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The effect of diazepam on myocardial function and coronary vascular tone after endotoxemia in the isolated rat heart model

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Abstract

Objective and design

Tumor necrosis factor alpha (TNF-α) has been implicated in the pathogenesis of cardiovascular disease and sepsis-associated cardiac dysfunction. Although initially described solely as a lipopolysaccharide (LPS)-induced macrophage product, evidence exists that cardiac myocytes themselves produce substantial amounts of TNF-α in response to ischemia as well as LPS. The use of phosphodiesterase inhibitors has been shown to decrease LPS-induced TNF-α elaboration. The aim of the present study was to determine the effect of diazepam (Type IV phosphodiesterase inhibitor) on (1) myocardial function and (2) coronary vascular flow after LPS-induced endotoxic shock in an isolated rat heart model.

Materials and methods

Endotoxemia was induced by intraperitoneal LPS administration in adult male Wistar rats. Hearts were isolated after 6 h and perfused in a working mode with oxygenated Krebs–Henseleit buffer at 37°C. Diazepam was mixed with Krebs–Henseleit buffer and administered (3.0 μg/ml) for 20 min.

Results

LPS-treated hearts showed depressed cardiac function and reduced coronary flow. Myocardial functional parameters (LVDP, +dP/dt, −dP/dt, RPP) and coronary flow (ml/min) were significantly (p < 0.01) improved by diazepam administration.

Conclusions

These findings suggest that diazepam can salvage myocardial function and undo coronary vascular constriction in the endotoxemic rat heart. These findings are clinically relevant to the treatment of cardiovascular depression caused by endotoxic shock.

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Acknowledgments

The authors would like to thank Carla Smith and Alison Rose for their assistance with the animals. This study was funded by the Fremantle Hospital Medical Research Foundation.

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Authors and Affiliations

  1. Fremantle Heart Institute, Fremantle Hospital, School of Surgery and Pathology, University of Western Australia, Fremantle, WA, Australia

    William M. L. Neethling

  2. Department of Cardiothoracic Surgery, Fremantle Hospital, Fremantle, WA, Australia

    Andrew J. Hodge

  3. Fremantle Heart Institute, Cell Biology Research Unit, Z Block, Fremantle Hospital, Alma Street, Fremantle, WA, 6959, Australia

    William M. L. Neethling

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Correspondence to William M. L. Neethling.

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Responsible Editor: Makoto Katori.

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Neethling, W.M.L., Hodge, A.J. The effect of diazepam on myocardial function and coronary vascular tone after endotoxemia in the isolated rat heart model. Inflamm. Res. 59, 907–913 (2010). https://doi.org/10.1007/s00011-010-0239-8

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  • DOI: https://doi.org/10.1007/s00011-010-0239-8

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