀治疗果糖喂养的大鼠增加血管BH 4含量，这与内皮NO合酶活性增加以及内皮O-2（-）产生减少有关。另一方面，给药β-氨基丁酸并不影响血管紧张素II诱导的血管收缩和内皮功能，但正常化果糖喂养大鼠的血压升高。联合治疗没有显示出协同作用，但添加剂的有益效果。本研究表明，HMG-CoA还原酶抑制剂和钙拮抗剂的联合治疗可预防胰岛素抵抗状态下的功能性血管疾病，可能导致预防或延迟高血压、糖尿病血管功能障碍和动脉粥样硬化的发展。
Deficiency of tetrahydrobiopterin (BH4) in the vascular tissue contributes to endothelial dysfunction through reduced eNOS activity and increased superoxide anion (O-2(-)) generation in the insulin-resistant state. We investigated the effects of atorvastatin, a 3-hydroxyl-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor; amlodipine, a calcium antagonist; and their combination on blood pressure, arterial relaxation and contraction, and vascular oxidative stress in aortas of high fructose-fed rats. Oral administration of atorvastatin for 8 weeks did not significantly lower blood pressure, but normalized angiotensin II-induced vasoconstriction and endothelial function in the fructose-fed rats. Atorvastatin treatment of fructose-fed rats increased vascular BH4 content, which was associated with an increase in endothelial NO synthase activity as well as a reduction in endothelial O-2(-) production. On the other hand, administration of amlodipine did not affect the angiotensin II-induced vasoconstriction and endothelial function, but normalized the elevated blood pressure in the fructose-fed rats. The combined treatment did not show synergistic but additive beneficial effects. The present study suggests that combined therapy of HMG-CoA reductase inhibitors and calcium antagonists prevents functional vascular disorders in the insulin-resistant state, possibly resulting in the protection against or delay of development of hypertension, vascular dysfunction in diabetes, and thereafter atherosclerosis.