Heart-rate reduction by If-channel inhibition with ivabradine restores collateral artery growth in hypercholesterolemic atherosclerosis.
Heart-rate reduction by If-channel inhibition with ivabradine restores collateral artery growth in hypercholesterolemic atherosclerosis.
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伊伐布雷定抑制 If 通道降低心率可恢复高胆固醇血症动脉粥样硬化患者的侧支动脉生长
DOI：
10.1093/eurheartj/ehr255
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发表时间：
2012
影响因子：
39.3
通讯作者：
U. Laufs
中科院分区：
文献类型：
--
作者：
S.H. Schirmer;A. Degen;M. Baumhäkel;F. Custodis;L. Schuh;M. Kohlhaas;E.B. Friedrich;F. Bahlmann;R. Kappl;C. Maack;M. Böhm;U. Laufs
目的侧支动脉保护组织免受缺血。动脉阻塞性疾病患者的心率与血管事件相关。在这里，我们测试了心率降低（HRR）对侧支动脉growth.Methods和resultsThe If通道抑制剂伊伐布雷定降低心率的野生型和载脂蛋白E（ApoE）−/−小鼠的11%和15%，并恢复ApoE−/−小鼠主动脉环的内皮依赖性舒张。微球灌注和血管造影显示，伊伐布雷定未改变野生型小鼠的后肢灌注，但改善了ApoE−/−小鼠的灌注，从40.5 ± 15.8-60.2 ± 18.5%结扎/未结扎后肢。美托洛尔降低心率（13%）未能改善内皮功能和灌注。伊伐布雷定处理ApoE−/−小鼠后，侧支组织中内皮型一氧化氮合酶（eNOS）、磷酸化eNOS的蛋白表达和eNOS活性增加。与一氧化氮抑制剂N（G）-硝基-L-精氨酸甲酯联合给药可消除伊伐布雷定对动脉生成的影响。伊伐布雷定给药后，ApoE−/−循环单核细胞和血浆中的经典炎性细胞因子表达降低，但在含侧支的后肢组织中未发生变化，其中血管周围巨噬细胞的数量也保持不变。然而，伊伐布雷定降低了ApoE−/−后肢组织中抗动脉生成细胞因子CXCL 10和CXCL 11以及平滑肌细胞标志物smoothelin和结蛋白的表达。野生型小鼠的内皮型一氧化氮合酶和炎性细胞因子表达无变化。伊伐布雷定并没有影响细胞因子的产生在HUVECs和THP 1单核细胞，并没有对膜电位的HUVECs在膜片钳experiments. ConclusionIvabradine诱导的HRR刺激适应性侧支动脉生长的影响。重要的作用机制包括改善内皮功能、eNOS活性和调节炎性细胞因子基因表达。
AimsCollateral arteries protect tissue from ischaemia. Heart rate correlates with vascular events in patients with arterial obstructive disease. Here, we tested the effect of heart-rate reduction (HRR) on collateral artery growth.Methods and resultsThe If-channel inhibitor ivabradine reduced heart rate by 11% in wild-type and 15% in apolipoprotein E (ApoE)−/−mice and restored endothelium-dependent relaxation in aortic rings of ApoE−/−mice. Microsphere perfusion and angiographies demonstrated that ivabradine did not change hindlimb perfusion in wild-type mice but improved perfusion in ApoE−/−mice from 40.5 ± 15.8–60.2 ± 18.5% ligated/unligated hindlimb. Heart rate reduction (13%) with metoprolol failed to improve endothelial function and perfusion. Protein expression of endothelial nitric oxide synthase (eNOS), phosphorylated eNOS, and eNOS activity were increased in collateral tissue following ivabradine treatment of ApoE−/−mice. Co-treatment with nitric oxide-inhibitor N (G)-nitro-L- arginine methyl ester abolished the effects of ivabradine on arteriogenesis. Following ivabradine, classical inflammatory cytokine expression was lowered in ApoE−/−circulating mononuclear cells and in plasma, but unaltered in collateral-containing hindlimb tissue, where numbers of perivascular macrophages also remained unchanged. However, ivabradine reduced expression of anti-arteriogenic cytokines CXCL10and CXCL11 and of smooth muscle cell markers smoothelin and desmin in ApoE−/−hindlimb tissue. Endothelial nitric oxide synthase and inflammatory cytokine expression were unchanged in wild-type mice. Ivabradine did not affect cytokine production in HUVECs and THP1 mononuclear cells and had no effect on the membrane potential of HUVECs in patch-clamp experiments.ConclusionIvabradine-induced HRR stimulates adaptive collateral artery growth. Important contributing mechanisms include improved endothelial function, eNOS activity, and modulation of inflammatory cytokine gene expression.
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影响因子：
20.1
作者：
Schirmer, Stephan H.;Fledderus, Joost O.;van Royen, Niels
通讯作者：
van Royen, Niels
冠状动脉闭塞
DOI：
--
发表时间：
1949
期刊：
影响因子：
--
作者：
K. Lamping;Wei Zheng;D. Xing;Lance P. Christensen;James B. Martins;R. Tomanek
通讯作者：
R. Tomanek
DOI：
10.1124/jpet.108.140533
发表时间：
2008-12-01
影响因子：
3.5
作者：
Baumhaekel, Magnus;Custodis, Florian;Boehm, Michael
通讯作者：
Boehm, Michael
冠状动脉疾病患者的冠状动脉侧支灌注：美托洛尔的作用。
影响因子：
39.3
作者：
M. Billinger;L. Raeber;C. Seiler;S. Windecker;B. Meier;O. Hess
通讯作者：
O. Hess
双嘧达莫通过内分泌亚硝酸盐/一氧化氮依赖性途径增强缺血诱导的动脉生成。
影响因子：
10.8
作者：
Venkatesh,PrasannaK;Pattillo,ChristopherB;Branch,Billy;Hood,Jay;Thoma,Steven;Illum,Sandra;Pardue,Sibile;Teng,Xinjun;Patel,RakeshP;Kevil,ChristopherG
通讯作者：
Kevil,ChristopherG