Depression of calcium dynamics in cardiac myocytes--a common mechanism of halogenated hydrocarbon anesthetics and solvents.
Individual halogenated hydrocarbons (HC) have recently been demonstrated to depress Ca2+ dynamics in cardiomyocytes during excitation-contraction coupling. In the present study, eight widely used HC were systematically compared for their effects on Ca2+ dynamics in neonatal rat cardiomyocytes by means of spectrofluorometric analysis of fura-2-Ca(2+)-binding. Cells were exposed to dichloromethane (DCM), dichloroethane (DCE), 1,1,2-trichloroethane (112-TCE), trichloroethylene (TRI), halothane (HAL), 1,1,1-trichloroethane (111-TCE), perchloroethylene (PER), or pentachlorethane (PCE) in an environmentally controlled chamber. All HC tested decreased the height of electrically induced cytosolic free Ca2+ ([Ca2+]i) transients in a concentration-dependent and reversible manner (IC50 0.15-18.06 mM) without significant effects on diastolic [Ca2+]i. The increase in [Ca2+]i induced by depolarization with 90 mM KCl was inhibited to a lesser degree. Investigations with thapsigargin (100 nM) and ryanodine (1 microM)-inhibitors of Ca2+ release from the sarcoplasmic reticulum-provided evidence that the tonic Ca2+ response after KCl depolarization depends mainly on sarcolemmal Ca2+ influx. The potency of the eight HC to inhibit Ca2+ dynamics in cardiomyocytes correlated with their octanol/water partition coefficients. Results support the hypothesis that alteration of Ca2+ dynamics in cardiomyocytes is a common mechanism of cardiotoxic HC actions.
Hoffmann
P
P
Cellular Toxicology Section, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Cincinnati, OH 45226.
Heinroth
K
K
Richards
D
D
Plews
P
P
Toraason
M
M
D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005025:Ethylene Dichlorides / Q000494:pharmacology; D016257:Fura-2; D006221:Halothane / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006846:Hydrocarbons, Halogenated / Q000494:pharmacology*; D008752:Methylene Chloride / Q000494:pharmacology; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism* / Q000648:ultrastructure; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012433:Ryanodine / Q000494:pharmacology; D012508:Sarcolemma / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism / Q000502:physiology; D012997:Solvents / Q000494:pharmacology*; D013050:Spectrometry, Fluorescence; D013729:Terpenes / Q000494:pharmacology; D019284:Thapsigargin; D014241:Trichloroethylene / Q000494:pharmacology
D000777:Anesthetics; D005025:Ethylene Dichlorides; D006846:Hydrocarbons, Halogenated; D012997:Solvents; D013729:Terpenes; D012433:Ryanodine; D014241:Trichloroethylene; D008752:Methylene Chloride; D011189:Potassium Chloride; D019284:Thapsigargin; D000252:Calcium-Transporting ATPases; D002118:Calcium; D016257:Fura-2; D006221:Halothane