Potential interest of anti-ischemic agents for limiting cyclosporin A nephrotoxicity.
Chronic administration of cyclosporin A induces nephrotoxicity in humans. This is related to a cyclosporin A-induced constriction of afferent glomerular arterioles and mesangial cells, which leads to a decrease in filtration pressure and creatinine clearance. Afterwards, cellular lesions are observed involving mainly tubular atrophy and interstitial fibrosis, both of which are nonspecific. The initial mechanism of its toxicity is not clearly explained. The current pharmacological approach is symptomatic in order to counteract or minimize the consequences of a prime cause, which still remains to be defined. However, cyclosporin A has a deletereous effect on mitochondrial functions and mainly on ATP synthesis, which occurs when Ca2+ accumulates in matrix mitochondria. The effects of trimetazidine, an antischemic drug used in the treatment of angina pectoris, have been assessed. This drug is effective in experimental models of hypoxia induced by cyclosporin A: it restores ATP synthesis previously decreased by Ca2+ and cyclosporin A, and releases a part of Ca2+ excess accumulated by mitochondria at concentrations reached in humans at usual dosage regimens. At higher concentrations, it reverses the mitochondrial permeability transition previously generated (opened) by Ca2+ and a pro-oxidant such as terbutylperoxide (t-BH). It was also observed that trimetazidine does not modify the immunosuppressive effects of cyclosporin A in various models. These data suggest that nephrotoxicity of cyclosporin A is not irrevocably linked to its immunosuppressive effect but that it may be possible to counteract at least partly its nephrotoxic effects without altering its effectiveness in preventing graft rejection.
Simon
N
N
Department of Pharmacology, University of Paris XII. Créteil, France. Tillement@univ-paris12.fr
Tillement
J P
JP
Albengres
E
E
Jaber
K
K
Hestin
D
D
Roux
F
F
Olivier
P
P
d'Athis
P
P
Kessler
M
M
Berland
Y
Y
Crevat
A
A
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D002118:Calcium / Q000378:metabolism; D003404:Creatinine / Q000652:urine; D016572:Cyclosporine / Q000009:adverse effects*; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000503:physiopathology; D008928:Mitochondria / Q000378:metabolism; D017202:Myocardial Ischemia / Q000188:drug therapy*; D014292:Trimetazidine / Q000494:pharmacology / Q000627:therapeutic use*; D014665:Vasodilator Agents / Q000494:pharmacology / Q000627:therapeutic use*
D014665:Vasodilator Agents; D016572:Cyclosporine; D000255:Adenosine Triphosphate; D003404:Creatinine; D014292:Trimetazidine; D002118:Calcium