ABSTRACT
Cyclosporin-A, a potent immunosuppressive agent is known to induce cellular toxic side effects by way of altering calcium homeostasis, including calcium/calmodulin mediated events. We studied the in vitro and in vivo effects of cyclosporin-A on rat brain nitric oxide synthase activity (the enzyme that mediates the conversion of L-arginine to citrulline and NO). CsA in concentrations of 22-4400 nM inhibited rat brain NOS activity in vitro and in 10 or 25 mg/kg wt/4 weeks of CsA treated rat brains in vivo. We report here that CsA by way of interfering with rat brain Ca2+/CaM mediated events may inhibit its NOS activity which ultimately may result in neurotoxicity.
Subject(s)
Animals , Brain/enzymology , Cyclosporine/pharmacology , Enzyme Inhibitors/pharmacology , Immunosuppressive Agents/pharmacology , Male , Nitric Oxide Synthase/antagonists & inhibitors , Rats , Rats, Sprague-DawleyABSTRACT
Cyclosporin A (CsA) is a cyclic undecapeptide that has been used extensively as an immunosuppressive drug in transplantation medicine and is known to interact with L-arginine dependent pathways. We studied the in vitro and in vivo effects of CsA on nitric oxide synthase (NOS) activity in the rat kidney. CsA in concentrations of 44-2200 nM in vitro, and 12.5 or 25 mg/kg body weight per 4 weeks treated rat kidneys in vivo, significantly stimulated NOS activity. CsA may alter the Ca2+/Cam-dependent NOS activity by interacting with rat kidney Ca2+/calmodulin dependent events.