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BMS309403 directly suppresses cardiac contractile function

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Abstract

BMS309403, a substance used as an inhibitor of adipocyte fatty acid-binding protein, has been suggested as a new therapeutic agent for treating type 2 diabetes mellitus and atherosclerosis; however, little is known about its possible side effects. The present study investigates the effects of BMS309403 on the cardiovascular system. We used isolated perfused heart preparations and single cardiomyocytes from adult rats for contractile analysis. The Ca2+ sensitivity of the myofilaments was investigated by using porcine cardiac skinned muscle fibers. BMS309403 induced a negative effect on the contractility of isolated perfused hearts leading to heart arrest without interfering in the electrocardiographic activity, suggesting electromechanical dissociation. Experiments with isolated cardiomyocytes showed that BMS309403 had a direct biphasic inhibitory effect on cardiomyocyte contraction, at higher concentrations by attenuating Ca2+ levels. This negative inotropic effect does not result from a direct effect on the myofilaments. BMS309403 has an acute cardiac depressant effect in vitro. The potential therapeutic applicability of this compound requires additional consideration.

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Abbreviations

ApoE:

Apolipoprotein E

BDM:

Butanedione monoxime

CF:

Coronary flow

ECG:

Electrocardiogram

FABP3:

Heart isoform of FABP

FABP4:

Adipocyte fatty acid-binding protein

FABP5:

Epidermal isoform of FABP

FABPs:

Fatty acid-binding proteins

HBSS:

Hank's balanced salts solution

HR:

Heart rate

KHS:

Krebs-Henseleit solution

LVP:

Left ventricular pressure

m HA :

Median heart arrest time

m IC :

Median irregular contraction time

SERCA:

Sarcoplasmatic reticulum Ca2+ ATPase

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Acknowledgments

We gratefully acknowledge the expert technical assistance of Petra Sakel. We thank Kathleen Eisenhofer for proofreading of this paper. This study was supported by the “Kompetenznetz Adipositas (Competence Network for Obesity)” funded by the German Federal Ministry of Education and Research (grant number 01GI0833).

Conflicts of interest

None.

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Authors and Affiliations

  1. Medical Clinic III, University of Technology Dresden, Fetscherstr. 74, 01307, Dresden, Germany

    Christiane Look, Monika Ehrhart-Bornstein, Stefan R. Bornstein & Valéria Lamounier-Zepter

  2. Molecular Muscle Physiology, Max-Delbrück-Center for Molecular Medicine, Berlin-Buch, Germany

    Ingo Morano

Authors
  1. Christiane Look
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  2. Ingo Morano
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  3. Monika Ehrhart-Bornstein
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  4. Stefan R. Bornstein
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  5. Valéria Lamounier-Zepter
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Correspondence to Christiane Look.

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Look, C., Morano, I., Ehrhart-Bornstein, M. et al. BMS309403 directly suppresses cardiac contractile function. Naunyn-Schmiedeberg's Arch Pharmacol 384, 255–263 (2011). https://doi.org/10.1007/s00210-011-0667-1

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  • DOI: https://doi.org/10.1007/s00210-011-0667-1

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