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Menadione-induced cardiotoxicity is associated with alteration in intracellular Ca2+ homeostasis
W F Tzeng1, T J Chiou, J Y Huang
1Department of Biology, Fu Jen University, Taipei, Taiwan, Republic of China.
Abstract:
Cardiotoxicity of menadione was elucidated in neonatal rat cardiomyocytes. When incubated with menadione, contraction of myocytes initially slowed down and eventually stopped. Later blebs appeared on the cell surface, leading to cell degeneration. During the time of diminished cellular contraction, a large portion of endogenous ATP was depleted whilst intracellular Ca2+ levels were increased. However, if menadione was washed out prior to termination of contraction, the myocytes survived and most of the cells resumed regular contraction. Preincubation of the cells with diltiazem (a Ca2+ antagonist), or fura-2 acetoxymethyl ester (a chelate for Ca2+), or antipain (a proteinase inhibitor) suppressed menadione's ability for cellular damage. These results indicate that menadione is toxic to cardiomyocytes, and that the increase of intracellular Ca2+ is related to the mechanism of cardiotoxicity of menadione.
Insights
Menadione causes cardiotoxicity by depleting ATP and increasing intracellular calcium in neonatal rat cardiomyocytes. Prompt removal of menadione can prevent cell damage and restore function.
Area of Science:
- Biochemistry
- Cardiology
- Cell Biology
Background:
- Menadione (Vitamin K3) is a synthetic compound with known pro-oxidant properties.
- Cardiotoxicity is a significant concern in pharmacology and toxicology, affecting heart muscle cells (cardiomyocytes).
- Understanding the mechanisms of drug-induced cardiotoxicity is crucial for patient safety.
Purpose of the Study:
- To investigate the cardiotoxic effects of menadione on neonatal rat cardiomyocytes.
- To elucidate the cellular mechanisms underlying menadione-induced cardiotoxicity.
- To identify potential protective strategies against menadione cardiotoxicity.
Main Methods:
- Neonatal rat cardiomyocytes were exposed to menadione in vitro.
- Cellular contraction, ATP levels, and intracellular calcium (Ca2+) concentrations were monitored.
- Effects of menadione washout and pre-treatment with specific inhibitors were assessed.
Main Results:
- Menadione exposure initially slowed and then stopped cardiomyocyte contraction.
- Significant depletion of adenosine triphosphate (ATP) and increased intracellular Ca2+ levels were observed.
- Reversibility of toxic effects was noted upon menadione washout.
- Cardiomyocyte damage was suppressed by diltiazem (Ca2+ antagonist), fura-2, and antipain (proteinase inhibitor).
Conclusions:
- Menadione exhibits significant cardiotoxicity in neonatal rat cardiomyocytes.
- Increased intracellular Ca2+ is implicated in the mechanism of menadione cardiotoxicity.
- Intervention with Ca2+ antagonists or proteinase inhibitors may offer protective effects against menadione-induced damage.