CARDIOTOXICITY OF DICHLOROMETHANE IN RATS AND IN CULTURED RAT CARDIACMYOCYTES

The purpose of the present study was to examine whether cardiac action s of dichloromethane (DCM) in vivo correlate with in vitro alterations of Ca2+ dynamics in cardiac myocytes. Electrically induced fluctuatio ns of cytosolic free Ca2+ concentration ([Ca2+](i)) were investigated in neonatal rat ventricular myocytes using spectrofluorometric analysi s of fura-2 binding. [Ca2+](i) transients were inhibited in a concentr ation-dependent and reversible manner with IC10 and IC50 values of 3.2 and 18.1 mM. Complete inhibition of [Ca2+](i) transients and cessatio n of beating were observed at 40.95 mM without morphological alteratio ns. Left ventricular pressure in urethane-anaesthetized rats was measu red by introducing a tip catheter by way of the carotid artery into th e left ventricle and ECG (lead II) was recorded by two needle electrod es. 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 administ ration provided protection against arrhythmia development due to CaCl2 infusion. These observations are consistent with the view that both t he negative inotropic effects of DCM and the protection from CaCl2-ind uced arrhythmia are mediated by an inhibition of Ca2+ dynamics in card iomyocytes.