Effects of Arsenic Trioxide on Protein Kinase C and Cytosolic Calcium in Ventriclar Myocardium of Guinea Pig.

Abstract

AIM To clarify the mechanisms of the cardiac side effects of arsenic trioxide (As2O3) in leukemia treatment, the effects of As2O3 on protein kinase C(PKC) and cytosolic calcium ([Ca2+]i) in ventriclar myocardium of guinea pig were investigated.METHODS Fluo-3/AM fluorescent probe tagged [Ca2+]i of guinea pig's ventriclar myocardium, detected the [Ca2+]i, by laser confocal microscopy before and after exposed to As2O3. Phosphorus radioisotope assay was used to detect the activity of PKC on cell membrane or in cytoplasm. DNA ladders of ventriclar myocardium in Tyrode's solution after exposed to As2O3 were evaluated.RESULTS The cytosolic [Ca2+]i did not change when incubated guinea pig's ventriclar myocardium in Tyrode's solution with 0.5μmol•L−1As2O3, after incubated in2μmol•L−1As2O3 for 6min, [Ca2+]i began to increase and was continuous increasing for about 9min. After exposed to 10μmol•L−1As2O3 for less than 3 min, the [Ca2+]i kept on increasing till the end (about 27min) of the examination and could not recover. The increasing of [Ca2+]i could be partly blocked by calcium channel blocking agents—verapamil and nifedipin. The PKC of myocardial cells began to rise after incubated in an As2O3 changing concentration culture media for 3 hours, which initial As2O3 was 10μmol•L−1, and the DNA ladders appeared after incubated in it for10 hours. No DNA ladders appeared when incubated in an As2O3 culture media in which the initial As2O3 concentration was under 5μmol•L−1.CONCLUSIONS As2O3 can active PKC, increase cytosolic [Ca2+]i and promote apoptosis of myocardial cells. The promoting apoptosis action of As2O3 is closely related to the lasting activation of PKC. The initial action target of As2O3 is cell membrane.