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Article
Contractile response of norepinephrine is modulated by caspase-3 in adult rat ventricular myocytes isolated from septic rat heart
Pharmacological Research
  • M. Chopra
  • Avadhesh C. Sharma, Philadelphia College of Osteopathic Medicine
Document Type
Article
Publication Date
1-1-2009
Abstract
Sepsis accounts for 50% of intensive care unit deaths due to cardiac dysfunction. The cellular mechanisms following norepinephrine (NE) during sepsis are undefined. Using a septic adult rat ventricular myocyte (ARVM) paradigm, we examined the molecular mechanism responsible for the blunted contractile response of NE. We tested the hypothesis that NE-induced increases in active caspase-3 contribute to sepsis-induced ARVM contractile dysfunction. Single ARVMs were isolated from hearts harvested from sham and septic male rats. The contractile properties and expression of caspase-3 cascade proteins were determined in ARVMs treated with NE with and without QVD-OPH, prazosin and atenolol to characterize the effect of NE on their mechanical properties. Septic ARVMs exhibited a significant decrease in peak shortening (PS) compared to sham ARVMs. The effect of NE on the PS of the sham ARVMs was more pronounced compared to the septic ARVMs, suggesting a blunted contractile response of NE. NE in the presence of QVD-OPH ameliorated the sepsis-induced decrease in PS at 18 h but not at 1 h, while the effect of NE on sepsis-induced contractile response remained unaffected at 18 h by prazosin and atenolol. An up-regulated expression of caspase-3 in NE-treated septic ARVMs was reversed by QVD-OPH, as seen by the increased number of septic ARVMs exhibiting caspase-3 fluorescence. Transfection of ARVMs using caspase-3 siRNA blocked sepsis-induced up-regulation of caspase-3 and increased PS following NE treatment. These data suggest that caspase-3 inhibition ameliorated sepsis-induced decreased ARVM contractility and blocked the blunted contractile response of NE. © 2009 Elsevier Ltd. All rights reserved.
Comments

This article was published in Pharmacological Research, Volume 60, Issue 4, Pages 303-313.

The published version is available at http://dx.doi.org/10.1016/j.phrs.2009.04.009.

Copyright © 2009 Elsevier.

Citation Information
M. Chopra and Avadhesh C. Sharma. "Contractile response of norepinephrine is modulated by caspase-3 in adult rat ventricular myocytes isolated from septic rat heart" Pharmacological Research Vol. 60 Iss. 4 (2009) p. 303 - 313
Available at: http://works.bepress.com/avadhesh_sharma/15/