Effects of Atorvastatin, Amlodipine, and Their Combination on Vascular Dysfunction in Insulin-Resistant Rats

被引:22
作者
Okamura, Tomio [1 ]
Tawa, Masashi [1 ]
Geddawy, Ayman [1 ]
Shimosato, Takashi [1 ]
Iwasaki, Hirotaka [1 ]
Shintaku, Haruo [2 ]
Yoshida, Yuichi [3 ]
Masada, Masahiro [3 ]
Shinozaki, Kazuya [1 ]
Imamura, Takeshi [1 ]
机构
[1] Shiga Univ Med Sci, Dept Pharmacol, Otsu, Shiga 5202192, Japan
[2] Osaka City Univ, Dept Pediat, Grad Sch Med, Osaka 5458585, Japan
[3] Chiba Univ, Biochem Lab, Fac Hort, Matsudo, Chiba 2718510, Japan
关键词
3-hydroxyl-3-methylglutaryl coenzyme A reductase inhibitor; calcium antagonist; nitric oxide; tetrahydrobiopterin; insulin resistance; NITRIC-OXIDE SYNTHASE; HYPERTENSIVE-RATS; GENE-TRANSFER; ENDOTHELIAL-CELLS; OXIDATIVE STRESS; BLOOD-PRESSURE; MESSENGER-RNA; TETRAHYDROBIOPTERIN; DISEASE; ATHEROSCLEROSIS;
D O I
10.1254/jphs.13178FP
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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.
引用
收藏
页码:76 / 85
页数:10
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