Cardiotoxicity of dichloromethane in rats and in cultured rat cardiac myocytes.
The purpose of the present study was to examine whether cardiac actions of dichloromethane (DCM) in vivo correlate with in vitro alterations of Ca(2+) dynamics in cardiac myocytes. Electrically induced fluctuations of cytosolic free Ca(2+) concentration ([Ca(2+)](i)) were investigated in neonatal rat ventricular myocytes using spectrofluorometric analysis of fura-2 binding. [Ca(2+)](i) transients were inhibited in a concentration-dependent and reversible manner with IC(10) and IC(50)values of 3.2 and 18.1 mm. Complete inhibition of [Ca(2+)](i) transients and cessation of beating were observed at 40.96 mm without morphological alterations. Left ventricular pressure in urethane-anaesthetized rats was measured by introducing a tip catheter by way of the carotid artery into the left ventricle and ECG (lead II) was recorded by two needle electrodes. Administration of 3.1, 6.2 or 12.4 mmol DCM/kg orally resulted in DCM blood concentrations between 1.0 and 1.6 mm accompanied by a dose-dependent decrease of contractility parameters. Moreover, DCM administration provided protection against arrhythmia development due to CaCl(2) infusion. These observations are consistent with the view that both the negative inotropic effects of DCM and the protection from CaCl(2)-induced arrhythmia are mediated by an inhibition of Ca(2+) dynamics in cardiomyocytes.
Hoffmann
P
P
SANOFI Recherche, Centre de Toulouse, France.
Müller
S P
SP
Heinroth
K
K
Büchner
E
E
Richards
D
D
Toraason
M
M