Dataset Information

Cardioprotective effects of 5-hydroxymethylfurfural mediated by inhibition of L-type Ca²⁺ currents.

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 Ca²⁺ current (I_Ca,L ) 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 Ca²⁺ channels. Reduced I_Ca,L density, shift of I_Ca,L steady-state inactivation curves toward negative membrane potentials and slower recovery of I_Ca,L 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 Ca²⁺ channels. Thus, 5-HMF is suggested as a beneficial additive to cardioplegic solutions, but adverse effects and contraindications of Ca²⁺ channel blockers have to be considered in therapeutic application of the drug.

SUBMITTER: Wolkart G

PROVIDER: S-EPMC5610158 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Publications

Cardioprotective effects of 5-hydroxymethylfurfural mediated by inhibition of L-type Ca<sup>2+</sup> currents.

Wölkart G G Schrammel A A Koyani C N CN Scherübel S S Zorn-Pauly K K Malle E E Pelzmann B B Andrä M M Ortner A A Mayer B B

British journal of pharmacology 20170909 20

<h4>Background and purpose</h4>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.<h4>Experimental approach</h4>The cardiovascular effects of 5-HMF were studied with pre-contracted porcine coronary arteries and rat isolated normoxic-perfused hear ...[more]

PMID: 28768052

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Project description:IntroductionHuman induced pluripotent stem cells (hiPSCs) harboring cardiac myosin heavy chain 6 promoter can differentiate into functional cardiomyocytes called "iCell cardiomyocytes" under blasticidin treatment condition. While iCell cardiomyocytes are expected to be used for predicting cardiotoxicity of drugs, their responses to antiarrhythmic agents remain to be elucidated. We first examined electrophysiological properties of iCell cardiomyocytes and mRNA levels of ion channels and Ca handling proteins, and then evaluated effects of class I antiarrhythmic agents on their Na+ and Ca2+ currents.MethodsiCell cardiomyocytes were cultured for 8-14 days (38-44 days after inducing their differentiation), according to the manufacturer's protocol. We determined their action potentials (APs) and sarcolemmal ionic currents using whole-cell patch clamp techniques, and also mRNA levels of ion channels and Ca handling proteins by RT-PCR. Effects of three class I antiarrhythmic agents, pirmenol, pilsicainide and mexiletine, on Na+ channel current (INa) and L-type Ca2+ channel current (ICaL) were evaluated by the whole-cell patch clamp.ResultsiCell cardiomyocytes revealed sinoatrial node-type (18%), atrial-type (18%) and ventricular-type (64%) spontaneous APs. The maximum peak amplitudes of INa, ICaL, and rapidly-activating delayed-rectifier K+ channel current were -62.7 ± 13.7, -8.1 ± 0.7, and 3.0 ± 1.0 pA/pF, respectively. The hyperpolarization-activated cation channel and inward-rectifier K+ channel currents were observed, whereas the T-type Ca2+ channel or slowly-activating delayed-rectifier K+ channel current was not detectable. mRNAs of Nav1.5, Cav1.2, Kir2.1, HCN4, KvLQT1, hERG and SERCA2 were detected, while that of HCN1, minK or MiRP was not. The class Ia antiarrhythmic agent pirmenol and class Ic agent pilsicainide blocked INa in a concentration-dependent manner with IC50 of 0.87 ± 0.37 and 0.88 ± 0.16 μM, respectively; the class Ib agent mexiletine revealed weak INa block with a higher IC50 of 30.0 ± 3.0 μM. Pirmenol, pilsicainide and mexiletine blocked ICaL with IC50 of 2.00 ± 0.39, 7.7 ± 2.5 and 5.0 ± 0.1 μM, respectively.ConclusionsIn iCell cardiomyocytes, INa was blocked by the class Ia and Ic antiarrhythmic agents and ICaL was blocked by all the class I agents within the ranges of clinical concentrations, suggesting their cardiotoxicity.

Dataset Information

Cardioprotective effects of 5-hydroxymethylfurfural mediated by inhibition of L-type Ca²⁺ currents.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

Cardioprotective effects of 5-hydroxymethylfurfural mediated by inhibition of L-type Ca<sup>2+</sup> currents.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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Dataset Information

Cardioprotective effects of 5-hydroxymethylfurfural mediated by inhibition of L-type Ca2+ currents.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

Cardioprotective effects of 5-hydroxymethylfurfural mediated by inhibition of L-type Ca&lt;sup&gt;2+&lt;/sup&gt; currents.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Cardioprotective effects of 5-hydroxymethylfurfural mediated by inhibition of L-type Ca²⁺ currents.

Cardioprotective effects of 5-hydroxymethylfurfural mediated by inhibition of L-type Ca<sup>2+</sup> currents.