Hydrocortisone has a protective effect on CyclosporinA-induced cardiotoxicity.
CyclosporinA (CsA) is an immunosuppressive drug which induces severe adverse effects such as cardiotoxicity and nephrotoxicity. In several therapeutic protocols CsA is used in association with corticosteroids to obtain better therapeutic results. Recently, our studies showed that CsA increases blood pressure while inhibit Nitric Oxide (NO) production in vivo. In this study we evaluated in rat cardiomyocytes the effects of CsA, used alone or in association with Hydrocortisone (HY), on intracellular calcium concentration, NO production and lipid peroxidation (MDA level). Our results demonstrated that CsA increased intracellular calcium and such effect was dose-dependent. HY used alone, slightly decreased intracellular calcium, while dramatically reduced CsA-induced calcium fluxes. CsA (3.2 microM) increased lipid peroxidation and this effect was blunted by HY. Both CsA and HY inhibited NO production in rat cardiomyocytes acting on this pathway synergically. Our results demonstrated that in rat cardiomyocytes, CsA toxicity is due to a calcium overload, which in turn induce lipid peroxidation and determines oxidative stress-induced cell injury. Treatment with HY effectively inhibits CsA-induced toxicity, decreasing lipid peroxidation as well as calcium intracellular concentration. Our findings seem to suggest that glucocorticoids may be effective in reducing CsA-induced cardiotoxicity at concentrations which are consistent with current therapeutic doses.
Florio
Salvatore
S
Department of Structures, Function and Biological Technologies, School of Veterinary Medicine, University of Naples Federico II, Naples, Italy.
Ciarcia
Roberto
R
Crispino
Luca
L
Pagnini
Ugo
U
Ruocco
Antonio
A
Kumar
Christine
C
D'Andrilli
Giuseppina
G
Russo
Ferdinando
F
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D016572:Cyclosporine / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D019610:Cytoprotection / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006854:Hydrocortisone / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000633:toxicity*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats
D007166:Immunosuppressive Agents; D009569:Nitric Oxide; D008315:Malondialdehyde; D016572:Cyclosporine; D002118:Calcium; D006854:Hydrocortisone