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

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.