Affordable Access

Publisher Website

Cardiotoxicity of calmidazolium chloride is attributed to calcium aggravation, oxidative and nitrosative stress, and apoptosis

Authors
Journal
Free Radical Biology and Medicine
0891-5849
Publisher
Elsevier
Publication Date
Volume
47
Issue
6
Identifiers
DOI: 10.1016/j.freeradbiomed.2009.05.028
Keywords
  • Calmidazolium
  • H9C2 Cells
  • Cardiotoxicity
  • Oxidative Stress
  • Mitochondrial Damage
  • Cardiomyocytes
  • Free Radicals

Abstract

Abstract The intracellular calcium concentration ([Ca] i) regulates cell viability and contractility in myocardial cells. Elevation of the [Ca] i level occurs by entry of calcium ions (Ca 2+) through voltage-dependent Ca 2+ channels in the plasma membrane and release of Ca 2+ from the sarcoplasmic reticulum. Calmidazolium chloride (CMZ), a subgroup II calmodulin antagonist, blocks L-type calcium channels as well as voltage-dependent Na + and K + channel currents. This study elaborates on the events that contribute to the cytotoxic effects of CMZ on the heart. We hypothesized that apoptotic cell death occurs in the cardiac cells through calcium accumulation, production of reactive oxygen species, and the cytochrome c-mediated PARP activation pathway. CMZ significantly increased the production of superoxide (O 2 •–) and nitric oxide (NO) as detected by FACS and confocal microscopy. CMZ induced mitochondrial damage by increasing the levels of intracellular calcium, lowering the mitochondrial membrane potential, and thereby inducing cytochrome c release. Apoptotic cell death was observed in H9c2 cells exposed to 25 μM CMZ for 24 h. This is the first report that elaborates on the mechanism of CMZ-induced cardiotoxicity. CMZ causes apoptosis by decreasing mitochondrial activity and contractility indices and increasing oxidative and nitrosative stress, ultimately leading to cell death via an intrinsic apoptotic pathway.

There are no comments yet on this publication. Be the first to share your thoughts.