Preventive Effect of Chronic Endothelin Type A Receptor Antagonist on Coronary Microvascular Spasm Induced by Repeated Epicardial Coronary Artery Endothelial Denudation in Pigs

Osugi, Taku; Saitoh, Shu‐ichi; Matumoto, Ken; Muto, Mituru; Aikawa, Kazuhiko; Ohkawara, Hiroshi; Sugimoto, Kouichi; Kamioka, Masashi; Ishibashi, Toshiyuki; Maruyama, Yukio

doi:10.5551/jat.2147

Cited by 7 publications

(4 citation statements)

References 34 publications

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“…Several clinical studies demonstrated higher ET-1 plasma levels in the coronary sinus -baseline as well as during CAS provocation -in patients with a positive epicardial CAS provocation test indicated by vasoconstriction in response to ACh, compared with patients with a normal vasodilatory response [25][26][27]. Although the endothelium is a major source of ET-1, it has been shown that ET-1 is also expressed in macrophages and intimal VSMCs in atherosclerotic tissue , repeated endothelial denudation of epicardial coronary arteries increased the plasma levels of ET-1 in coronary sinus blood compared with the control group without endothelial denudation, while the chronic administration of an ETA receptor antagonist prevented the coronary microvascular vasoconstrictive response to ACh 30. In a placebo-controlled clinical trial in patients with coronary microvascular dysfunction (defined by a ≤50% increase in coronary blood flow[CBF] in response to the maximal dose of ACh compared with baseline CBF) and non-obstructed CAD,Reriani et al demonstrated an improvement of microvascular endothelial function after long-term (>6 months) treatment with the ET A receptor antagonist atrasentan 31.…”

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confidence: 98%

Coronary Artery Spasm: The Interplay Between Endothelial Dysfunction and Vascular Smooth Muscle Cell Hyperreactivity

et al. 2020

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Patients with angina pectoris, the cardinal symptom of myocardial ischaemia, yet without significant flow-limiting epicardial artery stenosis represent a diagnostic and therapeutic challenge. Coronary artery spasm (CAS) is an established cause for anginal chest pain in patients with angiographically unobstructed coronary arteries. CAS may occur at the epicardial level and/or in the microvasculature. Although the underlying pathophysiological mechanisms of CAS are still largely unclear, endothelial dysfunction and vascular smooth muscle cell (VSMC) hyperreactivity seem to be involved as major players, although their contribution to induce CAS is still seen as controversial. This article will look at the role and possible mechanistic interplay between an impaired endothelial and VSMC function in the pathogenesis of CAS.

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confidence: 98%

Coronary Artery Spasm: The Interplay Between Endothelial Dysfunction and Vascular Smooth Muscle Cell Hyperreactivity

et al. 2020

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“…In a case reported by Vermeltfoort, the treatment with endothelin receptor antagonist bosentan successfully reduced the frequency and severity of chest pain in a patient with CAS [59]. The experiment on porcine model also demonstrated that administration of ET-A receptor antagonist is effective to prevent CAS [60]. Now endothelin-1 is widely believed to be one of the most potent endogenous vasoconstrictors which could initiate and maintain both epicardial and microvascular spasm.…”

Section: Endothelin-1mentioning

confidence: 99%

The Biochemical Markers Associated with the Occurrence of Coronary Spasm

Jin

Xia

et al. 2019

BioMed Research International

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Coronary artery spasm (CAS) is one of the mechanisms of angina pectoris. Unlike the diagnosis of acute myocardial infarction which is based on the elevation of cardiac markers, the diagnosis of CAS is difficult and sometimes requires sophisticated and risky provocative test which is not widely accepted in China. There is no well-established biomarker for the diagnosis or prediction of CAS. However, there are some biomarkers proven to be associated with the occurrence of CAS. For example, inflammatory factors including C-reactive protein and cytokines, lipoprotein (a), and cystatin-C might be precipitating factor for CAS. Rho-kinase as a mediator involved in multiple mechanisms of CAS, serotonin, and endothelin-1 as powerful vasoconstrictors leading to vasospasm were all observed being elevated in patients with CAS. Thioredoxin and nitrotyrosine reflected the oxidative status and could be observed to be elevated after the occurrence of CAS. In some cases doubted to be CAS without the evidence of provocative test, the blood test for the biomarkers mentioned above could be useful for the diagnosis of CAS.

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“…Nitric oxide (NO) is generated from L-arginine by constitutive endothelial NO synthase (eNOS) ( 5 ). In the vasculature, the bioactivity of eNOS and NO is regulated by the caveolins, which are scaffolding/regulatory proteins that are particularly abundant in the endothelial cell plasma membrane ( 6 , 7 ). Caveolin-1 (Cav-1) is the most important caveolar coat protein involved in the control of vascular reactivity by combining with eNOS ( 8 ).…”

Section: Introductionmentioning

confidence: 99%

Downregulated caveolin‑1 expression serves a potential role in coronary artery spasm by inducing nitric oxide production in�vitro

Cao

Jin

et al. 2018

Exp Ther Med

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The present study aimed to investigate the effects of downregulated caveolin-1 (Cav-1) expression on nitric oxide (NO) production in lipopolysaccharide (LPS)-damaged primary human umbilical vein endothelial cells (HUVECs) in a model of coronary artery spasm (CAS) microenvironment induced by acetylcholine (ACh) treatment. Small interfering RNA (siRNA)-mediated Cav-1 downregulation in HUVECs was confirmed by western blotting. The cell viability and superoxide dismutase (SOD) inhibition in HUVECs incubated with LPS (0, 10, 25, 50, 75 and 100 µg/ml) were measured by cell counting kit-8 assay and a SOD kit, respectively. Intracellular Ca2+ [(Ca2+)i] in Fluo4-acetoxymethyl ester-loaded cells was detected by fluorescence microscopy. NO levels in the cell culture supernatants were measured by the nitrate reductase method. The results indicated that transfection with Cav-1 siRNA, in particular siCav-1 (2), downregulated the Cav-1 protein expression. LPS at a dose of 75 µg/ml induced a significant decrease in HUVECs/si-NC and HUVECs/siCav-1 viability compared with the other concentrations of LPS. Compared with the effects of untreated cells, SOD inhibition in HUVECs/si-NC and HUVECs/siCav-1 was significantly decreased by LPS (75 µg/ml). In addition, ACh stimulation caused a greater increase in [Ca2+]i in HUVECs/si-NC as compared with LPS-treated HUVECs/si-NC. ACh stimulation also induced significantly higher NO levels in LPS-treated HUVECs/siCav-1 compared with LPS-treated HUVECs/si-NC cells (P<0.05). In conclusion, the downregulated Cav-1 expression served a key role in NO production in the in vitro model of CAS induced by ACh stimulation of LPS-damaged HUVECs.

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Preventive Effect of Chronic Endothelin Type A Receptor Antagonist on Coronary Microvascular Spasm Induced by Repeated Epicardial Coronary Artery Endothelial Denudation in Pigs

Cited by 7 publications

References 34 publications

Coronary Artery Spasm: The Interplay Between Endothelial Dysfunction and Vascular Smooth Muscle Cell Hyperreactivity

Coronary Artery Spasm: The Interplay Between Endothelial Dysfunction and Vascular Smooth Muscle Cell Hyperreactivity

The Biochemical Markers Associated with the Occurrence of Coronary Spasm

Downregulated caveolin‑1 expression serves a potential role in coronary artery spasm by inducing nitric oxide production in�vitro

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