Department of Physiology, Yonsei University College of Medicine, 50 Yonseiro, Seodaemun-gu, Seoul 03722, Republic of Korea.
Int J Mol Sci. 2023 Sep 12;24(18):13992. doi: 10.3390/ijms241813992.
Ezetimibe is a lipid-lowering agent that selectively inhibits cholesterol absorption by binding to the Niemann-Pick C1-like 1 (NPC1L1) protein. Although it is well known that administration of ezetimibe in hypercholesterolemia patients reduces the risk of cardiovascular events through attenuation of atherosclerosis, studies on the direct effect of ezetimibe on vascular function are not sufficient. The aim of the present study was to investigate the vascular effects of ezetimibe in rat mesenteric arteries. In the present study, 12-week-old male Sprague Dawley rats were used. After the rats were sacrificed, the second branches of the mesenteric arteries were isolated and cut into 2-3 mm segments and mounted in a multi-wire myography system to measure isometric tension. Ezetimibe reduced vasoconstriction induced by U46619 (500 nM) in endothelium-intact and endothelium-denuded arteries. Ezetimibe-induced vasodilation was not affected by the endothelial nitric oxide synthase (eNOS) inhibitor N-Nitro-L-arginine (L-NNA, 300 μM) or the non-selective potassium channel blocker, tetraethylammonium (TEA, 10 mM). Moreover, ezetimibe also completely blocked the contraction induced by an increase in external calcium concentration. Ezetimibe significantly reduced vascular contraction induced by L-type Ca channel activator (Bay K 8644, 30 nM). Treatment with ezetimibe decreased the phosphorylation level of 20 kDa myosin light chain (MLC) in vascular smooth muscle cells. In the present study, we found that ezetimibe has a significant vasodilatory effect in rat mesenteric resistance arteries. These results suggest that ezetimibe may have beneficial cardiovascular effects beyond its cholesterol-lowering properties.
依泽替米贝是一种降脂药，通过与尼曼-匹克 C1 样蛋白 1（NPC1L1）结合选择性抑制胆固醇吸收。尽管众所周知，在高胆固醇血症患者中使用依泽替米贝可通过减弱动脉粥样硬化来降低心血管事件的风险，但关于依泽替米贝对血管功能的直接作用的研究还不够充分。本研究旨在探讨依泽替米贝对大鼠肠系膜动脉的血管作用。在本研究中，使用了 12 周龄雄性 Sprague Dawley 大鼠。大鼠处死后，分离肠系膜动脉的第二分支并切成 2-3mm 段，然后安装在多丝肌描记系统中以测量等长张力。依泽替米贝可减轻内皮完整和去内皮的血管中 U46619（500nM）诱导的血管收缩。依泽替米贝诱导的血管舒张不受内皮型一氧化氮合酶（eNOS）抑制剂 N-硝基-L-精氨酸（L-NNA，300μM）或非选择性钾通道阻滞剂四乙铵（TEA，10mM）的影响。此外，依泽替米贝还完全阻断了由细胞外钙离子浓度增加引起的收缩。依泽替米贝显著减轻了由 L 型钙通道激活剂（Bay K 8644，30nM）引起的血管收缩。依泽替米贝处理降低了血管平滑肌细胞中 20kDa 肌球蛋白轻链（MLC）的磷酸化水平。在本研究中，我们发现依泽替米贝对大鼠肠系膜阻力动脉具有显著的血管舒张作用。这些结果表明，依泽替米贝可能具有除降低胆固醇以外的有益心血管作用。
