Ezetimibe Induces Vasodilation in Rat Mesenteric Resistance Arteries Through Inhibition of Extracellular Ca Influx

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2023 Sep 28

PMID 37762296

Authors

Eun Yi Oh

Chae Eun Haam

Sooyeon Choi

Seonhee Byeon

Soo-Kyoung Choi

Young-Ho Lee

Affiliations

Soon will be listed here.

Abstract

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.

References

Choi S, Ahn D, Lee Y . Comparison of contractile mechanisms of sphingosylphosphorylcholine and sphingosine-1-phosphate in rabbit coronary artery. Cardiovasc Res. 2009; 82(2):324-32. DOI: 10.1093/cvr/cvp054. View

Stokes K, Calahan L, Russell J, Gurwara S, Granger D . Role of platelets in hypercholesterolemia-induced leukocyte recruitment and arteriolar dysfunction. Microcirculation. 2006; 13(5):377-88. DOI: 10.1080/10739680600745877. View

Stokes K, Cooper D, Tailor A, Granger D . Hypercholesterolemia promotes inflammation and microvascular dysfunction: role of nitric oxide and superoxide. Free Radic Biol Med. 2002; 33(8):1026-36. DOI: 10.1016/s0891-5849(02)01015-8. View

Tamaki N, Ueno H, Morinaga Y, Shiiya T, Nakazato M . Ezetimibe ameliorates atherosclerotic and inflammatory markers, atherogenic lipid profiles, insulin sensitivity, and liver dysfunction in Japanese patients with hypercholesterolemia. J Atheroscler Thromb. 2012; 19(6):532-8. DOI: 10.5551/jat.10835. View

Nochioka K, Tanaka S, Miura M, Zhulanqiqige D, Fukumoto Y, Shiba N . Ezetimibe improves endothelial function and inhibits Rho-kinase activity associated with inhibition of cholesterol absorption in humans. Circ J. 2012; 76(8):2023-30. DOI: 10.1253/circj.cj-12-0331. View

van Heek M, France C, Compton D, McLeod R, Yumibe N, Alton K . In vivo metabolism-based discovery of a potent cholesterol absorption inhibitor, SCH58235, in the rat and rhesus monkey through the identification of the active metabolites of SCH48461. J Pharmacol Exp Ther. 1997; 283(1):157-63. View

Cooke J . The 1998 Nobel prize in Medicine: clinical implications for 1999 and beyond. Vasc Med. 1999; 4(2):57-60. DOI: 10.1177/1358836X9900400201. View

Jackson W . Potassium Channels in Regulation of Vascular Smooth Muscle Contraction and Growth. Adv Pharmacol. 2017; 78:89-144. PMC: 5518321. DOI: 10.1016/bs.apha.2016.07.001. View

AlTurki A, Marafi M, Dawas A, Dube M, Vieira L, Sherman M . Meta-analysis of Randomized Controlled Trials Assessing the Impact of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies on Mortality and Cardiovascular Outcomes. Am J Cardiol. 2019; 124(12):1869-1875. DOI: 10.1016/j.amjcard.2019.09.011. View

10.

Pajkowski M, Dudziak M, Chlebus K, Hellmann M . Assessment of microvascular function and pharmacological regulation in genetically confirmed familial hypercholesterolemia. Microvasc Res. 2021; 138:104216. DOI: 10.1016/j.mvr.2021.104216. View

11.

Jalloh M, Doroudgar S, Ip E . What is the impact of the 2017 cochrane systematic review and meta-analysis that evaluated the use of PCSK9 inhibitors for lowering cardiovascular disease and mortality?. Expert Opin Pharmacother. 2018; 19(7):739-741. DOI: 10.1080/14656566.2018.1464558. View

12.

Takase S, Matoba T, Nakashiro S, Mukai Y, Inoue S, Oi K . Ezetimibe in Combination With Statins Ameliorates Endothelial Dysfunction in Coronary Arteries After Stenting: The CuVIC Trial (Effect of Cholesterol Absorption Inhibitor Usage on Target Vessel Dysfunction After Coronary Stenting), a Multicenter.... Arterioscler Thromb Vasc Biol. 2016; 37(2):350-358. DOI: 10.1161/ATVBAHA.116.308388. View

13.

Pi X, Xie L, Patterson C . Emerging Roles of Vascular Endothelium in Metabolic Homeostasis. Circ Res. 2018; 123(4):477-494. PMC: 6205216. DOI: 10.1161/CIRCRESAHA.118.313237. View

14.

. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998; 339(19):1349-57. DOI: 10.1056/NEJM199811053391902. View

15.

Nissen S, Stroes E, Dent-Acosta R, Rosenson R, Lehman S, Sattar N . Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial. JAMA. 2016; 315(15):1580-90. DOI: 10.1001/jama.2016.3608. View

16.

Mourikis P, Zako S, Dannenberg L, Nia A, Heinen Y, Busch L . Lipid lowering therapy in cardiovascular disease: From myth to molecular reality. Pharmacol Ther. 2020; 213:107592. DOI: 10.1016/j.pharmthera.2020.107592. View

17.

Duan Y, Gong K, Xu S, Zhang F, Meng X, Han J . Regulation of cholesterol homeostasis in health and diseases: from mechanisms to targeted therapeutics. Signal Transduct Target Ther. 2022; 7(1):265. PMC: 9344793. DOI: 10.1038/s41392-022-01125-5. View

18.

Sandoo A, Veldhuijzen van Zanten J, Metsios G, Carroll D, Kitas G . The endothelium and its role in regulating vascular tone. Open Cardiovasc Med J. 2011; 4:302-12. PMC: 3040999. DOI: 10.2174/1874192401004010302. View

19.

Stapleton P, Goodwill A, James M, dAudiffret A, Frisbee J . Differential impact of familial hypercholesterolemia and combined hyperlipidemia on vascular wall and network remodeling in mice. Microcirculation. 2010; 17(1):47-58. PMC: 2952832. DOI: 10.1111/j.1549-8719.2009.00003.x. View

20.

Sirtori C . The pharmacology of statins. Pharmacol Res. 2014; 88:3-11. DOI: 10.1016/j.phrs.2014.03.002. View