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Calcium dynamics in cardiac myocytes as a target of dichloromethane cardiotoxicity
P Hoffmann1, S P Müller, K Heinroth
1SANOFI Recherche, Centre de Toulouse, France.
Abstract:
The purpose of the present study was to determine if cardiac actions of dichloromethane (DCM) in vivo correlate with in vitro alterations of Ca2+ dynamics in cardiac myocytes. Neonatal rat ventricular myocytes were obtained from 2- to 4-day-old rats, and electrically induced fluctuations of cytosolic free Ca2+ concentration ([Ca2+]i) in single cardiomyocytes were investigated using spectrofluorometric analysis of fura-2-[Ca2+]i binding. In cultured myocytes, cumulative exposure to 0.64-40.96 mM DCM resulted in a concentration-dependent and reversible decrease in the magnitude of [Ca2+]i transients with IC10 and IC50 values of 7.98 and 18.82 mM, respectively. Total inhibition of [Ca2+]i transients and cessation of beating were observed at 40.96 mM DCM. Suffusion with DCM for 40 min did not cause morphological alterations of the myocytes. In a urethane-anesthetized rat model, left ventricular pressure was measured by introducing a tip catheter via the carotid artery into the left ventricle, the ECG was recorded by two needle electrodes applied subcutaneously to the chest wall, and arterial pressure was measured via the femoral artery. Oral administration of 3.1-12.4 mmol DCM/kg resulted in DCM blood concentrations between 1.0 and 1.6 mM, accompanied by a dose-dependent decrease in contractile force and heart rate without influencing blood pressure and ECG tracings. Moreover, DCM treatment provided significant protection against arrhythmia development due to CaCl2-infusion. In spite of the slight discrepancy between DCM blood concentrations and in vitro concentrations of DCM for [Ca2+]i transient inhibition, present data are consistent with the view that cardiac effects after DCM exposure are mediated by alterations of Ca2+ dynamics during excitation-contraction coupling.
Insights
Dichloromethane (DCM) exposure in rats affects heart function by altering calcium (Ca2+) dynamics in cardiac cells. This study shows DCM decreases heart rate and contractile force, while protecting against arrhythmias.
Area of Science:
- Cardiovascular Physiology
- Cellular Electrophysiology
- Toxicology
Background:
- Dichloromethane (DCM) is a widely used solvent with potential cardiac effects.
- Understanding the mechanisms underlying DCM's cardiotoxicity is crucial for risk assessment.
Purpose of the Study:
- To investigate the correlation between in vivo cardiac actions of DCM and its in vitro effects on calcium (Ca2+) dynamics in cardiac myocytes.
- To elucidate the role of Ca2+ handling in DCM-induced cardiac alterations.
Main Methods:
- Neonatal rat ventricular myocytes were used for in vitro studies measuring cytosolic free Ca2+ concentration ([Ca2+]i) using fura-2 spectrofluorometry.
- In vivo studies involved anesthetized rats, measuring left ventricular pressure, ECG, and arterial pressure following DCM administration.
- Dose-dependent effects of DCM on [Ca2+]i transients, myocyte beating, and cardiac function were assessed.
Main Results:
- In vitro, DCM caused a concentration-dependent, reversible decrease in [Ca2+]i transients in cardiomyocytes, with IC50 of 18.82 mM.
- In vivo, oral DCM administration led to a dose-dependent reduction in heart rate and contractile force, without affecting blood pressure or ECG.
- DCM treatment demonstrated protective effects against calcium chloride-induced arrhythmias.
Conclusions:
- Cardiac effects of DCM exposure are mediated by alterations in Ca2+ dynamics during excitation-contraction coupling.
- The study provides evidence linking DCM's impact on cellular Ca2+ handling to observed in vivo cardiac functional changes.
- Despite concentration discrepancies, findings support DCM's influence on cardiac calcium regulation.