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5-羟甲基糠醛通过抑制 L 型钙电流发挥心脏保护作用。

Cardioprotective effects of 5-hydroxymethylfurfural mediated by inhibition of L-type Ca currents.

机构信息

Institute of Pharmaceutical Sciences, Department of Pharmacology and Toxicology, University of Graz, Graz, Austria.

Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.

出版信息

Br J Pharmacol. 2017 Oct;174(20):3640-3653. doi: 10.1111/bph.13967. Epub 2017 Sep 9.

DOI:10.1111/bph.13967
PMID:28768052
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5610158/
Abstract

BACKGROUND AND PURPOSE

The antioxidant 5-hydroxymethylfurfural (5-HMF) exerts documented beneficial effects in several experimental pathologies and is currently tested as an antisickling drug in clinical trials. In the present study, we examined the cardiovascular effects of 5-HMF and elucidated the mode of action of the drug.

EXPERIMENTAL APPROACH

The cardiovascular effects of 5-HMF were studied with pre-contracted porcine coronary arteries and rat isolated normoxic-perfused hearts. Isolated hearts subjected to ischaemia/reperfusion (I/R) injury were used to test for potential cardioprotective effects of the drug. The effects of 5-HMF on action potential and L-type Ca current (I ) were studied by patch-clamping guinea pig isolated ventricular cardiomyocytes.

KEY RESULTS

5-HMF relaxed coronary arteries in a concentration-dependent manner and exerted negative inotropic, lusitropic and chronotropic effects in rat isolated perfused hearts. On the other hand, 5-HMF improved recovery of inotropic and lusitropic parameters in isolated hearts subjected to I/R. Patch clamp experiments revealed that 5-HMF inhibits L-type Ca channels. Reduced I density, shift of I steady-state inactivation curves toward negative membrane potentials and slower recovery of I from inactivation in response to 5-HMF accounted for the observed cardiovascular effects.

CONCLUSIONS AND IMPLICATIONS

Our data revealed a cardioprotective effect of 5-HMF in I/R that is mediated by inhibition of L-type Ca channels. Thus, 5-HMF is suggested as a beneficial additive to cardioplegic solutions, but adverse effects and contraindications of Ca channel blockers have to be considered in therapeutic application of the drug.

摘要

背景与目的

抗氧化剂 5-羟甲基糠醛（5-HMF）在多种实验性病理中具有已证实的有益作用，目前正在临床试验中作为抗镰状细胞药物进行测试。在本研究中，我们研究了 5-HMF 的心血管作用，并阐明了药物的作用机制。

实验方法

使用预收缩的猪冠状动脉和大鼠离体正常氧合灌注心脏研究 5-HMF 的心血管作用。使用缺血/再灌注（I/R）损伤的分离心脏来测试药物的潜在心脏保护作用。通过膜片钳技术研究 5-HMF 对豚鼠分离心室肌细胞动作电位和 L 型钙电流（I ）的影响。

主要结果

5-HMF 浓度依赖性地松弛冠状动脉，并对大鼠离体灌注心脏产生负性肌力、正性松弛和正性变时作用。另一方面，5-HMF 改善了 I/R 分离心脏的收缩和松弛参数的恢复。膜片钳实验表明，5-HMF 抑制 L 型钙通道。I 密度降低、I 稳态失活曲线向负膜电位移动以及 I 从失活中恢复的速度减慢，这些都解释了观察到的心血管作用。

结论与意义

我们的数据揭示了 5-HMF 在 I/R 中的心脏保护作用，该作用是通过抑制 L 型钙通道介导的。因此，5-HMF 被建议作为心脏停搏液的有益添加剂，但在药物的治疗应用中必须考虑钙通道阻滞剂的不良反应和禁忌症。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c203/5610158/18a1e265b59f/BPH-174-3640-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c203/5610158/852e51764209/BPH-174-3640-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c203/5610158/d0085a20dbe5/BPH-174-3640-g003.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c203/5610158/ab185b219e82/BPH-174-3640-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c203/5610158/62870ec2fee2/BPH-174-3640-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c203/5610158/18a1e265b59f/BPH-174-3640-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c203/5610158/852e51764209/BPH-174-3640-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c203/5610158/fe06b84c9a9f/BPH-174-3640-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c203/5610158/d0085a20dbe5/BPH-174-3640-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c203/5610158/66fbdd4fdf28/BPH-174-3640-g004.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c203/5610158/62870ec2fee2/BPH-174-3640-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c203/5610158/18a1e265b59f/BPH-174-3640-g007.jpg

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