Calcium ionophore A23187 action on cardiac myocytes is accompanied by enhanced production of reactive oxygen species.
We show that rat neonatal cardiac myocytes exposed to 1 micromol/l of the calcium ionophore A23187 respond with an enhanced production of reactive oxygen species (ROS). This dose is not cytotoxic to the myocytes. A higher concentration (10 micromol/l) evokes less ROS production and is significantly cytotoxic 24 h after exposure, but not immediately after removal of the A23187, when ROS are measured. Both cell death and the decrease in mitochondrial potential are only partially sensitive to MPT inhibitor cyclosporin A. Experiments performed to elucidate the sources of ROS included use of the nitric oxide synthase (NOS) inhibitor L-NAME; NOS involvement was excluded. Experiments with the oxidative phosphorylation uncoupler CCCP revealed that mitochondria are at least partially responsible for the observed effect. Further studies with cyclooxygenase (COX) and lipoxygenase (LOX) inhibitors (indomethacin and MK886, respectively) showed that these enzymes could also be sources of ROS when the calcium level is elevated. Their effect appeared to be independent of phospholipase A(2) inhibition, suggesting that COX and LOX stimulation is not due to elevated substrate (arachidonic acid) concentration but rather to a direct effect of calcium.
Przygodzki
Tomasz
T
Department of General Biophysics, University of Lodz, Poland. tomaszp@biol.uni.lodz.pl
Sokal
Adam
A
Bryszewska
Maria
M
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000001:Calcimycin / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D016572:Cyclosporine; D004305:Dose-Response Relationship, Drug; D005453:Fluorescence; D007211:Indoles; D007213:Indomethacin; D007476:Ionophores / Q000494:pharmacology*; D008564:Membrane Potentials; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester; D018384:Oxidative Stress / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D002722:Chlorobenzenes
D000001:Calcimycin; D002118:Calcium; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D016572:Cyclosporine; D007211:Indoles; D007213:Indomethacin; D007476:Ionophores; D019331:NG-Nitroarginine Methyl Ester; D017382:Reactive Oxygen Species; C060893:MK-886; D002722:Chlorobenzenes