Combined effects of an 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor and angiotensin II receptor antagonist on nitric oxide bioavailability and atherosclerotic change in myocardial infarction-prone Watanabe heritable hyperlipidemic rabbits

被引:13
作者
Imanishi, Toshio [1 ]
Ikejima, Hideyuki [1 ]
Tsujioka, Atsushi [1 ]
Kuroi, Akio [1 ]
Kobayashi, Katsunobu [1 ]
Shiomi, Masashi [2 ,3 ]
Muragaki, Yasuteru
Mochizuki, Seiichi [4 ]
Goto, Masami [4 ]
Yoshida, Kiyoshi [5 ]
Akasaka, Takashi [1 ]
机构
[1] Wakayama Med Univ, Dept Cardiovasc Med, Wakayama 6418510, Japan
[2] Wakayama Med Univ, Dept Pathol, Wakayama 6418510, Japan
[3] Kobe Univ, Sch Med, Inst Expt Anim, Kobe, Hyogo 650, Japan
[4] Kawasaki Med Sch, Dept Med Engn, Kurashiki, Okayama, Japan
[5] Kawasaki Med Sch, Div Cardiol, Kurashiki, Okayama, Japan
关键词
nitric oxide; endothelium; statin; angiotensin II type I receptor blocker; nitrative stress;
D O I
10.1291/hypres.31.1199
中图分类号
R6 [外科学];
学科分类号
1002 ; 100210 ;
摘要
We investigated the effects of co-administration of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor and angiotensin II type 1 receptor blocker (ARB) on nitric oxide (NO) bioavailability in genetically hyperlipidemic rabbits with our newly developed NO sensor. A total of 36 myocardial infarction-prone Watanabe heritable hyperlipidemic (WHHLMI) rabbits equally derived (n=6 per group) were treated with 1) vehicle (control), 2) hydralazine (15 mg/kg/d), 3) the HMG-CoA reductase inhibitor pitavastatin (P: 0.5 mg/kg/d), 4) the ARB valsartan (V: 5 mg/kg/d), and 5) pitavastatin+valsartan (P+V) together without or 6) with N-G-nitro-L-arginine methyl ester (L-NAME) for 8 weeks. After treatment, acetylcholine (ACh)-induced NO production was measured as a surrogate for endothelium protective function, and vascular peroxynitrite (a product of superoxide and NO) was measured for assessing dysfunctional endothelial NO synthase activity. Plaque area was quantified by histology as well as optical coherence tomography (OCT). Intra-aortic infusion of ACh produced an increase in plasma NO concentration, which was significantly greater with all drug treatments than with the control. P+V increased ACh-induced NO by 4.1 nmol/L significantly more than either P or V singly. The vascular peroxynitrite concentration was 1.6 pmol/mg protein in the control group and significantly less than those in the P- and V-monotherapy-groups. The lowest peroxynitrite concentration was observed in the P+V group (0.4 pmol/mg protein), which was significantly lower than those in the P- and the V-monotherapy-groups. OCT and histology of the thoracic aorta revealed that the plaque area decreased significantly more with the combination than with the monotherapy. In conclusion, the combined treatment with an HMG-CoA reductase inhibitor and an ARB may have additive protective effects on endothelial function as well as atherosclerotic change.
引用
收藏
页码:1199 / 1208
页数:10
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