Inhibition of cation channels and suicidal death of human erythrocytes by zidovudine.
Zidovudine, a drug widely used in the treatment of AIDS, has been shown to influence cytosolic calcium activity in HIV-infected lymphocytes. Thus, zidovudine may modify the activity of Ca(2+)-permeable ion channels. In erythrocytes, activation of Ca(2+)-permeable cation channels stimulates eryptosis, the suicidal erythrocyte death. Eryptosis is characterized by cell shrinkage (apparent from a decrease of forward scatter) and phosphatidylserine (PS) exposure (apparent from annexin V-binding) at the erythrocyte surface. Triggers of eryptosis include isotonic cell shrinkage (Cl(-) replacement by gluconate), energy depletion (removal of glucose) or exposure to a variety of drugs including azathioprine. The present study explored, whether zidovudine influences the activity of erythrocytic Ca(2+)-permeable cation channels and eryptosis. Whole-cell patch-clamp recordings indeed revealed that zidovudine blocked the Ca(2+)-permeable cation channels activated by Cl(-) removal. In the presence of Cl(-) and glucose, the percentage of annexin V-binding cells was low and not significantly modified by the presence of zidovudine. Both, Cl(-) removal and glucose depletion increased annexin V-binding and decreased forward scatter, effects significantly blunted by zidovudine (2 microg/ml). According to Fluo3 fluorescence, zidovudine (2 microg/ml) did not significantly modify cytosolic Ca(2+) concentration under control conditions, but significantly blunted the increase in cytosolic Ca(2+) activity following glucose depletion. Furthermore, zidovudine significantly inhibited azathioprine-induced eryptosis. The present observations disclose a completely novel effect of zidovudine, i.e. its inhibitory influence on Ca(2+) entry and subsequent suicidal erythrocyte death during isotonic cell shrinkage or energy depletion.
Kucherenko
Yuliya
Y
Department of Physiology, University of Tübingen, Germany.
Geiger
Corinna
C
Shumilina
Ekaterina
E
Föller
Michael
M
Lang
Florian
F
D000814:Aniline Compounds; D017304:Annexin A5 / Q000378:metabolism; D001379:Azathioprine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects*; D003600:Cytosol / Q000378:metabolism; D004912:Erythrocytes / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D005942:Gluconates / Q000378:metabolism; D006801:Humans; D018408:Patch-Clamp Techniques; D012965:Sodium Chloride / Q000378:metabolism; D014966:Xanthenes; D015215:Zidovudine / Q000494:pharmacology*
D000814:Aniline Compounds; D017304:Annexin A5; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D005942:Gluconates; D014966:Xanthenes; C059715:Fluo-3; D012965:Sodium Chloride; D015215:Zidovudine; D001379:Azathioprine; C030691:gluconic acid; D002118:Calcium