Calcium channel blockers correct in vitro mitochondrial toxicity of cellulose acetate.
We studied the action of rinse solutions from cellulose acetate hemodialyzers on isolated mitochondria. We showed that concentrates from the rinses impaired the adenosine 5'-triphosphate (ATP) synthesis as reflected by the decrease in respiration during state 3 and in P/O ratio. This impairment results from a calcium release from mitochondria that is induced by rinse solution concentrates. The release, triggering the mitochondrial calcium carrier, would explain the decrease in ATP synthesis. Moreover, rinse solution concentrates hinder mitochondrial calcium storage. The rise in cytosolic calcium in hemodialyzed patients may be related, at least in part, to these findings, since a lack of ATP impairs the ATP-dependent cellular calcium-extrusion pumps. We also showed that calcium channel blockers, at therapeutically relevant doses, restore ATP synthesis and calcium storage in mitochondria impaired by rinse solution concentrates. Finally, these in vitro results were confirmed by experiments on cells in culture proving that Diltiazem counteracts the cytotoxicity of rinse solution concentrates. These findings are consistent with observations that these drugs suppress the increase in leukocyte cytosolic calcium in dialyzed patients. Moreover, this would help explain the efficiency of calcium channel blockers in cells without L-calcium channels.
Tabouy
L J
LJ
Laboratoire de Biophysique, Faculté de Pharmacie, Hôpital Sainte-Marguerite, Marseille, France.
Chauvet-Monges
A M
AM
Carles
G P
GP
Brunet
P J
PJ
Braguer
D L
DL
Rebouillon
P A
PA
Berland
Y F
YF
Crevat
A D
AD
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002482:Cellulose / Q000031:analogs & derivatives* / Q000633:toxicity; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D006435:Renal Dialysis / Q000009:adverse effects*
D002121:Calcium Channel Blockers; C005062:acetylcellulose; D002482:Cellulose; D002118:Calcium